@article {pmid39371183, year = {2024}, author = {Bearden, DR and Sportiello, K and Mweemba, M and Lungu, F and Mwanza-Kabaghe, S and Birbeck, G}, title = {Adherence, Adverse Events and Viral Control among Children and Adolescents with HIV in Zambia Switched to an Integrase Inhibitor Regimen.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.17.24313837}, pmid = {39371183}, abstract = {BACKGROUND: Based on recent World Health Organization recommendations, there has been a large-scale transition in Sub-Saharan Africa to integrase inhibitor (II)-based antiretroviral therapy (ART) regimens.

SETTING: This study was conducted at an urban referral center in Lusaka, Zambia.

METHODS: This study included 297 children and adolescents with HIV (CAWH) on ART for one year prior to enrollment and followed for 1-4 years after enrollment. ART adherence, ART regimen, and viral load were assessed periodically. Structured interviews were conducted with a subset of 95 children to assess adherence barriers and side effects.

RESULTS: Children on protease inhibitor (PI)-based regimens were more likely to report adherence problems than children taking II- or Efavirenz-based regimens (10% vs. 28%, p=0.03) and noted more days with missed doses (median 1 vs. 0, p=0.02). In interviews, the most common reasons given for poor adherence included bad medication taste, not being home when medications were due, and perceived side effects. The PI group was more likely to report that taste was a problem affecting adherence (22% vs. 4%, p=0.05) and headache as an ART side effect (17% vs. 4%, p=0.05). Switching from a PI- to an II-based regimen was associated with improved adherence (72% vs. 92%, p=0.01) and an undetectable viral load (67% vs. 78%).

CONCLUSIONS: Switching CAWH from PI-based to II-based regimens has many advantages including superior side effect profiles, adherence, and viral suppression. PI taste aversion may be a significant contributor to pediatric adherence issues. Palatability should be considered in pediatric HIV drug development.}, } @article {pmid39368616, year = {2024}, author = {Graney, PL and Chen, MY and Wood, RI and Wagner, CK}, title = {Developmental 17-OHPC exposure disrupts behavior regulated by the mesocorticolimbic dopaminergic system in rats.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {}, number = {}, pages = {173886}, doi = {10.1016/j.pbb.2024.173886}, pmid = {39368616}, issn = {1873-5177}, abstract = {The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals with the intention of reducing preterm birth. Although there is evidence that 17-OHPC is likely transferred from mother to fetus, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. Neonatal 17-OHPC exposure disrupts the development of the mesocorticolimbic dopaminergic pathway and associated behaviors in rats. 17-OHPC exposure altered dopaminergic innervation of prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents and altered performance in measures of decision-making, set-shifting, and reversal-learning tasks. The present study tested the effects of developmental 17-OHPC exposure on numerous cognitive behaviors mediated by the mesocorticolimbic dopaminergic system, such as decision-making in a delay discounting task, latent inhibition following conditioned taste aversion (CTA), and spatial memory in the Morris Water Maze (MWM). The present work also aimed to further investigate response omissions in rats exposed to 17-OHPC during development and the potential role of dopamine D2 receptor in altering omissions in a delay discounting task. 17-OHPC exposure rendered rats less sensitive to an Eticlopride-induced increase in omissions in a delay discounting task when compared to controls. Quinpirole flattened the discount curve in both groups but did not significantly affect omissions in 17-OHPC-exposed or control rats. Following CTA, sucrose-pre-exposed 17-OHPC-exposed rats demonstrated decreased latent inhibition when compared to controls. In Morris Water Maze testing, 17-OHPC-exposed rats did not differ from controls after the first day of testing or during probe testing. These results suggest that exposure to 17-OHPC altered aspects of decision-making and latent inhibition in adult male rats, without affecting performance in a measure of spatial learning and memory. Further, the insensitivity of 17-OHPC-exposed males to an Eticlopride-induced increase in omissions suggests a dysfunction in the D2 receptor following exposure to this clinically used synthetic progestin.}, } @article {pmid39362067, year = {2024}, author = {Womersley, JS and Obellianne, C and Padula, AE and Lopez, MF and Griffin, WC and Ball, LE and Berto, S and Grant, KA and Townsend, DM and Uys, JD and Mulholland, PJ}, title = {Adaptations in glutathione-based redox protein signaling pathways and alcohol drinking across species.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {180}, number = {}, pages = {117514}, doi = {10.1016/j.biopha.2024.117514}, pmid = {39362067}, issn = {1950-6007}, abstract = {Alcohol use disorder (AUD) is the most prevalent substance use disorder but there is incomplete knowledge of the underlying molecular etiology. Here, we examined the cytosolic proteome from the nucleus accumbens core (NAcC) of ethanol drinking rhesus macaques to identify ethanol-sensitive signaling proteins. The targets were subsequently investigated using bioinformatics, genetic, and pharmacological manipulations in mouse models of ethanol drinking. Of the 1000+ cytosolic proteins identified in our screen, 50 proteins differed significantly between control and ethanol drinking macaques. Gene Ontology analysis of the differentially expressed proteins identified enrichment in pathways regulating metabolic processes and proteasome activity. Because the family of Glutathione S-transferases (GSTs) was enriched in these pathways, validation studies targeted GSTs using bioinformatics and genetically diverse mouse models. Gstp1 and Gstm2 were identified in Quantitative Trait Loci and published gene sets for ethanol-related phenotypes (e.g., ethanol preference, conditioned taste aversion, differential expression), and recombinant inbred strains that inherited the C57BL/6J allele at the Gstp2 interval consumed higher amounts of ethanol than those that inherited the DBA/2J allele. Genetic deletion of Gstp1/2 led to increased ethanol consumption without altering ethanol metabolism or sucrose preference. Administration of the pharmacologic activator of Gstp1/2, carnosic acid, decreased voluntary ethanol drinking. Proteomic analysis of the NAcC cytosolic of heavy drinking macaques that were validated in mouse models indicate a role for glutathione-mediated redox regulation in ethanol-related neurobiology and the potential of pharmacological interventions targeting this system to modify excessive ethanol drinking.}, } @article {pmid39134007, year = {2024}, author = {Havton, GC and Tai, ATC and Vasisht, S and Davies, DL and Asatryan, L}, title = {Preclinical Evaluation of Sodium Butyrate's Potential to Reduce Alcohol Consumption: A Dose-Escalation Study in C57BL/6J Mice in Antibiotic-Enhanced Binge-Like Drinking Model.}, journal = {Pharmacology}, volume = {}, number = {}, pages = {1-13}, doi = {10.1159/000540882}, pmid = {39134007}, issn = {1423-0313}, abstract = {INTRODUCTION: In our earlier efforts to establish gut-brain axis during alcohol use disorder (AUD), we have demonstrated that supplementation of C57BL/6J male mice with 8 mg/mL sodium butyrate, a major short-chain fatty acid, in drinking water reduced ethanol intake and neuroinflammatory response in antibiotic (ABX)-enhanced voluntary binge-like alcohol consumption model, drinking in the dark (DID).

METHODS: To further evaluate the preclinical potential of SB, we have set a dose-escalation study in C57BL/6J male mice to test effects of ad libitum 20 mg/mL SB and 50 mg/mL SB and their combinations with ABX in the DID procedure for 4 weeks. Effects of these SB concentrations on ethanol consumption and bodily parameters were determined for the duration of the treatments. At the end of study, blood, liver, and intestinal tissues were collected to study any potential adverse effects ad to measure blood ethanol concentrations.

RESULTS: Increasing SB concentrations in the drinking water caused a loss in the protective effect against ethanol consumption and produced adverse effects on body and liver weights, reduced overall liquid intake. The hypothesis that these effects were due to aversion to SB smell/taste at these high concentrations were further tested in a follow up proof-of-concept study with intragastric gavage administration of SB. The higher gavage dose (320 mg/kg) caused reduction in ethanol consumption without any adverse effects.

CONCLUSION: Overall, these findings added more support for the therapeutic potential of SB in management of AUD, given a proper form of administration.}, } @article {pmid39137886, year = {2024}, author = {Ward-Fear, G and Bruny, M and Rangers, TB and Forward, C and Cooksey, I and Shine, R}, title = {Taste aversion training can educate free-ranging crocodiles against toxic invaders.}, journal = {Proceedings. Biological sciences}, volume = {291}, number = {2028}, pages = {20232507}, doi = {10.1098/rspb.2023.2507}, pmid = {39137886}, issn = {1471-2954}, mesh = {Animals ; *Alligators and Crocodiles/physiology ; *Introduced Species ; Taste ; Avoidance Learning ; Predatory Behavior ; Bufo marinus/physiology ; Western Australia ; }, abstract = {Apex predators play critical ecological roles, making their conservation a high priority. In tropical Australia, some populations of freshwater crocodiles (Crocodylus johnstoni) have plummeted by greater than 70% due to lethal ingestion of toxic invasive cane toads (Rhinella marina). Laboratory-based research has identified conditioned taste aversion (CTA) as a way to discourage consumption of toads. To translate those ideas into landscape-scale management, we deployed 2395 baits (toad carcasses with toxin removed and containing a nausea-inducing chemical) across four gorge systems in north-western Australia and monitored bait uptake with remote cameras. Crocodile abundance was quantified with surveys. Free-ranging crocodiles rapidly learned to avoid toad baits but continued to consume control (chicken) baits. Toad invasion at our sites was followed by high rates of crocodile mortality (especially for small individuals) at a control site but not at nearby treatment sites. In areas with high connectivity to other waterbodies, repeated baiting over successive years had continuing positive impacts on crocodile survival. In summary, we succeeded in buffering the often-catastrophic impact of invasive cane toads on apex predators.}, } @article {pmid39128699, year = {2024}, author = {Miranda, MI and Alcalá, A}, title = {Histamine H3 receptor activation in the insular cortex during taste memory conditioning decreases appetitive response but accelerates aversive memory extinction under an ad libitum liquid regimen.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2024.08.002}, pmid = {39128699}, issn = {1873-7544}, abstract = {Conditioned taste aversion (CTA) is a robust associative learning; liquid deprivation during this conditioning allows researchers to obtain readable measures of associative learning. Recent research suggests that thirst could be a crucial motivator that modulates conditioning and memory extinction processes, highlighting the importance of the body's internal state during learning. Furthermore, the histaminergic system is one of the major modulatory systems controlling several behavioral and neurobiological functions, such as feeding, water intake, and nociception. Therefore, this research aimed to assess the effect of H3 histaminergic receptor activation in the insular cortex (IC) during CTA. For this, we conditioned adult male Wistar rats under two regimens: water deprivation and water ad libitum. A classical CTA protocol was used for water deprivation. Before CTA acquisition, 10 μM R-α-methylhistamine (RAMH), an H3 receptor agonist, was injected into the IC. Results showed that RAMH injections decreased CTA in water-deprived rats without affecting the significant aversion conditioning in rats that were given water ad libitum. Moreover, RAMH accelerated the process of aversive memory extinction under ad libitum water conditions. According to our findings, the degree of liquid satiety differentially affected taste-aversive memory formation, and H3 histamine receptors were more involved under water deprivation conditions during acquisition. However, these receptors modulated the strength of aversive conditioning by altering the rate of aversive memory extinction in the absence of deprivation. In conclusion, histaminergic activity in the IC may influence taste memory dynamics through different mechanisms depending on the degree of liquid satiety or deprivation during conditioning.}, } @article {pmid39008013, year = {2024}, author = {Fuentes-Ramos, M and Barco, Á}, title = {Unveiling Transcriptional and Epigenetic Mechanisms Within Engram Cells: Insights into Memory Formation and Stability.}, journal = {Advances in neurobiology}, volume = {38}, number = {}, pages = {111-129}, pmid = {39008013}, issn = {2190-5215}, mesh = {*Epigenesis, Genetic ; *Memory/physiology ; Humans ; Animals ; *Neurons/metabolism ; Brain/metabolism ; Fear/physiology ; Transcription, Genetic ; }, abstract = {Memory traces for behavioral experiences, such as fear conditioning or taste aversion, are believed to be stored through biophysical and molecular changes in distributed neuronal ensembles across various brain regions. These ensembles are known as engrams, and the cells that constitute them are referred to as engram cells. Recent advancements in techniques for labeling and manipulating neural activity have facilitated the study of engram cells throughout different memory phases, including acquisition, allocation, long-term storage, retrieval, and erasure. In this chapter, we will explore the application of next-generation sequencing methods to engram research, shedding new light on the contribution of transcriptional and epigenetic mechanisms to engram formation and stability.}, } @article {pmid39004230, year = {2024}, author = {Batabyal, A and Wiley, B and Matsuoka, H and Komatsuzaki, Y and Lukowiak, K}, title = {Sensory input from osphradium is involved in fluoride detection that alters feeding and memory phenotype in Lymnaea stagnalis.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {115148}, doi = {10.1016/j.bbr.2024.115148}, pmid = {39004230}, issn = {1872-7549}, abstract = {Fluoride (F-) exposure in organisms remains a significant concern due to its widespread presence and potential health implications. Investigating its detection and subsequent effects on behaviour in aquatic organisms like Lymnaea stagnalis provides valuable insights. Our study focused on elucidating the sensory pathways involved in F- detection and its impact on feeding and memory formation. We explored two potential detection mechanisms: direct flow across the integument onto neurons; and sensory input to the central nervous system (CNS) via the osphradium-osphradial ganglion-osphradial nerve pathway (snails use this system for olfactory sensation of multiple compounds). Injection of F- into snails did not alter feeding behaviour or central neuronal activity, suggesting that internalization might not be the primary detection mode. In contrast, severing the osphradial nerve abolished F-'s suppressive effects on feeding and memory formation, implicating the osphradial pathway in F- sensing and behavioral changes. This finding supports the idea that osphradial nerve signaling mediates the behavioral effects of F-. Our study underscores the importance of sensory pathways in F- detection and behavioral modulation in L. stagnalis. Understanding these mechanisms could provide critical insights into how organisms respond to and adapt to environmental chemical stressors like F-.}, } @article {pmid38815558, year = {2024}, author = {Xu, LH and Ge, JG and Xiao, SF and Lu, QC and Ji, W and Ma, YQ and Song, JY and Zhang, XY and Cai, ML and Li, X and Zhou, X and Jiang, ZL}, title = {ANP alleviates motion sickness potentially through regulating endolymph volume in the inner ear increased by AVP.}, journal = {Neuroendocrinology}, volume = {}, number = {}, pages = {}, doi = {10.1159/000539586}, pmid = {38815558}, issn = {1423-0194}, abstract = {INTRODUCTION: Dimenhydrinate and scopolamine are frequently used drugs, but they cause drowsiness and performance decrement. Therefore, it is crucial to find peripheral targets and develop new drugs without central side effects. This study aims to investigate the anti-motion sickness action and inner ear-related mechanisms of ANP.

METHODS: Endolymph volume in the inner ear was measured with magnetic resonance imaging and expression of AQP2 and p-AQP2 was detected with Western blot analysis and immunofluorescence method.

RESULTS: Both rotational stimulus and intraperitoneal AVP injection induced conditioned taste aversion (CTA) to 0.15% sodium saccharin solution and an increase in the endolymph volume of the inner ear. However, intraperitoneal injection of ANP effectively alleviated the CTA behaviour, and reduced the increase in the endolymph volume after rotational stimulus. Intratympanic injection of ANP also inhibited rotational stimulus-induced CTA behaviour, but anantin peptide, an inhibitor of ANP receptor A (NPR-A), blocked this inhibitory effect of ANP. Both rotational stimulus and intraperitoneal AVP injection increased the expression of AQP2 and p-AQP2 in the inner ear of rats, but these increases were blunted by ANP injection. In in-vitro experiments, ANP addition decreased AVP-induced increases in the expression and phosphorylation of AQP2 in cultured endolymphatic sac epithelial cells.

CONCLUSION: Therefore, the present study suggests that ANP could alleviate motion sickness through regulating endolymph volume of the inner ear increased by AVP, and this action of ANP is potentially mediated by activating NPR-A and antagonising the increasing effect of AVP on AQP2 expression and phosphorylation.}, } @article {pmid38660288, year = {2024}, author = {Rana, H and Panchal, M and Thakkar, V and Gandhi, T and Dholakia, M}, title = {Investigating in-vitro functionality and in-vivo taste assessment of eco-friendly Tadalafil Pastilles.}, journal = {Heliyon}, volume = {10}, number = {8}, pages = {e29543}, pmid = {38660288}, issn = {2405-8440}, abstract = {Tadalafil (TDL) has poor bioavailability due to the less aqueous solubility and bitter taste. Oral solid dosage forms, especially tablets, have a broad market worldwide. Constraints of tablets are a long process, pollution, high processing cost, and requiring more excipient. The research was performed to optimize an eco-friendly immediate-acting pastille of TDL to put forward an alternate formulation to a tablet using advanced data mining tools. Another objective is to assess the taste masking of TDL using the Brief Access Taste Aversion (BATA) model. The amount of PEG-4000, Polyox N-10, and Kyron T-314 were chosen as critical material attributes from failure mode effect analysis. Box-Behnken design (BBD) was utilized to optimize the pastilles and ascertained the significant impact of chosen variables on disintegration time and % CDR at 10 min. The control strategy and optimal region were located using an overlay plot. The pastilles were able to release the drug within 15 min due to faster disintegration. The formulated pastilles were of uniform size, shape, and mechanical strength. The bitter taste of TDL was masked and confirmed by the BATA model. The newer formulation may be helpful in the industry due to its eco-friendly, single-step, and economical process. It unlocks a new direction in the field of oral solid dosage form as an alternative to tablets.}, } @article {pmid38656972, year = {2024}, author = {Perez, CI and Luis-Islas, J and Lopez, A and Diaz, X and Molina, O and Arroyo, B and Moreno, MG and Lievana, EG and Fonseca, E and Castañeda-Hernández, G and Gutierrez, R}, title = {Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons.}, journal = {PloS one}, volume = {19}, number = {4}, pages = {e0300544}, doi = {10.1371/journal.pone.0300544}, pmid = {38656972}, issn = {1932-6203}, mesh = {Animals ; *GABAergic Neurons/drug effects/metabolism ; Rats ; Mice ; *Anti-Obesity Agents/pharmacology ; Male ; *Obesity/drug therapy/metabolism ; Feeding Behavior/drug effects ; Hypothalamic Area, Lateral/drug effects/metabolism ; Hypothalamus/drug effects/metabolism ; Mice, Transgenic ; Weight Loss/drug effects ; Rats, Sprague-Dawley ; *Bridged Bicyclo Compounds, Heterocyclic ; }, abstract = {Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.}, } @article {pmid38639079, year = {2024}, author = {Rivi, V and Batabyal, A and Benatti, C and Sarti, P and Blom, JMC and Tascedda, F and Lukowiak, K}, title = {A translational and multidisciplinary approach to studying the Garcia effect, a higher form of learning with deep evolutionary roots.}, journal = {The Journal of experimental biology}, volume = {227}, number = {8}, pages = {}, doi = {10.1242/jeb.247325}, pmid = {38639079}, issn = {1477-9145}, support = {//Natural Sciences and Engineering Research Council of Canada/ ; //Regione Emilia Romagna/ ; //Università Degli Studi di Modena e Reggio Emila/ ; }, abstract = {Animals, including humans, learn and remember to avoid a novel food when its ingestion is followed, hours later, by sickness - a phenomenon initially identified during World War II as a potential means of pest control. In the 1960s, John Garcia (for whom the effect is now named) demonstrated that this form of conditioned taste aversion had broader implications, showing that it is a rapid but long-lasting taste-specific food aversion with a fundamental role in the evolution of behaviour. From the mid-1970s onward, the principles of the Garcia effect were translated to humans, showing its role in different clinical conditions (e.g. side-effects linked to chemotherapy). However, in the last two decades, the number of studies on the Garcia effect has undergone a considerable decline. Since its discovery in rodents, this form of learning was thought to be exclusive to mammals; however, we recently provided the first demonstration that a Garcia effect can be formed in an invertebrate model organism, the pond snail Lymnaea stagnalis. Thus, in this Commentary, after reviewing the experiments that led to the first characterization of the Garcia effect in rodents, we describe the recent evidence for the Garcia effect in L. stagnalis, which may pave the way for future studies in other invertebrates and mammals. This article aims to inspire future translational and ecological studies that characterize the conserved mechanisms underlying this form of learning with deep evolutionary roots, which can be used to address a range of different biological questions.}, } @article {pmid38587941, year = {2024}, author = {Michaud, NL and Bouton, ME}, title = {An analysis of reinstatement after extinction of a conditioned taste aversion.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {50}, number = {2}, pages = {144-160}, doi = {10.1037/xan0000378}, pmid = {38587941}, issn = {2329-8464}, support = {/NH/NIH HHS/United States ; }, abstract = {Taste aversion learning has sometimes been considered a specialized form of learning. In several other conditioning preparations, after a conditioned stimulus (CS) is conditioned and extinguished, reexposure to the unconditioned stimulus (US) by itself can reinstate the extinguished conditioned response. Reinstatement has been widely studied in fear and appetitive Pavlovian conditioning, as well as operant conditioning, but its status in taste aversion learning is more controversial. Six taste-aversion experiments with rats therefore sought to discover conditions that might encourage it there. The results often yielded little to no evidence of reinstatement, and we also found no evidence of concurrent recovery, a related phenomenon in which responding to a CS that has been conditioned and extinguished is restored if a second CS is separately conditioned. However, a key result was that reinstatement occurred when the conditioning procedure involved multiple closely spaced conditioning trials that could have allowed the animal to learn that a US presentation signaled or set the occasion for another trial with a US. Such a mechanism is precluded in many taste aversion experiments because they often use very few conditioning trials. Overall, the results suggest that taste aversion learning is experimentally unique, though not necessarily biologically or evolutionarily unique. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, } @article {pmid38562680, year = {2024}, author = {Taxier, LR and Flanigan, ME and Haun, HL and Kash, TL}, title = {Retrieval of an ethanol-conditioned taste aversion promotes GABAergic plasticity in the insular cortex.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.03.20.585950}, pmid = {38562680}, abstract = {UNLABELLED: Blunted sensitivity to ethanol's aversive effects can increase motivation to consume ethanol; yet, the neurobiological circuits responsible for encoding these aversive properties are not fully understood. Plasticity in cells projecting from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for taste aversion learning and retrieval, suggesting this circuit's potential involvement in modulating the aversive properties of ethanol. Here, we tested the hypothesis that GABAergic activity onto IC-BLA projections would be facilitated following the retrieval of an ethanol-conditioned taste aversion (CTA). Consistent with this hypothesis, frequency of mIPSCs was increased following retrieval of an ethanol-CTA across cell layers in IC-BLA projection neurons. This increase in GABAergic plasticity occurred in both a circuit-specific and learning-dependent manner. Additionally, local inhibitory inputs onto layer 2/3 IC-BLA projection neurons were greater in number and strength following ethanol-CTA. Finally, DREADD-mediated inhibition of IC parvalbumin-expressing cells blunted the retrieval of ethanol-CTA in male, but not female, mice. Collectively, this work implicates a circuit-specific and learning-dependent increase in GABAergic tone following retrieval of an ethanol-CTA, thereby advancing our understanding of how the aversive effects of ethanol are encoded in the brain.

SIGNIFICANCE STATEMENT: Sensitivity to the aversive properties of ethanol contributes to motivation to consume alcohol. However, the plasticity-associated mechanisms through which ethanol's aversive effects are represented within neural circuits are largely unidentified. In the present study, we used whole-cell patch clamp electrophysiology combined with synaptic input mapping to identify alterations in GABAergic plasticity within the insula, and within cells projecting from the insula to the basolateral amygdala. We demonstrate learning and circuit-specific alterations in GABAergic tone following retrieval of an ethanol-conditioned taste aversion, as well as a male-specific role for Parvalbumin-expressing interneurons in modulating the strength of an ethanol-conditioned taste aversion. Combined, these findings provide novel insights into how the aversive properties of ethanol are encoded within brain circuitry.}, } @article {pmid38492666, year = {2024}, author = {Trevisonno, J and Venter, C and Pickett-Nairne, K and Bégin, P and Cameron, SB and Chan, ES and Cook, VE and Factor, JM and Groetch, M and Hanna, MA and Jones, DH and Wasserman, RL and Mack, DP}, title = {Food aversion and anxiety represent primary patient barriers to food oral immunotherapy.}, journal = {The journal of allergy and clinical immunology. In practice}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaip.2024.03.014}, pmid = {38492666}, issn = {2213-2201}, abstract = {While oral immunotherapy (OIT) for food allergy is a reasonable treatment option, barriers to this procedure's implementation have not been extensively evaluated from a patient perspective OBJECTIVE: We evaluated the barriers patients face during OIT administration, including anxiety and taste aversion, and evaluated the role of healthcare professionals, especially dietitians METHODS: A survey in Canada and the US involved families currently enrolled in food OIT programmes RESULTS: Of responses from 379 participants, fear of reaction was the most common barrier to OIT initiation, with 45.6% reporting it being a "very significant" barrier with other fears reported. However, taste aversion represented the prominent obstacle to continuation. Taste aversion was associated with slower buildup (p=0.02), and reduction in dose (p=0.002). Taste aversion was a strongly age-dependent barrier for initiation (p<0.001) and continuation (p<0.002), with older children over 6 years of age reporting it as a very significant barrier (p<0.001). Boredom was reported as a concern for specific allergens such as peanut, egg, sesame, and hazelnuts (p<0.05), emphasizing the need for diverse food options. Notably, 59.9% of respondents mixed OIT foods with sweet items. Despite these dietary concerns, dietitians were underutilized, with only 9.5% of respondents having seen a dietitian and the majority finding dietitian support helpful with greater certainty about the exact dose (p<0.001) CONCLUSIONS: Taste aversion and anxiety represent primary patient-related barriers to OIT. Taste aversion was highly age-dependent, with older patients being more affected. Dietitians and psychology support were underutilized, representing a critical target to improve adherence and OIT success.}, } @article {pmid38471095, year = {2024}, author = {Osler, AL and Alfredo, KA and Mihelcic, JR}, title = {Chlorine Water Taste Threshold and Acceptability among Indigenous and Non-Indigenous Populations in Rural Panama.}, journal = {Environmental science & technology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.est.3c05630}, pmid = {38471095}, issn = {1520-5851}, abstract = {Although gains in access to water services over the past two decades have been large, more than two billion people still lack access to safely managed drinking water. This study examines and compares free chlorine taste and acceptability thresholds of rural Indigenous Ngäbe and rural Latino Panamanians to study if taste aversion may be a limiting factor in chlorination of community systems in Panama using the three-alternative forced choice test methodology. This study is the first to establish a best-estimate taste threshold for a rural Indigenous group and the only study in Latin America to report best-estimate taste thresholds using those methods. Median taste thresholds were 0.87 mg/L Cl2 for Indigenous Ngäbe participants (n = 82) and 1.64 mg/L Cl2 for Latino participants (n = 64), higher than both the minimum concentration for biologically safe water (0.2 mg/L) and the recommended concentration range in Panama (0.3-0.8 mg/L). Median acceptability thresholds were established much higher than taste thresholds at 3.45 mg/L Cl2. The results show that the ability to accurately taste chlorine may not be the limiting factor for adoption of safe water initiatives in remote and Indigenous communities.}, } @article {pmid38383904, year = {2024}, author = {Ramirez, LA and Przybysz, KR and Pitock, JR and Starr, EM and Yang, H and Glover, EJ}, title = {Attenuated incubation of ethanol-induced conditioned taste aversion in a model of dependence.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {38383904}, issn = {1432-2072}, support = {AA029130/AA/NIAAA NIH HHS/United States ; AA022538/AA/NIAAA NIH HHS/United States ; AA024208/AA/NIAAA NIH HHS/United States ; AA026577/AA/NIAAA NIH HHS/United States ; }, abstract = {RATIONALE: Preclinical studies report attenuated ethanol-induced conditioned taste aversion (CTA) following chronic ethanol exposure, suggesting that tolerance develops to the aversive properties of ethanol. However, these studies are confounded by pre-exposure to the unconditioned stimulus (US; ethanol), which is well known to hinder conditioning.

OBJECTIVES: This study was designed to determine whether chronic ethanol exposure produces tolerance to the aversive properties of ethanol in the absence of a US pre-exposure confound.

METHODS: CTA was performed in adult male and female Long-Evans rats by pairing 0.1% ingested saccharin with an intraperitoneal injection of ethanol (1.5 or 2.0 g/kg) or saline. Rats were then rendered ethanol dependent using chronic intermittent ethanol (CIE) vapor exposure. Controls were exposed to room air (AIR). The effect of chronic ethanol on CTA expression and reconditioning were examined following vapor exposure.

RESULTS: Prior to vapor exposure, both sexes developed CTA to a comparable degree with 2.0 g/kg producing greater CTA than 1.5 g/kg ethanol. Following vapor exposure, AIR controls exhibited an increase in CTA magnitude compared to pre-vapor levels. This effect was largely absent in CIE-exposed rats. Re-conditioning after vapor exposure facilitated increased CTA magnitude to a similar degree in AIR- and CIE-exposed males. In contrast, CTA magnitude was unchanged by re-conditioning in females.

CONCLUSIONS: These data suggest that chronic ethanol does not facilitate tolerance to the aversive properties of ethanol but rather attenuates incubation of ethanol-induced CTA. Loss of CTA incubation suggests that CIE exposure disrupts circuits encoding aversion.}, } @article {pmid38332437, year = {2024}, author = {Boakes, RA and Badolato, C and Rehn, S}, title = {Taste aversion learning during successive negative contrast.}, journal = {Learning & behavior}, volume = {}, number = {}, pages = {}, pmid = {38332437}, issn = {1543-4508}, support = {ARC DP17010392//Australian Research Council/ ; }, abstract = {Previous experiments found that acceptance of saccharin by rats was reduced if they had prior experience of sucrose or some other highly palatable solution. This study tested whether such successive negative contrast (SNC) effects involve acquisition of an aversion to the new taste. In three experiments, rats were switched from sucrose exposure in Stage 1 to a less palatable solution containing a new taste in Stage 2. In Experiments 1 and 2, a novel flavor was added to a saccharin solution at the start of Stage 2. In Experiment 1, preference tests revealed a weak aversion to the added vanilla flavor in the Suc-Sacch group, while in Experiment 2 an aversion was found in the Suc-Sacch group to the salty flavor that was used, compared with controls given access either saccharin or water in Stage 1. In Experiment 3, the Suc-Quin group, given quinine solution in Stage 2, displayed a greater aversion to quinine than a Water-Quin control group. These results support the suggestion that taste aversion learning plays a role in the initial suppression of intakes in a qualitative consummatory SNC effect. However, in the light of other evidence, it seems that the unusual persistence of successive negative contrast when rats are switched from sucrose to saccharin is not due to a long-lasting reduction in the value of saccharin.}, } @article {pmid38303664, year = {2024}, author = {Przybysz, KR and Ramirez, LA and Pitock, JR and Starr, EM and Yang, H and Glover, EJ}, title = {A translational rodent model of individual differences in sensitivity to the aversive properties of ethanol.}, journal = {Alcohol, clinical & experimental research}, volume = {}, number = {}, pages = {}, doi = {10.1111/acer.15267}, pmid = {38303664}, issn = {2993-7175}, support = {AA022538/AA/NIAAA NIH HHS/United States ; AA024208/AA/NIAAA NIH HHS/United States ; AA026577/AA/NIAAA NIH HHS/United States ; AA029130/AA/NIAAA NIH HHS/United States ; }, abstract = {BACKGROUND: A strong relationship exists between individual sensitivity to the aversive properties of ethanol and risk for alcohol use disorder (AUD). Despite this, our understanding of the neurobiological mechanisms underlying the subjective response to ethanol is limited. A major contributor to this lack of knowledge is the absence of preclinical models that enable exploration of this individual variability such as is possible in studies of humans.

METHODS: Adult male and female Long-Evans rats were trained to associate a novel tastant (saccharin) with acute exposure to either saline or ethanol (1.5 g/kg or 2.0 g/kg i.p.) over three conditioning days using a standard conditioned taste aversion (CTA) procedure. Variability in sensitivity to ethanol-induced CTA was phenotypically characterized using a median split across the populations studied.

RESULTS: When examining group averages, both male and female rats exposed to saccharin paired with either dose of ethanol exhibited lower saccharin intake relative to saline controls indicative of ethanol-induced CTA. Examination of individual data revealed a bimodal distribution of responses uncovering two distinct phenotypes present in both sexes. CTA-sensitive rats exhibited a rapid and progressive reduction in saccharin intake with each successive ethanol pairing. In contrast, saccharin intake was unchanged or maintained after an initial decrease from baseline levels in CTA-resistant rats. While CTA magnitude was similar between male and female CTA-sensitive rats, among CTA-resistant animals females were more resistant to the development of ethanol-induced CTA than males. Phenotypic differences were not driven by differences in baseline saccharin intake.

CONCLUSIONS: These data parallel work in humans by revealing individual differences in sensitivity to the aversive properties of ethanol that emerge immediately after initial exposure to ethanol in both sexes. This model can be used in future studies to investigate the neurobiological mechanisms that confer risk for AUD.}, } @article {pmid38298775, year = {2024}, author = {Douton, JE and Carelli, RM}, title = {Unraveling Sex Differences in Affect Processing: Unique Oscillatory Signaling Dynamics in the Infralimbic Cortex and Nucleus Accumbens Shell.}, journal = {Biological psychiatry global open science}, volume = {4}, number = {1}, pages = {354-362}, doi = {10.1016/j.bpsgos.2023.08.011}, pmid = {38298775}, issn = {2667-1743}, abstract = {BACKGROUND: Negative affect is prevalent in psychiatric diseases such as depression and addiction. Projections from the infralimbic cortex (IL) to the nucleus accumbens shell (NAcSh) are causally linked to learned negative affect as 20 Hz optogenetic stimulation of this circuit reduces conditioned taste aversion (CTA) in male but not female rats. However, the prior study did not provide insight into how innate versus learned negative affect are processed in these areas across sex.

METHODS: To address this issue, local field potential activity was simultaneously recorded in the IL and NAcSh in response to intraoral infusion of rewarding (saccharin) and aversive (quinine) tastants and following induction of a CTA in male and female Sprague Dawley rats.

RESULTS: Local field potential oscillatory activity within each brain region to saccharin varied across sex. In males, CTA increased IL resting-state power, which was correlated with the strength of the learned aversion, and reduced beta power and IL-NAcSh coherence. In females, CTA increased gamma power in the NAcSh. Similar effects were observed in males and females after CTA in theta-low gamma phase-amplitude coupling. Finally, while quinine produced similar effects in oscillatory power across sex, females showed differences in phase-amplitude coupling within the NAcSh that may be linked to aversion resistance.

CONCLUSIONS: We revealed sex-specific hedonic processing in the IL and NAcSh and how oscillatory signaling is disrupted in learned negative affect, revealing translationally relevant insight into potential treatment strategies that can help to reduce the deleterious effects of learned negative affect in psychiatric illnesses.}, } @article {pmid38215678, year = {2023}, author = {Yoshida, Y and Fujishiro, S and Kawai, R and Kawabata, F}, title = {Characterization of taste sensitivities to amino acids and sugars by conditioned taste aversion learning in chickens.}, journal = {Animal : an international journal of animal bioscience}, volume = {18}, number = {2}, pages = {101050}, doi = {10.1016/j.animal.2023.101050}, pmid = {38215678}, issn = {1751-732X}, abstract = {Taste plays an essential role in regulating the feeding behaviors of animals. The present study aimed to characterize the taste sensory profiles of amino acids and sugars in chickens. To achieve this, we employed a conditioned taste aversion learning method, which is characterized by a specific pairing of gastrointestinal malaise and taste perception. Our findings revealed that chickens were able to learn to avoid L-Val, L-Lys, and L-His through conditioned taste aversion learning, and exhibited a strong aversion to L-Arg. These results suggest that chickens are primarily sensitive to basic amino acids, including L-Lys, which is a crucial limiting amino acid in feeds. Interstingly, this sensitivity to basic amino acids in chickens contrasts with humans, who are mainly sensitive to acidic amino acids as umami taste. Furthermore, despite the absence of a mammalian sweet taste receptor gene in the chicken genome, we demonstrated that chickens learned to avoid glucose, galactose, sucrose, and maltose by conditioned taste aversion learning. Taken together, the present study provides the idea that chickens possess a gustatory perception toward specific amino acids and sugars for the detection of beneficial nutrients in their feeds.}, } @article {pmid38211776, year = {2024}, author = {Briones-Vidal, MG and Reyes-García, SE and Escobar, ML}, title = {NEUROTROPHIN-3 INTO THE INSULAR CORTEX STRENGTHENS CONDITIONED TASTE AVERSION MEMORY.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {114857}, doi = {10.1016/j.bbr.2024.114857}, pmid = {38211776}, issn = {1872-7549}, abstract = {Memory consolidation is an essential process of long-term memory formation. Neurotrophins have been suggested as key regulators of activity dependent changes in the synaptic efficacy and morphology, which are considered the downstream mechanisms of memory consolidation. The neurotrophin 3 (NT-3), a member of the neurotrophin family, and its high affinity receptor TrkC, are widely expressed in the insular cortex (IC), a region with a critical role in the consolidation of the conditioned taste aversion (CTA) paradigm, in which an animal associates a novel taste with nausea. Nevertheless, the role of this neurotrophin in the cognitive processes that the IC mediates remains unexamined. To answer whether NT-3 is involved in memory consolidation at the IC, adult male Wistar rats were administered with NT-3 or NT-3 in combination with the Trk receptors inhibitor K252a into the IC, immediately after CTA acquisition under two different conditions: a strong-CTA (0.2M lithium chloride i.p.) or a weak-CTA (0.1M lithium chloride i.p.). Our results show that NT-3 strengthens the memory trace of CTA, transforming a weak conditioning into a strong one, in a Trk-dependent manner. The present evidence suggests that NT-3 has a key role in the consolidation process of an aversive memory in a neocortical region.}, } @article {pmid38204574, year = {2023}, author = {Zhang, FX and Xie, XH and Guo, ZX and Wang, HD and Li, H and Wu, KLK and Chan, YS and Li, YQ}, title = {Evaluating proxies for motion sickness in rodent.}, journal = {IBRO neuroscience reports}, volume = {15}, number = {}, pages = {107-115}, pmid = {38204574}, issn = {2667-2421}, abstract = {Motions sickness (MS) occurs when the brain receives conflicting sensory signals from vestibular, visual and proprioceptive systems about a person's ongoing position and/or motion in relation to space. MS is typified by symptoms such as nausea and emesis and implicates complex physiological aspects of sensations and sensorimotor reflexes. Use of animal models has been integral to unraveling the physiological causality of MS. The commonly used rodents (rat and mouse), albeit lacking vomiting reflex, reliably display phenotypic behaviors of pica (eating of non-nutritive substance) and conditioned taste aversion (CTAver) or avoidance (CTAvoi) which utilize neural substrates with pathways that cause gastrointestinal malaise akin to nausea/emesis. As such, rodent pica and CTAver/CTAvoi have been widely used as proxies for nausea/emesis in studies dealing with neural mechanisms of nausea/emesis and MS, as well as for evaluating therapeutics. This review presents the rationale and experimental evidence that support the use of pica and CTAver/CTAvoi as indices for nausea and emesis. Key experimental steps and cautions required when using rodent MS models are also discussed. Finally, future directions are suggested for studying MS with rodent pica and CTAver/CTAvoi models.}, } @article {pmid38161042, year = {2023}, author = {Lockwood, DR and Cassell, JA and Smith, JC and Houpt, TA}, title = {Patterns of ingestion of rats during chronic oral administration of lithium chloride.}, journal = {Physiology & behavior}, volume = {}, number = {}, pages = {114454}, doi = {10.1016/j.physbeh.2023.114454}, pmid = {38161042}, issn = {1873-507X}, abstract = {Chronic lithium administration to rodents is used to explore the potential neural mechanisms of mood stabilization, as well as to model the side effects of chronic lithium on multiple organ systems. Oral administration of lithium in the maintenance diet or drinking water is convenient, but lithium can acutely affect intake and it can mediate acquisition of conditioned taste aversions. We compared ad libitum food and fluid intake by male rats with LiCl or NaCl solutions as their sole source of fluid across 20 days, with a commonly used dosage of LiCl (24 mM: 1 g / L LiCl). To quantify the pattern of intake, rats were housed in cages equipped with lickometers to detect licks and infrared photobeams to detect food access with 6-s resolution. To determine if rats formed a CTA to LiCl, they were subsequently tested with access to NaCl. Rats showed an immediate avoidance of the LiCl solution, as seen on the first day of access by an increased latency to initiate drinking and a decreased size of drinking bouts. Rats showed a differential response to LiCl vs. NaCl after as few as 5 licks. Chronic consumption of LiCl solution led to significantly decreased food and fluid intake compared to baseline, with concomitant weight loss. The decreased intake was realized by marked changes in the pattern of drinking and feeding bouts: a decrease in per-lick volume and a decrease in licks per drinking bout, and an increase in feeding bout duration resulting in an overall decrease in eating rate. Conversely, chronic NaCl access led to an increase in drinking bout number and licks/bout. The avoidance of LiCl was likely a combination of toxic effects of ingested LiCl and rapid acquisition of a learned aversion to the taste of LiCl, as shown by an extinguishable generalized aversion to NaCl solution during subsequent NaCl test days. The marked effect of chronic oral LiCl on ingestion may impact the oral dosing of lithium as well as the rat's metabolic status.}, } @article {pmid38154277, year = {2023}, author = {Gradowski, L}, title = {From fringe to mainstream: The Garcia effect.}, journal = {Studies in history and philosophy of science}, volume = {103}, number = {}, pages = {114-122}, doi = {10.1016/j.shpsa.2023.12.004}, pmid = {38154277}, issn = {0039-3681}, abstract = {The rejection of research results is sometimes thought to be justified in cases of individuals embracing fringe ideas that depart significantly from prevailing orthodoxy, or in cases of individuals who lack appropriate expertise or credentials. The case of John Garcia exhibits both of these dimensions, and illustrates that such rejection can delay scientific advancements. Garcia's work decisively challenged what was the orthodoxy in psychology in the midcentury: behaviorism. Behaviorist learning theorists suffered from theory-entrenchment insofar as they failed to acknowledge Garcia's anomalous research findings that ran counter to their theoretical expectations. The case study also illustrates that theories on the margins can become embraced as a result of advancements in adjacent research fields. Studying how Garcia's work moved from fringe to mainstream results in lessons for the philosophy of science and epistemology more generally. Only when we see the mechanisms of exclusion at work can we understand how science and other knowledge production systems can inadvertently act counterproductively via gatekeeping practices that filter out unorthodox points of view.}, } @article {pmid38048984, year = {2023}, author = {Dornellas, APS and Thiele, TE and Navarro, M}, title = {Chemogenetic inhibition of locus coeruleus to rostromedial tegmental nucleus noradrenergic pathway increases light cycle ethanol drinking in male and female mice and blunts ethanol-induced CTA.}, journal = {Neuropharmacology}, volume = {}, number = {}, pages = {109809}, doi = {10.1016/j.neuropharm.2023.109809}, pmid = {38048984}, issn = {1873-7064}, abstract = {We recently showed that chemogenetic activation of the locus coeruleus (LC) to the rostromedial tegmental nucleus (RMTg) noradrenergic (NE) pathway significantly blunted binge-like ethanol drinking and induced aversive-like behaviors in mice. The aim of the present study is to determine if silencing this TH + LC → RMTg noradrenergic pathway promotes increased levels of binge-like ethanol intake and reduced ethanol-induced conditioned taste aversion (CTA). To this end, both male and female TH-ires-cre mice on a C57BL/6 J background were cannulated in the RMTg and injected in the LC with rAVV viruses that encode cre-dependent Gi-expressing designer receptor exclusively activated by designer drugs (DREADDs), or its control, to directly control the activity of NE neurons. Inhibition of the LC to RMTg pathway had no effect on the binge-ethanol drinking in a "drinking-in-the-dark" (DID) paradigm. However, when using this paradigm during the light cycle, silencing of this circuit significantly increased ethanol intake without altering sucrose drinking. Moreover, we found that inhibition of this circuit significantly attenuated an ethanol-induced CTA. In addition, when compared to control animals, pairing RMTg-directed Clozapine N-oxide (CNO) with an i.p. injection of 1.5 g/kg ethanol reduced c-Fos activation in the LC, and increased c-Fos expression in the ventral tegmental area (VTA) in Gi-expressing mice. Our data show that inhibition of the TH + LC to the RMTg pathway significantly increased ethanol drinking as well as attenuated ethanol-induced CTA, supporting the involvement of the LC to RMTg noradrenergic circuit as an important protective mechanism against excessive ethanol consumption.}, } @article {pmid37989122, year = {2023}, author = {Dong, XC and Xu, DY}, title = {Research progress on the role and mechanism of GDF15 in body weight regulation.}, journal = {Obesity facts}, volume = {}, number = {}, pages = {}, doi = {10.1159/000535089}, pmid = {37989122}, issn = {1662-4033}, abstract = {BACKGROUND: Growth differentiation factor-15 (GDF-15) is a member of the growth differentiation factor subfamily in the transforming growth factor beta superfamily. GDF15 has multiple functions and can regulate biological processes. High levels of GDF15 in the circulation can affect metabolic processes. Studies have shown that GDF15 is associated with changes in body weight.

SUMMARY: This review reviews the current knowledge on the relationship between GDF15 and body weight change, focusing on the role and mechanism of GDF15 in body weight regulation. GDF15 plays an important role in reducing food intake, improving insulin resistance, and breaking down fat, suggesting that GDF15 has an important regulatory effect on body weight. The mechanism by which GDF15 causes reduced food intake may be related to changes in food preference, delayed gastric emptying, and conditioned taste aversion. GDF15 can combat insulin resistance induced by inflammation or protect β-cell from apoptosis. GDF15 probably promote lipolysis through a brain-somatic tissue circuit. Several factors and related signaling pathways are also mentioned that can contribute to the effects of GDF15 on reducing weight.

KEY MESSAGE: GDF15 plays an important role in weight regulation and provides a new direction for the treatment of obesity. Its effects on resisting obesity are of great significance to inhibiting the progression of metabolic diseases. It is expected to become a new target for regulating body weight, improving obesity, and treating metabolic diseases such as diabetes.}, } @article {pmid37883032, year = {2023}, author = {Rehn, S and Boakes, RA and Dwyer, DM}, title = {Switching from sucrose to saccharin: Extended successive negative contrast is not maintained by hedonic changes.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {49}, number = {4}, pages = {289-295}, doi = {10.1037/xan0000362}, pmid = {37883032}, issn = {2329-8464}, support = {//Experimental Psychology Society/ ; }, abstract = {Previous experiments found that acceptance of saccharin by rats was reduced if they had prior experience of sucrose or some other highly palatable solution. This reduction in saccharin consumption was particularly extended after a switch from sucrose. On the surface, this seems to correspond to a successive negative contrast (SNC) effect. This term was coined by C. F. Flaherty to describe the situation where consumption of a target solution is reduced by prior experience of a more valuable solution, typically a more concentrated version of the target solution. However, SNC effects are normally transient and assessed relative to a nonshifted control. Here, we confirm that the reduction in consumption seen when shifting from sucrose to saccharin is persistent and is seen relative to the traditional unshifted control. In addition, an analysis of licking microstructure showed that the shift from sucrose to saccharin suppressed the hedonic value of saccharin relative to controls, but this effect was less persistent than consumption suppression. Interestingly, a similar dissociation is observed in extinction of conditioned taste aversion (CTA): suppression of consumption produced by CTA is far more persistent than suppression of hedonic value. The comparison of results across procedures suggests that persistent SNC produced by a qualitative downshift from sucrose to saccharin appears different from quantitative downshifts in the concentration of a single solution, and qualitative downshift effects may involve CTA. (PsycInfo Database Record (c) 2023 APA, all rights reserved).}, } @article {pmid37882427, year = {2023}, author = {Expósito, AN and Vázquez-Agredos, A and Menchén, S and Gámiz, F and Gallo, M}, title = {Taste Neophobia, Latent Inhibition of Taste Aversion and Object Recognition Memory in Adolescent Rats.}, journal = {Psicothema}, volume = {35}, number = {4}, pages = {423-431}, doi = {10.7334/psicothema2022.256}, pmid = {37882427}, issn = {1886-144X}, abstract = {BACKGROUND: Adolescence in mammals is a period marked by increased novelty-seeking and enhanced responsiveness to the stressful properties of novel stimuli. Despite the need to taste potentially toxic novel foods during the adolescent growth spurt, there has been little study of taste neophobia and its attenuation.

METHOD: Four experiments were carried out to compare taste neophobia and related memory processes in male and female adolescent (PND28) and adult (PND70) Wistar rats. Experiments 1 and 2 evaluated attenuation of taste neophobia to cider vinegar (3%) and sodium saccharin (0.1%) solutions were evaluated. Additionally, to test the role of memory in neophobia during adolescence, latent inhibition of taste aversion and object recognition memory were assessed in Experiment 3 and Experiment 4, respectively.

RESULTS: Adolescent and adult rats exhibited taste neophobia to the saccharin solution but adolescent rats required more exposure trials than adults to recognize the vinegar solution as safe. Both groups exhibited similar latent inhibition of taste aversion and object recognition memory. No sex effect was significant.

CONCLUSIONS: Contrary to the accepted view associating adolescence with reduced neophobia, adolescent rats exhibited taste neophobia which even increased when sour tastes were encountered.}, } @article {pmid37818887, year = {2023}, author = {Chikamoto, N and Fujimoto, K and Nakai, J and Totani, Y and Hatakeyama, D and Ito, E}, title = {Expression Level Changes in Serotonin Transporter are Associated with Food Deprivation in the Pond Snail Lymnaea stagnalis.}, journal = {Zoological science}, volume = {40}, number = {5}, pages = {382-389}, doi = {10.2108/zs230027}, pmid = {37818887}, issn = {0289-0003}, abstract = {In the pond snail Lymnaea stagnalis, serotonin (5-HT) plays an important role in feeding behavior and its associated learning (e.g., conditioned taste aversion: CTA). The 5-HT content in the central nervous system (CNS) fluctuates with changes in the nutritional status, but it is also expected to be influenced by changes in the serotonin transporter (SERT) expression level. In the present study, we identified SERT in Lymnaea and observed its localization in 5-HTergic neurons, including the cerebral giant cells (CGCs) in the cerebral ganglia and the pedal A cluster neurons and right and left pedal dorsal 1 neurons in the pedal ganglia by in situ hybridization. Real-time PCR revealed that the SERT mRNA expression level was lower under severe food deprivation than under mild food deprivation in the whole CNS as well as in a single CGC. These results inversely correlated with previous data that the 5-HT content in the CNS was higher in the severely food-deprived state than in the mildly food-deprived state. Furthermore, in single CGCs, we observed that the 5-HT level was significantly increased in the severely food-deprived state compared with the mildly food-deprived state. Our present findings suggest that changes in the SERT expression level associated with food deprivation may affect 5-HT signaling, probably contributing to learning and memory mechanisms in Lymnaea.}, } @article {pmid37816597, year = {2023}, author = {Hurley, SW and Douton, JE and Carelli, RM}, title = {Neuronal Ensembles in the Infralimbic Cortex Dynamically Process Distinct Aspects of Hedonic Value.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1523/JNEUROSCI.0253-23.2023}, pmid = {37816597}, issn = {1529-2401}, abstract = {Hedonic processing is critical for guiding appropriate behavior, and the infralimbic cortex (IL) is a key neural substrate associated with this function in rodents and humans. We used deep brain, in vivo calcium imaging and taste reactivity (TR) in freely behaving male and female Sprague Dawley rats to examine whether the infralimbic cortex is involved in encoding innate versus conditioned hedonic states. In experiment 1, we examined the IL neuronal ensemble responsiveness to intraoral innately rewarding (sucrose) versus aversive (quinine) tastants. Most IL neurons responded to either sucrose only or both sucrose and quinine, with fewer neurons selectively processing quinine. Among neurons that responded to both stimuli, some appear to encode hedonic processing. In experiment 2, we examined how IL neurons process devalued sucrose using conditioned taste aversion (CTA). We found that neurons that responded exclusively to sucrose were disengaged while additional quinine-exclusive neurons were recruited. Moreover, tastant-specific neurons that did not change their neuronal activity after CTA appeared to encode objective hedonic value. However, other neuronal ensembles responded to both tastants and appear to encode distinct aspects of hedonic processing. Specifically, some neurons responded differently to quinine and sucrose and shifted from appetitive-like to aversive-like activity after CTA, thus encoding the subjective hedonic value of the stimulus. Conversely, neurons that responded similarly to both tastants were heightened after CTA. Our findings show dynamic shifts in IL ensembles encoding devalued sucrose and support a role for parallel processing of objective and subjective hedonic value.Significance StatementDisrupted affective processing contributes to psychiatric disorders including depression, substance use disorder, and schizophrenia. We assessed how the infralimbic cortex, a key neural substrate involved in affect generation and affect regulation, processes innate and learned hedonic states using deep brain in vivo calcium imaging in freely behaving rats. We report that unique infralimbic cortex ensembles encode stimulus subjective and objective hedonic value. Further, our findings support similarities and differences in innate versus learned negative affective states. This study provides insight into the neural mechanisms underlying affect generation and help establish a foundation for the development of novel treatment strategies to reduce negative affective states that arise in many psychiatric disorders.}, } @article {pmid37806503, year = {2023}, author = {Ranmal, SR and Nhouchi, Z and Keeley, A and Adler, L and Lavarde, M and Pensé-Lhéritier, AM and Tuleu, C}, title = {Taste assessment for Paediatric Drug Development: A Comparison of Bitterness Taste Aversion in Children versus Naïve and Expert Young Adult Assessors.}, journal = {International journal of pharmaceutics}, volume = {}, number = {}, pages = {123494}, doi = {10.1016/j.ijpharm.2023.123494}, pmid = {37806503}, issn = {1873-3476}, abstract = {Medicines for children often taste bitter, presenting a significant challenge to treatment compliance. However, most studies on paediatric drug development rely on adult volunteers for sensory research, and the level of expertise required from these assessors is unclear. This study aimed to address this gap by investigating perceived bitterness aversion to taste strips impregnated with different concentrations of quinine hydrochloride in 439 school-aged children. Expert (n=26) and naïve (n=65) young adult assessors evaluated quinine solutions as well as taste strips, for methodological bridging purposes. All assessors differentiated the aversiveness of the taste strips in a dose dependent manner. Younger children aged 4-8 years had difficulty discriminating higher bitter concentrations, whereas pre-adolescents 9-11 years and naive adults showed better discrimination at the top of the scale. Naive assessors showed similar bitter perception as children. However, the results were slightly different between strips and solution in adults. These findings highlight the key role that adult panels can play in paediatric formulation development. Taste strips show promise as a safe and pragmatic tool for sensory pharmaceutical evaluations, though further studies are warranted to establish the relationship between age and hedonic taste perception using compounds with diverse physicochemical and sensory qualities.}, } @article {pmid37805119, year = {2023}, author = {Gutiérrez-Vera, B and Reyes-García, SE and Escobar, ML}, title = {Brief environmental enrichment elicits metaplasticity on the insular cortex in vivo and reduces the strength of conditioned taste aversion.}, journal = {Neurobiology of learning and memory}, volume = {}, number = {}, pages = {107840}, doi = {10.1016/j.nlm.2023.107840}, pmid = {37805119}, issn = {1095-9564}, abstract = {Environmental enrichment (EE) is known to improve memory and cognition and modulate the impact of aversive stimuli in animals, promoting the development of resilience to stressful situations. Likewise, it is known that EE can modulate synaptic plasticity as is the case of long-term potentiation (LTP). These findings have been described initially in ex vivo preparations, suggesting that the effects of EE are the result of an early modification of the synaptic excitability and transmission. In this regard, it is known that metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. In addition, we have shown that CTA extinction allows the induction but not the maintenance of IC-LTP of the Bla-IC pathway. Recently, we also showed that prior exposure to environmental enrichment for three weeks reduces the strength of CTA, restoring the brain-derived neurotrophic factor (BDNF) levels in the IC. The present study aimed to analyze the effects of brief exposure to an enriched environment on the strength of aversive memory, as well as on the in vivo IC-LTP. To do so, adult rats were exposed for seven days to an EE, either before CTA training or LTP induction in the Bla-IC pathway. Our results demonstrate that a seven-day exposure to an enriched environment attenuates the aversive response to a strong CTA and allows the induction but not the maintenance of LTP in the insular cortex. These findings provide evidence that metaplastic regulation in a neocortical region takes part in the mechanisms through which brief exposure to enriched environments attenuates an aversive response.}, } @article {pmid37805008, year = {2023}, author = {Kobayashi, S and Kajiwara, M and Cui, Y and Sako, T and Sasabe, T and Hayashinaka, E and Wada, Y and Kobayashi, M}, title = {Activation of multiple neuromodulatory systems in alert rats acquiring conditioned taste aversion revealed by positron emission tomography.}, journal = {Brain research}, volume = {}, number = {}, pages = {148617}, doi = {10.1016/j.brainres.2023.148617}, pmid = {37805008}, issn = {1872-6240}, abstract = {Conditioned taste aversion (CTA) is an essential ability for animals to consume food safely and is regulated by neuromodulatory systems including the dopamine, noradrenaline, serotonin, and acetylcholine systems. However, because few studies focused on a comprehensive understanding of whole-brain activities, how these neuromodulators contribute to the process of CTA remains an open issue. [18]F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) can visualize activated regions within the whole brain simultaneously and noninvasively. This study aimed to understand the mechanisms of CTA, especially focusing on the retrieval process after CTA acquisition by FDG-PET imaging. CTA was established in rats who received an intraoral application of saccharin solution (IOAS) on the first day (Day1), a LiCl i.p. injection after an IOAS on Day2, and an IOAS on Day3 (CTA group). The subtraction images of Day3 of the SHAM group, which received a 0.9% NaCl (saline) injection instead of a LiCl on Day2, from those of Day3 of the CTA group revealed increases in FDG signals in multiple brain regions including the substantia nigra, ventral tegmental area, locus coeruleus, dorsal raphe, and nucleus basalis magnocellularis, in addition to the hippocampus and nociception-related regions, including the parabrachial nucleus and solitary nucleus. On the other hand, the visceral pain induced by the LiCl injection increased FDG signals in the primary and secondary somatosensory and insular cortices in addition to the parabrachial nucleus and solitary nucleus. These results suggest that the retrieval process of CTA induces brain regions producing neuromodulators and pain-related brainstem.}, } @article {pmid37774959, year = {2023}, author = {Lamb, RJ and Schindler, CW and Ginsburg, BC}, title = {Effects of an Ethanol-Paired Conditioned Stimulus on Responding for Ethanol Suppressed by a Conditioned-Taste-Aversion.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.alcohol.2023.09.008}, pmid = {37774959}, issn = {1873-6823}, abstract = {Ethanol-Paired Conditioned Stimuli (CS) can increase ethanol responding either in extinction or occurring at low rates late in a session. To examine the generality of CS induced increases in ethanol-responding, we examined if a CS could increase responding suppressed by Conditioned-Taste-Aversion (CTA), which presumably suppresses responding by changing ethanol's valence from positive to negative. Rats were trained to respond for ethanol under a Random Interval (RI) schedule. We then removed the lever and paired Random-Time ethanol deliveries with illumination of a stimulus light (i.e., CS) for ten sessions. Results were compared with a Truly Random Control group, in which the light and ethanol deliveries occurred independently. In a subsequent experiment, rats were treated similarly, except the light served as a discriminative stimulus, as the lever was extended and ethanol deliveries were available under a RI during light presentations. After this training, the lever was returned and rats again responded for ethanol. Subsequently, sessions were followed by LiCl administration. When responding reached low levels, LiCl administration stopped and the light was occasionally illuminated during the session. Responding during the light presentation was compared to responding during the period preceding light presentation. Responding partially recovered across ten sessions and was greater during light presentations than in the period before it in all three groups. Increases were not reliably different between the groups indicating that explanations for these increases such as CS-induced increases in motivation or approach towards the light are unlikely to be correct. The most likely explanation for these light-induced increases is that during sessions in which the light had been presented previously, LiCl had never been presented and thus, the light had come to signal that ethanol was safe to drink.}, } @article {pmid37759600, year = {2023}, author = {Nakai, J and Namiki, K and Fujimoto, K and Hatakeyama, D and Ito, E}, title = {FOXO in Lymnaea: Its Probable Involvement in Memory Consolidation.}, journal = {Biology}, volume = {12}, number = {9}, pages = {}, doi = {10.3390/biology12091201}, pmid = {37759600}, issn = {2079-7737}, support = {JPMJSP2128//Japan Science and Technology Agency/ ; none//Waseda University/ ; }, abstract = {Food deprivation activates forkhead box O (FOXO), a transcription factor downstream of insulin receptors. In the pond snail Lymnaea stagnalis, insulin signaling and food deprivation improve memory consolidation following conditioned taste aversion (CTA) learning. We investigated the subcellular localization of FOXO in Lymnaea and changes in its expression levels following food deprivation, CTA learning, and insulin administration. Immunohistochemistry revealed that Lymnaea FOXO (LymFOXO) was located in the central nervous system (CNS) neuronal cytoplasm in food-satiated snails but was mainly in neuronal nuclei in food-deprived snails. Following CTA acquisition, LymFOXO translocated to the nuclei in food-satiated snails and remained in the nuclei in food-deprived snails. Contrary to our expectations, insulin administered to the CNS did not induce LymFOXO translocation into the nuclei in food-satiated snails. Real-time PCR was used to quantify LymFOXO mRNA levels, its target genes, and insulin signaling pathway genes and revealed that LymFOXO mRNA was upregulated in food-deprived snails compared to food-satiated snails. Insulin applied to isolated CNSs from food-satiated snails increased LymFOXO compared to vehicle-treated samples. Food deprivation prepares FOXO to function in the nucleus and enhances CTA learning in snails. Insulin application did not directly affect LymFOXO protein localization. Thus, insulin administration may stimulate pathways other than the LymFOXO cascade.}, } @article {pmid37745477, year = {2023}, author = {Ramirez, LA and Przybysz, KR and Pitock, JR and Starr, EM and Yang, H and Glover, EJ}, title = {Attenuated incubation of ethanol-induced conditioned taste aversion in a model of dependence.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.09.13.557582}, pmid = {37745477}, abstract = {RATIONALE: Preclinical studies report attenuated ethanol-induced conditioned taste aversion (CTA) following chronic ethanol exposure, suggesting that tolerance develops to the aversive properties of ethanol. However, these studies are confounded by pre-exposure to the unconditioned stimulus (US; ethanol), which is well known to hinder conditioning.

OBJECTIVES: This study was designed to determine whether chronic ethanol exposure produces tolerance to the aversive properties of ethanol in the absence of a US pre-exposure confound.

METHODS: CTA was performed in adult male and female Long-Evans rats by pairing 0.1% ingested saccharin with an intraperitoneal injection of ethanol (1.5 or 2.0 g/kg) or saline. Rats were then rendered ethanol dependent using chronic intermittent ethanol (CIE) vapor exposure. Controls were exposed to room air (AIR). The effect of chronic ethanol on CTA expression and reconditioning were examined following vapor exposure.

RESULTS: Prior to vapor exposure, both sexes developed CTA to a comparable degree with 2.0 g/kg producing greater CTA than 1.5 g/kg ethanol. Following vapor exposure, AIR controls exhibited an increase in CTA magnitude compared to pre-vapor levels. This effect was absent in CIE-exposed rats. These group differences were eliminated upon re-conditioning after vapor exposure.

CONCLUSIONS: These data suggest that chronic ethanol does not facilitate tolerance to the aversive properties of ethanol but rather, attenuates incubation of ethanol-induced CTA. Loss of CTA incubation suggests that CIE exposure disrupts circuits encoding aversion.}, } @article {pmid37713319, year = {2023}, author = {Barnhart, WR and Dial, LA and Jordan, AK and Studer-Perez, EI and Kalantzis, MA and Musher-Eizenman, DR}, title = {Higher meal disengagement and meal presentation are uniquely related to psychological distress and lower quality of life in undergraduate students.}, journal = {Journal of American college health : J of ACH}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/07448481.2023.2245912}, pmid = {37713319}, issn = {1940-3208}, abstract = {Objective: Picky eating, which occurs in emerging adulthood and is associated with psychological distress and quality of life, has historically been conceptualized as unidimensional despite research suggesting it is a multifaceted construct. Participants: An undergraduate sample (N = 509; Mage = 19.96). Methods: A cross-sectional survey assessed picky eating facets (food variety, meal disengagement, meal presentation, and taste aversion), disordered eating, anxiety, depression, stress, obsessive compulsive disorder (OCD), and social phobia symptoms, and quality of life. Results: Meal disengagement was uniquely related to higher anxiety, depression, stress, and social phobia symptoms and lower quality of life, whereas meal presentation was uniquely related to higher anxiety, stress, and OCD symptoms, beyond covariates and disordered eating. Food variety and taste aversion were not uniquely related to outcomes. Conclusions: Considering picky eating multidimensionally may yield important insights beyond the broader construct in terms of its relationship with psychological well-being in undergraduates.}, } @article {pmid37626986, year = {2023}, author = {Rivi, V and Batabyal, A and Lukowiak, K and Benatti, C and Rigillo, G and Tascedda, F and Blom, JMC}, title = {LPS-Induced Garcia Effect and Its Pharmacological Regulation Mediated by Acetylsalicylic Acid: Behavioral and Transcriptional Evidence.}, journal = {Biology}, volume = {12}, number = {8}, pages = {}, doi = {10.3390/biology12081100}, pmid = {37626986}, issn = {2079-7737}, support = {L.R. N. 20/2002 PROGETTI DI RICERCA SUI METODI ALTERNATIVI ALL'UTILIZZO DI ANIMALI//Regione Emilia Romagna/ ; FAR 2016//Department of Life Sciences - University of Modena and Reggio Emilia/ ; 227993-2019//Natural Sciences and Engineering Research Council of Canada/ ; }, abstract = {Lymnaea stagnalis learns and remembers to avoid certain foods when their ingestion is followed by sickness. This rapid, taste-specific, and long-lasting aversion-known as the Garcia effect-can be formed by exposing snails to a novel taste and 1 h later injecting them with lipopolysaccharide (LPS). However, the exposure of snails to acetylsalicylic acid (ASA) for 1 h before the LPS injection, prevents both the LPS-induced sickness state and the Garcia effect. Here, we investigated novel aspects of this unique form of conditioned taste aversion and its pharmacological regulation. We first explored the transcriptional effects in the snails' central nervous system induced by the injection with LPS (25 mg), the exposure to ASA (900 nM), as well as their combined presentation in untrained snails. Then, we investigated the behavioral and molecular mechanisms underlying the LPS-induced Garcia effect and its pharmacological regulation by ASA. LPS injection, both alone and during the Garcia effect procedure, upregulated the expression levels of immune- and stress-related targets. This upregulation was prevented by pre-exposure to ASA. While LPS alone did not affect the expression levels of neuroplasticity genes, its combination with the conditioning procedure resulted in their significant upregulation and memory formation for the Garcia effect.}, } @article {pmid37406868, year = {2023}, author = {Nakajima, S and Umemoto, S and Nagaishi, T}, title = {Food avoidance learning based on swimming in laboratory mice (Mus musculus).}, journal = {Behavioural processes}, volume = {}, number = {}, pages = {104910}, doi = {10.1016/j.beproc.2023.104910}, pmid = {37406868}, issn = {1872-8308}, abstract = {Although it is now well documented that laboratory rats learn to avoid the flavored substance consumed immediately before running in activity wheels or swimming in water buckets, research on this activity-based flavor avoidance learning in other species is limited. Recently, running-based flavor avoidance learning has been demonstrated in laboratory mice by employing a method of resistance-to-habituation of neophobic reaction to novel food; mice that repeatedly experience running after encountering a novel food have a prolonged tendency to reject that food compared to control mice without paired running. The present article reports a series of attempts to obtain evidence of flavor avoidance learning based on swimming rather than running using this resistance-to-habituation method. Swimming-based flavor avoidance was clearly demonstrated in a differential conditioning paradigm; however, its demonstration in a simple conditioning paradigm requires a post-training choice test of the target food and another type of food. These results are likely due to the short swimming time (20min) and the formation of weak flavor aversion.}, } @article {pmid37382606, year = {2023}, author = {Kagan, D and Hollings, J and Batabyal, A and Lukowiak, K}, title = {Five-minute exposure to a novel appetitive food substance is sufficient time for a microRNA-dependent long-term memory to form.}, journal = {Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology}, volume = {}, number = {}, pages = {}, pmid = {37382606}, issn = {1432-1351}, support = {227993-2019//Natural Sciences and Engineering Research Council of Canada/ ; }, abstract = {The Garcia effect is a unique form of conditioned taste aversion which requires that a novel food stimulus be followed sometime later by a sickness state associated with the novel food stimulus. The long-lasting associative memory resulting from the Garcia effect ensures that organisms avoid toxic foods in their environment. Considering its ecological relevance, we sought to investigate whether a brief encounter (5 min) with a novel, appetitive food stimulus can cause a persisting long-term memory (LTM) to form that would in turn block the Garcia effect in Lymnaea stagnalis. Furthermore, we wanted to explore whether that persisting LTM could be modified by the alteration of microRNAs via an injection of poly-L-lysine (PLL), an inhibitor of Dicer-mediated microRNA biogenesis. The Garcia effect procedure involved two observations of feeding behavior in carrot separated by a heat stress (30 °C for 1 h). Exposing snails to carrot for 5 min caused a LTM to form and persist for 1 week, effectively preventing the Garcia effect in snails. In contrast, PLL injection following the 5-min carrot exposure impaired LTM formation, allowing the Garcia effect to occur. These results provide more insight into LTM formation and the Garcia effect, an important survival mechanism.}, } @article {pmid37352906, year = {2023}, author = {Su, S and Wei, Z and Huang, H and Yoshizawa, T and Inui, T and Funahashi, M}, title = {Conditioned nausea induced by cisplatin and emetine identified by a taste reactivity test in rats.}, journal = {Physiology & behavior}, volume = {}, number = {}, pages = {114278}, doi = {10.1016/j.physbeh.2023.114278}, pmid = {37352906}, issn = {1873-507X}, abstract = {No prior studies have shown that gaping reactions are produced with the avoidance of conditioned taste caused by cisplatin and emetine. Therefore, we tried to demonstrate it using a taste reactivity test in rats and found the gaping reactions induced when saccharin is readministered after gustatory conditioning that paired saccharin with cisplatin or emetine. Since conditioned gaping reactions indicate the aversion to saccharin taste and conditioned nausea, the present study suggest that the taste aversion is induced by cisplatin and emetine. It was also found that with intraperitoneal injections of emetine alone, gaping almost never occurs.}, } @article {pmid37333122, year = {2023}, author = {Przybysz, KR and Ramirez, LA and Pitock, JR and Starr, EM and Yang, H and Glover, EJ}, title = {A translational rodent model of individual differences in sensitivity to the aversive properties of ethanol.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.06.08.544209}, pmid = {37333122}, abstract = {BACKGROUND: A strong relationship exists between individual sensitivity to the aversive properties of ethanol and risk for alcohol use disorder (AUD). Despite this, our understanding of the neurobiological mechanisms underlying subjective response to ethanol is relatively poor. A major contributor to this is the absence of preclinical models that enable exploration of this individual variability similar to studies performed in humans.

METHODS: Adult male and female Long-Evans rats were trained to associate a novel tastant (saccharin) with acute exposure to either saline or ethanol (1.5 g/kg or 2.0 g/kg i.p.) over three conditioning days using a standard conditioned taste aversion (CTA) procedure. Variability in sensitivity to ethanol-induced CTA was phenotypically characterized using a median split across the populations studied.

RESULTS: When examining group averages, both male and female rats that had saccharin paired with either dose of ethanol exhibited reduced saccharin intake relative to saline controls of ethanol-induced CTA. Examination of individual data revealed a bimodal distribution of responses uncovering two distinct phenotypes present in both sexes. CTA-sensitive rats exhibited a rapid and progressive reduction in saccharin intake with each successive ethanol pairing. In contrast, saccharin intake was unchanged or maintained after an initial decrease from baseline levels in CTA-resistant rats. While CTA magnitude was similar between male and female CTA-sensitive rats, CTA-resistant females were more resistant to the development of ethanol-induced CTA than their male counterparts. Phenotypic differences were not driven by differences in baseline saccharin intake. CTA sensitivity correlated with behavioral signs of intoxication in only a subset of rats.

CONCLUSIONS: These data parallel work in humans by revealing individual differences in sensitivity to the aversive properties of ethanol that emerge immediately after initial exposure to ethanol in both sexes. This model can be leveraged in future studies to investigate the neurobiological mechanisms that confer risk for AUD.}, } @article {pmid37306398, year = {2023}, author = {Cote, JM and Hood, A and Kwon, B and Smith, JC and Houpt, TA}, title = {Behavioral and neural responses to high strength magnetic fields are reduced in otolith mutant mice.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/ajpregu.00317.2022}, pmid = {37306398}, issn = {1522-1490}, abstract = {Static high magnetic fields (MFs) interact with the vestibular system of humans and rodents. In rats and mice, exposure to MFs causes perturbations such as head movements, circular locomotion, suppressed rearing, nystagmus, and conditioned taste aversion acquisition. To test the role of otoconia, two mutant mouse models were examined: head-tilt Nox3[het] (het) and tilted Opt1[tlt] (tlt), with mutations respectively in Nox3, encoding the NADPH oxidase 3 enzyme, and Opt1, encoding the opterin1 proton channel, which are normally expressed in the otolith organs, and are critical for otoconia formation. Consequently, both mutants show a near complete loss of otoconia in the utricle and saccule, and are non-responsive to linear acceleration. Mice were exposed to a 14.1 T MF for 30 min. After exposure, locomotor activity, conditioned taste aversion and c-Fos (in het) were assessed. Wild-type mice exposed to the MF showed suppressed rearing, increased latency to rear, locomotor circling, and c-Fos in brainstem nuclei related to vestibular processing (prepositus, spinal vestibular, and supragenual nuclei). Mutant het mice showed no response to the magnet and were similar to sham animals in all assays. Unlike het, tlt mutants exposed to the MF showed significant locomotor circling and suppressed rearing compared to sham controls, although they failed to acquire a taste aversion. The residual responsiveness of tlt vs het mice might reflect a greater semicircular deficit in het mice. These results demonstrate the necessity of the otoconia for the full effect of exposure to high MFs, but also suggest a semicircular contribution.}, } @article {pmid37190662, year = {2023}, author = {Gao, ZY and Huang, CM and Cheng, CN and Huang, AC}, title = {D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting.}, journal = {Brain sciences}, volume = {13}, number = {4}, pages = {}, doi = {10.3390/brainsci13040697}, pmid = {37190662}, issn = {2076-3425}, abstract = {Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.}, } @article {pmid37113545, year = {2023}, author = {Yu, YH and Tsai, AC and Ou, CY and Cheng, CN and Chang, FC and Shyu, BC and Huang, ACW}, title = {Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states.}, journal = {Frontiers in psychiatry}, volume = {14}, number = {}, pages = {1119803}, pmid = {37113545}, issn = {1664-0640}, abstract = {INTRODUCTION: Understanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine's conditioning, and the neutral states via saccharin extinction processes after morphine's conditioning.

METHODS: All rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus.

RESULTS: The results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning.

CONCLUSION: Altogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.}, } @article {pmid36906931, year = {2023}, author = {Chen, A and Wang, R and Kang, Y and Liu, J and Wu, J and Zhang, Y and Zhang, Y and Shao, L}, title = {Tongue-brain-transported ZnO NPs induced abnormal taste perception.}, journal = {Advanced healthcare materials}, volume = {}, number = {}, pages = {e2203316}, doi = {10.1002/adhm.202203316}, pmid = {36906931}, issn = {2192-2659}, abstract = {Nanoparticles (NPs) can be transported to the brain, especially the nerve, because of their small size and high biological activity. Our previous studies confirmed that zinc oxide (ZnO) NPs could enter the brain through the tongue-brain pathway, but it is unclear whether they would further affect synaptic transmission and brain perception. In this study, we found that tongue-brain-transported ZnO NPs could cause a decrease in taste sensitivity and taste aversion learning ability, indicating abnormal taste perception. Moreover, the release of miniature excitatory postsynaptic currents, the frequency of action potential release and the expression of c-fos were decreased, suggesting that the synaptic transmission was reduced. To further explore the mechanism, we carried out protein chip detection of inflammatory factors and found that neuroinflammation occurs. Importantly, we found that neuroinflammation originated from neurons. The JAK-STAT signaling pathway was activated, which inhibited the Neurexin1-PSD95-Neurologigin1 pathway and c-fos expression. Blocking the activation of the JAK-STAT pathway prevented neuroinflammation and the reduction in Neurexin1-PSD95-Neurologigin1. These results indicate that ZnO NPs could be transported by the tongue-brain pathway and lead to abnormal taste perception by neuroinflammation-induced deficits in synaptic transmission. Our study reveals the influence of ZnO NPs on neuronal function and provides a novel mechanism. This article is protected by copyright. All rights reserved.}, } @article {pmid36898644, year = {2023}, author = {Miranda, MI and Alcalá, A and Vera-Rivera, G and Rangel-Hernández, JA}, title = {Differential effects of thirst and satiety on conditioned taste aversion acquisition, retrieval, and memory extinction.}, journal = {Physiology & behavior}, volume = {}, number = {}, pages = {114143}, doi = {10.1016/j.physbeh.2023.114143}, pmid = {36898644}, issn = {1873-507X}, abstract = {Thirst is an essential motivational component that could modulate the strength of conditioning; pioneer studies show that the rats' sexual dimorphism observed in the rate of aversive memory extinction of conditioned taste aversion (CTA) is affected by the state of fluid deprivation. On the other hand, previous evidence suggests that fluid intake volume and temporal context before and during conditioning may influence CTA. Furthermore, although CTA has been demonstrated using various types of stimuli, neural processing and homeostatic regulation of water and nutritional balance may differ depending on the stimulus used and the conditioning stages. Therefore, this study explored the effects of state motivated by thirst and satiation, using saccharin, as a non-caloric sweet stimulus, during CTA and the aversive memory extinction process under similar contextual and temporal conditions. First, we implemented an ad libitum water protocol in male and female adult rats to evaluate saccharin aversive memory formation; we compared this with a traditional CTA with liquid deprivation in the same context and temporal consumption conditions. Furthermore, we evaluated whether liquid satiety affects the acquisition or the aversive memory retrieval differentially. Our results show that the ad libitum liquid regimen allows reliable quantifications of basal water consumption, monitored every hour for more than five days. We observed a reliable CTA, where the magnitude of aversive memory and its extinction is significantly higher in both male and female rats; the strong CTA observed is substantially due to the satiety state during taste aversion memory retrieval. Our data show that although liquid deprivation does not affect CTA acquisition, it does induce weakness in the magnitude of aversive retrieval expression and fast aversive memory extinction, similarly in male and females. Overall, the results indicate that the need to satiate the demand for liquids during retrieval prevails over the conditioned aversion learned, suggesting, that thirst is a source of temporary variables dominating the aversive responses during CTA retrieval.}, } @article {pmid36898496, year = {2023}, author = {Arthurs, J and Pauli, J and Palmiter, RD}, title = {Activation of parabrachial tachykinin 1 neurons counteracts some behaviors mediated by parabrachial CGRP neurons.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2023.03.003}, pmid = {36898496}, issn = {1873-7544}, abstract = {Many threats activate parabrachial neurons expressing calcitonin gene-related peptide (CGRP[PBN]) which transmit alarm signals to forebrain regions. Most CGRP[PBN] neurons also express tachykinin 1 (Tac1), but there are also Tac1-expressing neurons in the PBN that do not express CGRP (Tac1+;CGRP- neurons). Chemogenetic or optogenetic activation of all Tac1[PBN] neurons in mice elicited many physiological/behavioral responses resembling the activation of CGRP[PBN] neurons, e.g., anorexia, jumping on a hot plate, avoidance of photostimulation; however, two key responses opposed activation of CGRP[PBN] neurons. Activating Tac1[PBN] neurons did not produce conditioned taste aversion and it elicited dynamic escape behaviors rather than freezing. Activating Tac1+;CGRP- neurons, using an intersectional genetic targeting approach, resembles activating all Tac1[PBN] neurons. These results reveal that activation of Tac1+;CGRP- neurons can suppress some functions attributed to the CGRP[PBN] neurons, which provides a mechanism to bias behavioral responses to threats.}, } @article {pmid36856894, year = {2023}, author = {Muñiz Moreno, J and Loy, I}, title = {Taste aversion learning in the snail Cornu aspersum.}, journal = {Animal cognition}, volume = {}, number = {}, pages = {}, pmid = {36856894}, issn = {1435-9456}, abstract = {The present study was conducted to provide evidence of conditioned taste aversion learning (CTA) in the snail Cornu aspersum, using quinidine as the aversive stimulus in a procedure of Pavlovian Conditioning of Tentacle Lowering. Subjects were split into two groups: paired and unpaired. During the devaluation phase, subjects from the "paired group" received the US followed by the quinidine exposure, while subjects from the "unpaired group" received the quinidine and, 30 min later, the US. Subjects which had received the US paired with the quinidine showed a decrease of the conditioned response (CR), in contrast to subjects which had received the quinidine and the US unpaired. These results provide a useful CTA procedure in terrestrial snails. The implication of the results for learning and the physiological correlates is discussed.}, } @article {pmid36762112, year = {2023}, author = {Ou, CY and Yu, YH and Wu, CW and Kozłowska, A and Shyu, BC and Huang, ACW}, title = {Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats.}, journal = {Frontiers in pharmacology}, volume = {14}, number = {}, pages = {1062169}, pmid = {36762112}, issn = {1663-9812}, abstract = {To re-examine the paradoxical effect hypothesis of abused drugs, the present study concerned whether different doses of morphine disparately affect neuronal activity and associations among the subareas of the medial prefrontal cortex (mPFC: cingulate cortex 1-Cg1, prelimbic cortex-PrL, infralimbic cortex-IL), the subregions of the nucleus accumbens (NAc; both core and shell), and the basolateral amygdala (BLA) following conditioned taste aversion (CTA) and conditioned place preference (CPP). All rats were given a 0.1% saccharin solution for 15-min, and they were intraperitoneally injected with saline or 20, 30, or 40 mg/kg morphine to form the aversive CTA learning. Later, half of the rats were tested for CPP (including the CTA and then CPP tests) for 30-min. Finally, the immunohistochemical staining with c-Fos was conducted after the behavioral test. After the CTA test, c-Fos (%) in the Cg1 and PrL (but not the IL) was more in 20-40 mg/kg of the morphine groups; c-Fos (%) in the NAc core, NAc shell, and BLA was more in the 30-40 mg/kg morphine group. After the CPP test, the Cg1, PrL, IL, and BLA showed more c-Fos (%) in 20 mg/kg morphine; the NAc core showed fewer in c-Fos (%) in the 30-40 mg/kg morphine groups. The mPFC subregions (e.g., Cg1, PrL, and IL), NAc subareas (e.g., NAc core and NAc shell), and BLA were involved in the different doses of morphine injections. The correlation analysis showed that a positive correlation was observed between PrL and IL with NAc core with low doses of morphine and with NAc shell with increasing doses of morphine after the CTA test. After the CPP, an association between PrL and NAc core and NAc shell at low doses and between IL and BLA and NAc shell with increasing doses of morphine. Therefore, different neural substrates and the neural connectivity are observed following different doses of morphine and after the CTA and CPP tests. The present data extend the paradoxical effect hypothesis of abused drugs.}, } @article {pmid36635250, year = {2022}, author = {Kolatt Chandran, S and Yiannakas, A and Kayyal, H and Salalha, R and Cruciani, F and Mizrahi, L and Khamaisy, M and Stern, S and Rosenblum, K}, title = {Intrinsic excitability in layer IV-VI anterior insula to basolateral amygdala projection neurons correlates with the confidence of taste valence encoding.}, journal = {eNeuro}, volume = {}, number = {}, pages = {}, doi = {10.1523/ENEURO.0302-22.2022}, pmid = {36635250}, issn = {2373-2822}, abstract = {Avoiding potentially harmful, and consuming safe food is crucial for the survival of living organisms. However, the perceived valence of sensory information can change following conflicting experiences. Pleasurability and aversiveness are two crucial parameters defining the perceived valence of a taste and can be impacted by novelty. Importantly, the ability of a given taste to serve as the conditioned stimulus (CS) in conditioned taste aversion (CTA), is dependent on its valence. Activity in anterior insula (aIC) layer IV-VI pyramidal neurons projecting to the basolateral amygdala (BLA) is correlated with, and necessary for CTA learning and retrieval, as well as the expression of neophobia towards novel tastants, but not learning taste familiarity. Yet, the cellular mechanisms underlying the updating of taste valence representation in this specific pathway are poorly understood. Here, using retrograde viral tracing and whole -cell patch-clamp electrophysiology in trained mice, we demonstrate that the intrinsic properties of deep-lying layer IV-VI, but not superficial layer I-III aIC-BLA neurons, are differentially modulated by both novelty and valence, reflecting the subjective predictability of taste valence arising from prior experience. These correlative changes in the profile of intrinsic properties of LIV-VI aIC-BLA neurons were detectable following both simple taste experiences, as well as following memory retrieval, extinction learning and reinstatement.Significance statementLearning to form aversive or safe taste memories is dependent on genetic predisposition as well as previous experiences. In mice, anterior insula neurons projecting to the basolateral amygdala (aIC-BLA) are indispensable for learning and retrieving learned taste aversion. Kolatt Chandran et al. demonstrate that the intrinsic properties of aIC-BLA neurons, represent the certainty of taste valence prediction, but not percept. Predictive valence-specific changes are reflected through excitability, being low when taste outcome is highly predictive (i.e., following aversive taste memory retrieval or unreinforced familiarization), and high when taste valence is uncertain (i.e., following novelty or aversive taste memory extinction). In addition, the results propose a neuronal mechanism underlying the long delay between taste and visceral discomfort in conditioned taste aversion.}, } @article {pmid36571995, year = {2022}, author = {Yuan, Y and Yan, Z and Lao, Q and Jiang, N and Wu, S and Lu, Q and Han, J and Zhao, S}, title = {Discovery of a potent and long-acting Xenopus GLP-1-based GLP-1/glucagon/Y2 receptor triple agonist.}, journal = {European journal of medicinal chemistry}, volume = {247}, number = {}, pages = {115036}, doi = {10.1016/j.ejmech.2022.115036}, pmid = {36571995}, issn = {1768-3254}, abstract = {The combination of incretin-based therapies and PYY analogue has shown great potential for the treatment of type 2 diabetes (T2DM) and obesity. In this study we developed the first example of a unimolecular triple agonist peptide to simultaneously target GLP-1, glucagon and Y2 receptors, aiming for superior weight loss and better glycemic control. The strategy for constructing such a unimolecular triple agonist peptide is the conjugation of the GLP-1R/GCGR dual-agonistic moiety and PYY moiety via maleimide-thiol specific reaction. A novel triple agonist peptide, 3b, was identified via stepwise structure optimization, long-acting modification and in vitro receptor screens. Peptide 3b exhibited potent and balanced GCGR and GLP-1R activities as well as potent and highly selective Y2R activity. Peptide 3b potently reduced food intake without triggering nausea associated behavior in kaolin consumption and conditioned taste aversion assays. In diet induced obesity (DIO) mice, a lower dose of 3b achieved significantly better effects on lipid metabolism, body weight, and glycemic control than higher dose of GLP-1R mono-agonist, GLP-1R/GCGR dual agonist and GLP-1R/Y2R dual agonist counterparts. Collectively, these data support the therapeutic potential of our GLP-1R/GCGR/Y2R triple agonist 3b as a novel anti-obesity and anti-diabetic agent. Targeting GLP-1R, GCGR and Y2R with unimolecular triple agonist peptide offers a route to develop new obesity and T2DM treatments.}, } @article {pmid36563678, year = {2022}, author = {Lavi, A and Sehgal, M and de Sousa, AF and Ter-Mkrtchyan, D and Sisan, F and Luchetti, A and Okabe, A and Bear, C and Silva, AJ}, title = {Local memory allocation recruits memory ensembles across brain regions.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2022.11.018}, pmid = {36563678}, issn = {1097-4199}, abstract = {Memories are thought to be stored in ensembles of neurons across multiple brain regions. However, whether and how these ensembles are coordinated at the time of learning remains largely unknown. Here, we combined CREB-mediated memory allocation with transsynaptic retrograde tracing to demonstrate that the allocation of aversive memories to a group of neurons in one brain region directly affects the allocation of interconnected neurons in upstream brain regions in a behavioral- and brain region-specific manner in mice. Our analysis suggests that this cross-regional recruitment of presynaptic neurons is initiated by downstream memory neurons through a retrograde mechanism. Together with statistical modeling, our results indicate that in addition to the anterograde flow of information between brain regions, the establishment of interconnected, brain-wide memory traces relies on a retrograde mechanism that coordinates memory ensembles at the time of learning.}, } @article {pmid36548243, year = {2022}, author = {Gore-Langton, JK and Varlinskaya, EI and Werner, DF and , }, title = {Ethanol-induced conditioned taste aversion and associated neural activation in male rats: Impact of age and adolescent intermittent ethanol exposure.}, journal = {PloS one}, volume = {17}, number = {12}, pages = {e0279507}, doi = {10.1371/journal.pone.0279507}, pmid = {36548243}, issn = {1932-6203}, abstract = {Individuals that initiate alcohol use at younger ages and binge drink during adolescence are more susceptible to developing alcohol use disorder. Adolescents are relatively insensitive to the aversive effects of alcohol and tend to consume significantly more alcohol per occasion than adults, an effect that is conserved in rodent models. Adolescent typical insensitivity to the aversive effects of alcohol may promote greater alcohol intake by attenuating internal cues that curb its consumption. Attenuated sensitivity to the aversive effects of alcohol is also retained into adulthood following protracted abstinence from adolescent intermittent ethanol (AIE) exposure. Despite these effects, much remains unknown regarding the neural contributors. In the present study, we used a conditioned taste aversion (CTA) paradigm to investigate neuronal activation in late-developing forebrain structures of male adolescents and adult cFos-LacZ transgenic rats as well as in AIE adults following consumption of 0.9% sodium chloride previously paired with an intraperitoneal injection of 0, 1.5 or 2.5 g/kg of ethanol. Adults that were non-manipulated or received water exposure during adolescence showed CTA to both ethanol doses, whereas adolescents displayed CTA only to the 2.5 g/kg ethanol dose. Adults who experienced AIE did not show CTA. Adults displayed increased neuronal activation indexed via number of β-galactosidase positive (β-gal+) cells in the prefrontal and insular cortex that was absent in adolescents, whereas adolescents but not adults had a reduced number of β-gal+ cells in the central amygdala. Adults also displayed greater cortical-insular functional connectivity than adolescents as well as insular-amygdalar and prefrontal cortex-accumbens core functional connectivity. Like adolescents, adults previously exposed to AIE displayed reduced prefrontal-insular cortex and prefrontal-accumbal core functional connectivity. Taken together, these results suggest that attenuated sensitivity to the aversive effects of ethanol is related to a loss of an insular-prefrontal cortex-accumbens core circuit.}, } @article {pmid36509179, year = {2022}, author = {Kikuchi, E and Inui, T and Su, S and Sato, Y and Funahashi, M}, title = {Chemogenetic inhibition of the bed nucleus of the stria terminalis suppresses the intake of a preferable and learned aversive sweet taste solution in male mice.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {114253}, doi = {10.1016/j.bbr.2022.114253}, pmid = {36509179}, issn = {1872-7549}, abstract = {Conditioned taste aversion (CTA) is established by pairing a taste solution as a conditioned stimulus (CS) with visceral malaise as an unconditioned stimulus (US). CTA decreases the taste palatability of a CS. The bed nucleus of the stria terminalis (BNST) receives taste inputs from the brainstem. However, the involvement of the BNST in CTA remains unclear. Thus, this study examined the effects of chemogenetic inhibition of the BNST neurons on CS intake after CTA acquisition. An adeno-associated virus was microinjected into the BNST of male C57/BL6 mice to induce the inhibitory designer receptor hM4Di. The mice received a pairing of 0.2% saccharin solution (CS) with 0.3M lithium chloride (2% BW, intraperitoneal). After conditioning, the administration of clozapine-N-oxide (CNO, 1mg/kg) significantly enhanced the suppression of CS intake on the retrieval of CTA compared with its intake following saline administration (p < 0.01). We further assessed the effect of BNST neuron inhibition on the intake of water and taste solutions (saccharin, sucralose, sodium chloride, monosodium glutamate, quinine hydrochloride, and citric acid) using naïve (not learned CTA) mice. CNO administration significantly decreased the intake of saccharin and sucralose (p < 0.05). Our results indicate that BNST neurons mediate sweet taste and regulate sweet intake, regardless of whether sweets should be ingested or rejected. BNST neurons may be inhibited in the retrieval of CTA, thereby suppressing CS intake.}, } @article {pmid36508476, year = {2022}, author = {Hatakeyama, D and Chikamoto, N and Fujimoto, K and Kitahashi, T and Ito, E}, title = {Comparison between relative and absolute quantitative real-time PCR applied to single-cell analyses: Transcriptional levels in a key neuron for long-term memory in the pond snail.}, journal = {PloS one}, volume = {17}, number = {12}, pages = {e0279017}, doi = {10.1371/journal.pone.0279017}, pmid = {36508476}, issn = {1932-6203}, abstract = {Quantitative real-time PCR (qPCR) is a powerful method for measuring nucleic acid levels and quantifying mRNA levels, even in single cells. In the present study, we compared the results of single-cell qPCR obtained by different quantification methods (relative and absolute) and different reverse transcription methods. In the experiments, we focused on the cerebral giant cell (CGC), a key neuron required for the acquisition of conditioned taste aversion in the pond snail Lymnaea stagnalis, and examined changes in the mRNA levels of 3 memory-related genes, cAMP-response element binding proteins (LymCREB1 and LymCREB2) and CREB-binding protein (LymCBP), during memory formation. The results obtained by relative quantification showed similar patterns for the 3 genes. For absolute quantification, reverse transcription was performed using 2 different methods: a mixture of oligo d(T) primers and random primers (RT method 1); and gene-specific primers (RT method 2). These methods yielded different results and did not show consistent changes related to conditioning. The mRNA levels in the samples prepared by RT method 2 were up to 3.3 times higher than those in samples prepared by RT method 1. These results suggest that for qPCR of single neurons, the efficacy and validity do not differ between relative and absolute quantification methods, but the reverse transcription step critically influences the results of mRNA quantification.}, } @article {pmid36444166, year = {2022}, author = {Al-Kuraishy, HM and Al-Gareeb, AI and Alexiou, A and Papadakis, M and Nadwa, EH and Albogami, SM and Alorabi, M and Saad, HM and Batiha, GE}, title = {Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure.}, journal = {Journal of diabetes}, volume = {}, number = {}, pages = {}, doi = {10.1111/1753-0407.13334}, pmid = {36444166}, issn = {1753-0407}, abstract = {Type 2 diabetes mellitus (T2DM) is a chronic endocrine disorder due to the reduction of insulin sensitivity and relative deficiency of insulin secretion. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta (TGF-β) superfamily and was initially identified as macrophage inhibitory cytokine-1 (MIC-1). GDF15 is considered a cytokine with an anti-inflammatory effect and increases insulin sensitivity, reduces body weight, and improves clinical outcomes in diabetic patients. GDF15 acts through stimulation of glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), which is highly expressed in the brain stem to induce taste aversion. Metformin belongs to the group of biguanides that are derived from the plant Galega officinalis. It is interesting to note that metformin is an insulin-sensitizing agent used as a first-line therapy for T2DM that has been shown to increase the circulating level of GDF15. Thus, the present review aims to determine the critical association of the GDF15 biomarker in T2DM and how metformin agents affect it. This review illustrates that metformin activates GDF15 expression, which reduces appetite and leads to weight loss in both diabetic and nondiabetic patients. However, the present review cannot give a conclusion in this regard. Therefore, experimental, preclinical, and clinical studies are warranted to confirm the potential role of GDF15 in T2DM patients.}, } @article {pmid36439968, year = {2022}, author = {Panayi, MC and Killcross, S}, title = {Outcome devaluation by specific satiety disrupts sensory-specific Pavlovian-to-instrumental transfer.}, journal = {Frontiers in behavioral neuroscience}, volume = {16}, number = {}, pages = {983480}, pmid = {36439968}, issn = {1662-5153}, abstract = {Reward predictive cues can selectively motivate instrumental behaviors that predict the same rewarding outcomes, an effect known as specific Pavlovian-to-instrumental transfer (PIT). This selective effect is thought to be mediated by a representation of the sensory specific properties of an outcome, that has become associated with both the Pavlovian cue and the instrumental response during initial learning. Specific satiety is a common method of outcome devaluation that reduces an outcome's value but might also lead to the habituation of the outcome's sensory properties. Previous research has demonstrated that specific PIT is insensitive to changes in specific outcome value following taste aversion devaluation, as well as general satiety manipulations, and therefore specific satiety should not disrupt specific PIT by reducing outcome value. The present rodent experiments used a specific satiety devaluation procedure immediately prior to a specific PIT test to show that habituation of these outcome specific sensory representations can disrupt its efficacy as a stimulus and abolish the specific PIT effect. Experiment 1 employed a two-lever choice test to show that a non-devalued stimulus supports specific PIT, whereas a devalued stimulus abolished the specific PIT effect. Experiment 2 replicated this procedure while controlling for response competition by using a single-lever test to confirm that a devalued stimulus abolishes the specific PIT effect. These findings demonstrate that specific satiety can disrupt the ability of an outcome specific representation to support specific PIT. Given previous findings that specific PIT is insensitive to changes in outcome value by general satiety and taste aversion devaluation, this suggests that specific satiety devaluation might disrupt the use of sensory specific outcome representations to guide behavior via a mechanism that is independent of the outcome's current value.}, } @article {pmid36382058, year = {2022}, author = {Yoshida, Y and Tanaka, R and Fujishiro, S and Nishimura, S and Tabata, S and Kawabata, F}, title = {Conditioned Taste Aversion to L-Amino Acid Taste Stimuli and Oral Transcriptional Changes to Type 1 Taste Receptors T1R1 and T1R3 on Chronic Exposure to L-Alanine Solution in Chickens.}, journal = {The journal of poultry science}, volume = {59}, number = {4}, pages = {348-356}, pmid = {36382058}, issn = {1349-0486}, abstract = {Elucidating taste sensing systems in chickens is an important step toward understanding poultry nutrition. Amino acid taste receptors, type 1 taste receptors 1 and 3 (T1R1 and T1R3, respectively), are expressed in chicken taste cells, and chicken T1R1/T1R3 is activated by L-alanine (L-Ala) and L-serine (L-Ser), but not by L-proline (L-Pro). However, it is not clear whether chickens have a gustatory perception of L-amino acids. Here, we found that chickens conditioned to avoid either L-Ala, L-Ser, or L-Pro solutions could successfully learn to avoid the corresponding L-amino acid solution in the conditioned taste aversion (CTA) test. Because CTA is a well-established learning paradigm generated specifically by pairing gustatory perception and gastrointestinal malaise, the present study suggests that chickens can sense L-amino acids by gustatory perception. In addition, we found that the expression of the T1R1 and T1R3 genes was significantly downregulated in response to chronic exposure to L-Ala solution, but not to acute oral stimulation. Taken together, the present study suggests that chickens have a gustatory perception of L-amino acids, and the expression of T1R1/T1R3 mRNAs in the oral cavity can be regulated by L-amino acid intake. Since chickens can detect L-Pro solutions, additional amino acid receptors, other than T1R1/T1R3, may be involved in L-amino acid taste detection in chickens.}, } @article {pmid36368526, year = {2022}, author = {Reich, N and Hölscher, C}, title = {Beyond appetite: Acylated ghrelin as a learning, memory and fear behavior-modulating hormone.}, journal = {Neuroscience and biobehavioral reviews}, volume = {143}, number = {}, pages = {104952}, doi = {10.1016/j.neubiorev.2022.104952}, pmid = {36368526}, issn = {1873-7528}, mesh = {Humans ; *Ghrelin/metabolism ; *Memory/physiology ; Appetite ; Fear/physiology ; Amygdala/physiology ; Hippocampus/physiology ; }, abstract = {Although often referred to as a hunger hormone, recent evidence highlights a neuroprotective function of acylated ghrelin (AG) and a substantial role in the regulation of declarative and aversive memories as well as fear behavior. As such, in this review, we i) evaluate what specific stages and forms of memory, as well as which respective brain areas are affected by acylated ghrelin, ii) illustrate the plasticity-associated signaling pathways of AG in the hippocampus, also involving memory resolution-enhancing neurogenesis, iii) elucidate how the peptide modulates neurotransmitter systems (glutamate, γ-aminobutyric acid, dopamine, serotonin), iV) clarify the role of AG in conditioned taste aversion, novelty learning and the formation of spatial, recognition, auditory fear, contextual fear and passive avoidance memories in the hippocampus and amygdala as well as V) solve the mystery behind AG, its impact on the 5-HT system, the recently established link to post-traumatic stress disorder and the either fear-suppressing or fear-potentiating effects under neutral and acutely stressed conditions or chronic stress, respectively.}, } @article {pmid36261035, year = {2022}, author = {Staszko, SM and Boughter, JD and Fletcher, ML}, title = {The impact of familiarity on cortical taste coding.}, journal = {Current biology : CB}, volume = {32}, number = {22}, pages = {4914-4924.e4}, pmid = {36261035}, issn = {1879-0445}, support = {R01 DC016833/DC/NIDCD NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Cerebral Cortex/physiology ; *Taste/physiology ; Taste Perception/physiology ; Neurons/physiology ; Recognition, Psychology ; }, abstract = {The role of the gustatory region of the insular cortex in mediating associative taste learning, such as conditioned taste aversion, has been well studied. However, while associative learning plays a role in some taste behaviors, such as avoiding toxins, animals often encounter taste stimuli in their natural environment without explicit consequences. This type of inconsequential experience with sensory stimuli has been studied in other sensory systems, generally with the finding that neuronal responses habituate with repeated sensory exposure. This study sought to determine the effect of taste familiarity on population taste coding in the mouse gustatory cortex (GC). Using microendoscope calcium imaging, we studied the taste responses of visually identifiable neurons over 5 days of taste experience, during which animals could freely choose to consume taste stimuli. We found that the number of active cells in the insular cortex, as well as the number of cells characterized as taste-responsive, significantly decreased as animals became familiar with taste stimuli. Moreover, the magnitude of taste-evoked excited responses increased while inhibited responses decreased with experience. By tracking individual neurons over time, we identified a subpopulation of stable neurons present on all days of the taste familiarity paradigm and further characterized their taste coding properties. The population-level response across these stable cells was distinct for each taste quality when taste stimuli were novel, but population responses for readily consumed stimuli became more correlated as the stimuli became familiar. Overall, these results highlight the effects of familiarity on both taste-specific and non-taste responses in the gustatory cortex.}, } @article {pmid36248606, year = {2022}, author = {López, M and Dwyer, DM and Gasalla, P and Jove, C and Begega, A}, title = {Characterizing Hedonic Responses to Flavors Paired with Internal Pain and Nausea through the Taste Reactivity Test in Rats.}, journal = {Bio-protocol}, volume = {12}, number = {18}, pages = {}, pmid = {36248606}, issn = {2331-8325}, abstract = {Feeding behavior is a complex experience that involves not only sensory (i.e., visual, odor, taste, or texture) but also affective or emotional aspects (i.e., pleasure, palatability, or hedonic value) of foods. As such, behavioral tests that assess the hedonic impact of foods are necessary to fully understand the factors involved in ingestive behavior. In this protocol, we use the taste reactivity (TR) test to characterize the hedonic responses of rats to flavors paired with either lithium chloride-induced nausea or internal pain produced by hypertonic NaCl, two treatments that reduce voluntary consumption. This application of the TR test demonstrates how emetic and non-emetic (somatic pain in particular) treatments produce dissociable patterns of hedonic reactions to fluids: only emetic treatments result in the production of aversive orofacial responses, reflecting conditioned nausea, whereas somatic pain produces immobility, reflecting conditioned fear. Other methods, such as the microstructural analysis of licking behavior, do not reliably distinguish conditioned nausea and fear, a key advantage of the more selective TR procedure. This protocol also contains guidance for adaptation to other species and designs.}, } @article {pmid36190750, year = {2022}, author = {Buabang, EK and Boddez, Y and Wolf, OT and Moors, A}, title = {The role of goal-directed and habitual processes in food consumption under stress after outcome devaluation with taste aversion.}, journal = {Behavioral neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1037/bne0000439}, pmid = {36190750}, issn = {1939-0084}, abstract = {People are more likely to engage in various suboptimal behaviors such as overeating, addictive behaviors, and short-sighted financial decision-making when they are under stress. Traditional dual-process models propose that stress can impair the ability to engage in goal-directed behavior so that people have to rely on habitual behavior. Support for this idea comes from a study by Schwabe and Wolf (2010), in which stressed participants continued to perform a learned instrumental behavior leading to a liquid after the liquid was devalued with a satiation procedure. Based on these findings, suboptimal behavior under stress is often seen as habitual. In the present study, we conducted a conceptual replication of the study by Schwabe and Wolf (2010). Instead of using a satiation procedure to achieve the outcome devaluation, we devalued outcomes through taste aversion. We did not replicate the pattern of findings by Schwabe and Wolf (2010). Our results indicate instead that stressed participants were sensitive to outcome values when the outcomes became truly aversive and hence that their behavior was goal-directed. This suggests either that (a) habitual processes are subject to boundary conditions or (b) the processes responsible for the findings of Schwabe and Wolf (2010) were never habitual to begin with. This may have far-reaching implications for explaining suboptimal behavior under stress in general. (PsycInfo Database Record (c) 2022 APA, all rights reserved).}, } @article {pmid36183862, year = {2022}, author = {Bishnoi, IR and Cloutier, CJ and Tyson, CD and Matic, VM and Kavaliers, M and Ossenkopp, KP}, title = {Infection, learning, and memory: Focus on immune activation and aversive conditioning.}, journal = {Neuroscience and biobehavioral reviews}, volume = {142}, number = {}, pages = {104898}, doi = {10.1016/j.neubiorev.2022.104898}, pmid = {36183862}, issn = {1873-7528}, mesh = {Animals ; *Lipopolysaccharides/pharmacology ; *Avoidance Learning ; Lithium Chloride/pharmacology ; Behavior, Animal/physiology ; Conditioning, Psychological/physiology ; Taste ; }, abstract = {Here we review the effects of immune activation primarily via lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, on hippocampal and non-hippocampal-dependent learning and memory. Rodent studies have found that LPS alters both the acquisition and consolidation of aversive learning and memory, such as those evoking evolutionarily adaptive responses like fear and disgust. The inhibitory effects of LPS on the acquisition and consolidation of contextual fear memory are discussed. LPS-induced alterations in the acquisition of taste and place-related conditioned disgust memory within bottle preference tasks and taste reactivity tests (taste-related), in addition to conditioned context avoidance tasks and the anticipatory nausea paradigm (place-related), are highlighted. Further, conditioned disgust memory consolidation may also be influenced by LPS-induced effects. Growing evidence suggests a central role of immune activation, especially pro-inflammatory cytokine activity, in eliciting the effects described here. Understanding how infection-induced immune activation alters learning and memory is increasingly important as bacterial and viral infections are found to present a risk of learning and memory impairment.}, } @article {pmid36056214, year = {2022}, author = {Liu, J and Wu, R and Johnson, B and Zhang, Y and Zhu, Q and Li, JX}, title = {Selective TAAR1 agonists induce conditioned taste aversion.}, journal = {Psychopharmacology}, volume = {239}, number = {10}, pages = {3345-3353}, pmid = {36056214}, issn = {1432-2072}, support = {R01DA034806/DA/NIDA NIH HHS/United States ; R21DA040777/DA/NIDA NIH HHS/United States ; R01DA034806/DA/NIDA NIH HHS/United States ; R21DA040777/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; *Antipsychotic Agents/chemistry/pharmacology ; Aversive Agents/chemistry/pharmacology ; Humans ; Mammals ; Oxazoles ; Phenethylamines/pharmacology ; Rats ; *Receptors, G-Protein-Coupled/agonists ; Saccharin/pharmacology ; Sodium Chloride ; Taste/drug effects ; *Taste Perception/drug effects ; }, abstract = {RATIONALE: Trace amine-associated receptor 1 (TAAR1) is the best-studied receptor of trace amines, a group of biogenic amines expressed at a relatively low level in the mammalian brain. Growing evidence suggests that TAAR1 plays a critical role in various neuropsychiatric disorders. Given that selective TAAR1 agonists were shown to produce pro-cognition and antipsychotic-like effects as well as to suppress drug use and relapse, they have been proposed to be novel treatments for mental disorders such as schizophrenia and addiction. However, the aversive effects of selective TAAR1 agonists remain largely unknown.

OBJECTIVES: Here, we evaluated whether the selective TAAR1 full agonist RO5166017 and partial agonist RO5263397 could induce conditioned taste aversion (CTA).

RESULTS: We found that RO5166017 and RO5263397 produced significant aversions to both saccharin and NaCl taste novelty. Furthermore, RO5166017 produced CTA to saccharin in TAAR1 heterozygous knockout (taar1[±]) and wild-type rats but not in TAAR1 homozygous knockout rats (taar1[-/-]), suggesting that TAAR1 was sufficient for the taste aversive stimulus property of RO5166017.

CONCLUSIONS: Taken together, our data indicate that selective TAAR1 agonists could produce strong CTA. Our study urges careful evaluations of the aversive effects of TAAR1 agonists before translating them to clinical use for the treatment of mental disorders.}, } @article {pmid35944659, year = {2022}, author = {Niedringhaus, M and West, EA}, title = {Prelimbic cortex neural encoding dynamically tracks expected outcome value.}, journal = {Physiology & behavior}, volume = {256}, number = {}, pages = {113938}, doi = {10.1016/j.physbeh.2022.113938}, pmid = {35944659}, issn = {1873-507X}, support = {R00 DA042934/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Cerebral Cortex ; *Conditioning, Classical ; Cues ; Extinction, Psychological ; Rats ; *Reward ; }, abstract = {Animals must modify their behavior based on updated expected outcomes in a changing environment. Prelimbic cortex (PrL) neural encoding during learning predicts, and is necessary for, appropriately altering behavior based on a new expected outcome value following devaluation. We aimed to determine how PrL neural activity encodes reward predictive cues after the expected outcome value of those cues is decreased following conditioned taste aversion. In one post-devaluation session, rats were tested under extinction to determine their ability to alter their behavior to the expected outcome values (i.e., extinction test). In a second post-devaluation session, rats were tested with the newly devalued outcome delivered so that the rats experienced the updated outcome value within the session (i.e., re-exposure test). We found that PrL neural encoding of the cue associated with the devalued reward predicted the ability of rats to suppress behavior in the extinction test session, but not in the re-exposure test session. While all rats were able to successfully devalue the outcome during conditioned taste aversion, a subset of rats continued to consume the devalued outcome in the re-exposure test session. We found differential patterns of PrL neural encoding in the population of rats that did not avoid the devalued outcome during the re-exposure test compared to the rats that successfully avoided the devalued outcome. Our findings suggest that PrL neural encoding dynamically tracks expected outcome values, and differential neural encoding in the PrL to reward predictive cues following expected outcome value changes may contribute to distinct behavioral phenotypes.}, } @article {pmid35931277, year = {2022}, author = {Ascencio Gutierrez, V and Carrillo, AA and Boersma, GJ and Tamashiro, KLK and Moran, TH and Iñiguez, SD and Treesukosol, Y}, title = {Effect of early-life stress or fluoxetine exposure on later-life conditioned taste aversion learning in Sprague-Dawley rats.}, journal = {Neuroscience letters}, volume = {787}, number = {}, pages = {136818}, doi = {10.1016/j.neulet.2022.136818}, pmid = {35931277}, issn = {1872-7972}, support = {R16 GM145552/GM/NIGMS NIH HHS/United States ; SC2 GM109811/GM/NIGMS NIH HHS/United States ; }, mesh = {*Adverse Childhood Experiences ; Animals ; Avoidance Learning ; Body Weight ; *Fluoxetine/pharmacology ; Lithium Chloride/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Saccharin ; Taste ; }, abstract = {In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35-48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.}, } @article {pmid35918017, year = {2022}, author = {Tachibana, T and Nakatani, A and Khan, S and Makino, R and Cline, MA}, title = {Effect of lithium chloride on food intake, cloacal temperature, voluntary activity, and crop-emptying rate in chicks.}, journal = {Comparative biochemistry and physiology. Part A, Molecular & integrative physiology}, volume = {273}, number = {}, pages = {111284}, doi = {10.1016/j.cbpa.2022.111284}, pmid = {35918017}, issn = {1531-4332}, mesh = {Animals ; Anorexia ; *Chickens/physiology ; Eating ; Lipopolysaccharides/pharmacology ; Lithium/pharmacology ; *Lithium Chloride/pharmacology ; Mammals ; Taste ; Temperature ; Zymosan/pharmacology ; }, abstract = {Infections frequently accompany with non-specific symptoms such as anorexia and hyperthermia. In addition, there may be unpleasant sensations such as visceral discomfort during infection. Lipopolysaccharide (LPS), a Gram-negative bacteria cell wall component, is known to induce the unpleasant sensation of conditioned taste aversion in mammals. However, the relationship between unpleasant sensations and changes in behavior and physiological conditions has not been investigated extensively in birds. Lithium chloride (LiCl) is a compound that induces unpleasant sensations, including visceral discomfort, although its effects on behavior and physiological conditions have also not been investigated extensively in birds. Thus, the present study was aimed to investigate the effect of an intraperitoneal (IP) injection of LiCl on conditioned visual aversion, food intake, cloacal temperature, voluntary activity, crop-emptying rate, and blood constituents in chicks (Gallus gallus). We also examined the effect of IP injections of LPS and zymosan, a cell wall component of fungus, on conditioned visual aversion formation. First, IP injection of LiCl was confirmed to induce conditioned visual aversion in chicks. An IP injection of LiCl significantly decreased food intake, voluntary activity, and crop-emptying rate but did not affect the temperature. In addition, the injection of LiCl significantly increased plasma corticosterone concentration, indicating that LiCl serves as a stressor in chicks. Finally, IP injections of LPS and zymosan were found to induce conditioned visual aversion in chicks. Collectively, these results suggest that LiCl induces conditioned aversion, anorexia, hypoactivity, and inhibition of crop-emptying in chicks. In addition, LPS and zymosan would induce unpleasant sensations in chicks.}, } @article {pmid35913117, year = {2022}, author = {Bai, L and Sivakumar, N and Yu, S and Mesgarzadeh, S and Ding, T and Ly, T and Corpuz, TV and Grove, JCR and Jarvie, BC and Knight, ZA}, title = {Enteroendocrine cell types that drive food reward and aversion.}, journal = {eLife}, volume = {11}, number = {}, pages = {}, pmid = {35913117}, issn = {2050-084X}, support = {RF1 NS116626/NS/NINDS NIH HHS/United States ; R01 DK106399/DK/NIDDK NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Animals ; Cholecystokinin/metabolism ; *Enteroendocrine Cells/metabolism ; *Food ; Food Preferences ; Mice ; Reward ; Taste ; }, abstract = {Animals must learn through experience which foods are nutritious and should be consumed, and which are toxic and should be avoided. Enteroendocrine cells (EECs) are the principal chemosensors in the GI tract, but investigation of their role in behavior has been limited by the difficulty of selectively targeting these cells in vivo. Here, we describe an intersectional genetic approach for manipulating EEC subtypes in behaving mice. We show that multiple EEC subtypes inhibit food intake but have different effects on learning. Conditioned flavor preference is driven by release of cholecystokinin whereas conditioned taste aversion is mediated by serotonin and substance P. These positive and negative valence signals are transmitted by vagal and spinal afferents, respectively. These findings establish a cellular basis for how chemosensing in the gut drives learning about food.}, } @article {pmid35878079, year = {2022}, author = {Sánchez, J and Dwyer, DM and Honey, RC and de Brugada, I}, title = {Perceptual learning after rapidly alternating exposure to taste compounds: Assessment with different indices of generalization.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {48}, number = {3}, pages = {169-178}, doi = {10.1037/xan0000333}, pmid = {35878079}, issn = {2329-8464}, support = {/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Association Learning/physiology ; Conditioning, Classical ; *Discrimination Learning ; Generalization, Psychological ; Humans ; Learning ; Male ; Rats ; *Taste/physiology ; }, abstract = {Exposure to two similar stimuli (AX and BX; e.g., two tastes) reduces the extent to which a conditioned response later established to BX generalizes to AX. This example of perceptual learning is more evident when AX and BX are exposed in an alternating manner (AX, BX, AX, BX,…) than when AX and BX occur in separate blocks (e.g., AX, AX,…BX, BX,…). We examined in male rats (N = 126) the impact of rapid alternation to AX and BX on generalization of a taste aversion from BX to AX. Experiment 1 showed that such alternating presentations (with 5-min intervals between AX and BX) reduced generalization relative to blocked exposure; but only as assessed by consumption levels and not by lick cluster size (an index of hedonic reactions). Experiment 1 also showed that the nature of exposure did not affect how A influenced performance to a novel conditioned taste, Y. Experiment 2 replicated the pattern of results involving the different influences of rapidly alternating and blocked exposure on generalization from BX to AX, and showed that this effect was only evident when rats received access to water during the 5-min intervals between AX and BX. These results reinforce parallels between perceptual learning effects in rats and humans, both at empirical and theoretical levels. (PsycInfo Database Record (c) 2022 APA, all rights reserved).}, } @article {pmid35864815, year = {2022}, author = {Shanmugamprema, D and Muthuswamy, K and Ponnusamy, V and Subramanian, G and Velusamy, T and Krishnan, V and Subramaniam, S}, title = {CD36 and GPR120 mediated orogustatory perception of dietary lipids and its physiological implication in the pygmy mouse Mus booduga.}, journal = {Journal of animal physiology and animal nutrition}, volume = {106}, number = {6}, pages = {1408-1419}, doi = {10.1111/jpn.13755}, pmid = {35864815}, issn = {1439-0396}, mesh = {Mice ; Animals ; *Taste Buds/metabolism ; Dietary Fats/metabolism ; CD36 Antigens/genetics/metabolism ; Taste Perception/genetics ; Taste ; Linoleic Acid/metabolism ; Receptors, G-Protein-Coupled/metabolism ; }, abstract = {Fat taste perception has long been concerned in the regulation of dietary fat intake. Substantial experimental evidence defends fat as a sixth taste modality, but its allied peripheral mechanisms are not yet well established. The present study aimed to analyse the diet-induced changes in fat taste perception and its associated physiological variations in Mus booduga. Four groups of animals were used for the present study and were fed any one of the following diet; normal diet (10% fat), low-fat diet (4% fat), high-fat diet (36% fat), or high-fat diet (HFD) (36% fat) + rapeseed oil (HFRDO) (14%) for 9 weeks. The animals were then subjected to metabolic tolerance, fat preference, and conditioned taste aversion studies. Diet-induced alterations in the expression of genes associated with lipogenesis, inflammation, and fat taste (CD36 and GPR120) were analysed. Capacitative calcium signalling induced by both linoleic acid and grifolic acid in taste bud cells (TBCs) was also analysed. In result, both the HFD and HFDRO groups revealed deterioration in glucose homoeostasis and displayed decreased preference scores for fatty acids, which are associated with lower CD36 expression and increased GPR120 expression in TBCs. Furthermore, change in [Ca[2+] ]i induced by LA was also compromised in CD36 positive TBCs along with elevated systemic inflammatory and lipidemic responses in both these obese groups. Overall, for the first time, our results support that chronic HFD feeding alters the CD36 and GPR120 mediated fat taste perception in M. booduga.}, } @article {pmid35784020, year = {2022}, author = {Aiyer, A and Bunuba Rangers, and Bell, T and Shine, R and Somaweera, R and Bruny, M and Ward-Fear, G}, title = {Taking the bait: Developing a bait delivery system to target free-ranging crocodiles and varanid lizards with a novel conservation strategy.}, journal = {Ecology and evolution}, volume = {12}, number = {6}, pages = {e8933}, pmid = {35784020}, issn = {2045-7758}, abstract = {In tropical Australia, conditioned taste aversion (CTA) can buffer vulnerable native predators from the invasion of a toxic prey species (cane toads, Rhinella marina). Thus, we need to develop methods to deploy aversion-inducing baits in the field, in ways that maximize uptake by vulnerable species (but not other taxa). We constructed and field-tested baiting devices, in situ with wild animals. Apparatus were set next to waterbodies and baited concurrently at multiple locations (over water, water's edge, and on the bank). Baits were checked and replaced twice daily during the trial; remote cameras recorded visitation by native predators. Bait longevity was compared at sun-exposed and shaded locations over 12 h. The strength required to remove baits from apparatus was measured in varanids and crocodiles. The device promoted high rates of bait uptake by freshwater crocodiles (47% baits consumed), varanid lizards (19% baits consumed), and non-target taxa (34% baits consumed). Targeting specific predators can be achieved by manipulating bait location and time of deployment, as well as the force required to dislodge the bait. Crocodiles were best targeted with over-water baits, whereas varanid lizards preferred baits located at the edges of waterbodies. When testing bait longevity in ambient conditions, during the daytime baits desiccated fully within 12 h, and faster in the sun than in the shade. Based on studies using captive animals, the "pulling force" strength of reptilian predators scaled with body size and was greater in crocodiles than in varanid lizards. We present the first conservation baiting protocol designed specifically for reptiles. Our results demonstrate the feasibility of widespread and taxon-specific deployment of aversion-inducing baits to buffer the impacts of invasive cane toads, and our methods are applicable (with modification) to other research and management programs globally.}, } @article {pmid35762652, year = {2022}, author = {Sun, H and Li, J and Yan, J and Sun, B and Wei, X and Song, L and Yan, J}, title = {Decreased taste sensitivity to sucrose in dopamine D3 receptor mutant mice.}, journal = {Chemical senses}, volume = {47}, number = {}, pages = {}, doi = {10.1093/chemse/bjac014}, pmid = {35762652}, issn = {1464-3553}, mesh = {Animals ; *Dysgeusia/genetics ; Mice ; RNA, Messenger/genetics ; *Receptors, Dopamine D3/genetics ; Sucrose/pharmacology ; *Taste/physiology ; *Taste Buds/metabolism ; }, abstract = {Dopamine plays a key role in food rewards and sweet-taste stimulation. We examined the basis for behavioral responses to sweet taste in dopamine D3 receptor-deficient (D3-/-) mice by determining whether the absence of D3 receptors affects the sensitivity to dilute sucrose solutions. In experiment 1, we measured the intensity generalization threshold of conditioned taste aversion (CTA) to a 0.2 M sucrose solution. Results showed that the generalization thresholds were 0.025-0.05 M in D3-/- mice and 0.0025-0.005 M in wild-type (WT) mice. In experiment 2, we found that D3-/- and WT mice had similar capabilities to form and extinguish CTAs. Since the intensity generalization threshold is mainly due to a combination of sweet-taste sensitivity and the robust nature of CTA formation, the results showed that taste sensitivity to sucrose in D3-/- mice was lower than that in WT mice. In experiment 3, to test whether the peripheral sensory signaling may also be affected by the disruption of the dopamine D3 receptors, the mRNA expression levels of sweet-taste-related proteins in taste buds of D3-/- mice were determined. The T1R1 and BDNF mRNA expression levels in D3-/- mice were higher than the controls, whereas T1R2, T1R3, α-gustducin, and TRPM5 mRNA were similar. These findings suggest that disruption of dopamine D3 receptor-mediated signaling decreases the sweet-taste sensitivity and alters the mRNA expression levels of some taste-related molecules.}, } @article {pmid35697908, year = {2022}, author = {Lyu, H and Mizunami, M}, title = {Conditioned taste aversion in the cricket Gryllus bimaculatus.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {9751}, pmid = {35697908}, issn = {2045-2322}, mesh = {Animals ; Avoidance Learning ; *Conditioning, Classical ; Lithium Chloride/pharmacology ; Mammals ; Sucrose/pharmacology ; *Taste ; }, abstract = {Conditioned taste aversion (CTA) is a form of classical conditioning in which animals associate the taste of a food with illness caused by toxin contained in the food. CTA in mammals is achieved with a long interval of up to several hours between food ingestion and illness induced by LiCl injection. Insects also exhibit CTA, but not much is known about its features. We investigated whether the cricket Gryllus bimaculatus exhibits CTA when ingestion of a sugar solution is followed by LiCl injection. Crickets that ingested sucrose solution 5-10 min before LiCl injection exhibited reduction of sucrose consumption tested 24 or 48 h after injection compared to that tested 24 h before injection. In contrast, crickets that ingested sucrose solution 5-10 min after LiCl injection or 1 h or 8 h before or after injection did not exhibit reduction of sucrose consumption, indicating that reduction of sucrose consumption by CTA training is pairing-specific. We conclude that CTA in crickets is similar to that in mammals in that one-trial pairing is sufficient to achieve memory retention for days, but it differs in that it is achieved with a relatively short interval (< 1 h) between food ingestion and toxin injection.}, } @article {pmid35679998, year = {2022}, author = {Reyes-García, SE and Gutiérrez-Vera, B and Escobar, ML}, title = {Calcineurin requirement for in vivo insular cortex LTD and CTA-extinction.}, journal = {Neurobiology of learning and memory}, volume = {193}, number = {}, pages = {107647}, doi = {10.1016/j.nlm.2022.107647}, pmid = {35679998}, issn = {1095-9564}, mesh = {Animals ; *Avoidance Learning/physiology ; *Calcineurin/metabolism ; Cerebral Cortex/physiology ; Insular Cortex ; Male ; Rats ; Rats, Wistar ; Taste/physiology ; }, abstract = {Currently, it is widely accepted that memory extinction involves the formation of a new associative memory rather than unlearning of the information previously acquired. Nonetheless, the cellular and molecular mechanisms underlying this process are still unclear. In this regard, it has been suggested that while kinases modulate conditioning and LTP, phosphatases are relevant for extinction and LTD. In particular, the protein phosphatase calcineurin (CaN) has been involved in the extinction of some behavioral tasks along with LTD. Indeed, studies of our research group have demonstrated that induction of LTD in the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) pathway facilitates the extinction of conditioned taste aversion (CTA), while the induction of LTP in this pathway slows it down. In addition, we have shown that the extinction of CTA elicits an increase of CaN. The aim of the present study was to evaluate the participation of calcineurin in the extinction of CTA and in the expression of in vivo LTD in the Bla-IC pathway. For this purpose, we chemically inhibited calcineurin in the IC of adult male Wistar rats, either during CTA-extinction or thirty minutes after LTD induction in the Bla-IC pathway. Our results show that calcineurin inhibition slows down the CTA-extinction and blocks the maintenance of LTD. Furthermore, we show that CaN levels increase after LTD induction. These findings support the idea that calcineurin is a key molecular actor for both CTA extinction and LTD expression in the IC, a highly relevant neocortical area for the processing of aversively motivated learning tasks, suggesting that both processes are associated at a molecular level.}, } @article {pmid35644274, year = {2022}, author = {Gutiérrez-Vera, B and Rivera-Olvera, A and Escobar, ML}, title = {Environmental enrichment attenuates conditioned taste aversion through the restoration of BDNF levels in the insular cortex.}, journal = {Behavioural brain research}, volume = {430}, number = {}, pages = {113947}, doi = {10.1016/j.bbr.2022.113947}, pmid = {35644274}, issn = {1872-7549}, mesh = {Animals ; Avoidance Learning ; Brain-Derived Neurotrophic Factor/*metabolism ; Cerebral Cortex/physiology ; Insular Cortex ; Rats ; Rats, Wistar ; *Taste ; }, abstract = {It has been shown that exposure to an enriched environment (EE) can modulate the physiological impact of aversive stimuli in animals, promoting adaptive attitudes, as well as the development of resilience to stressful situations. These changes are known to be related to increased levels of some trophic factors, such as brain-derived neurotrophic factor (BDNF), which has been considered a regulatory protein for synaptic plasticity in the adult brain. Our previous studies have demonstrated that in the insular cortex (IC), a brain region of the temporal lobe implicated in the acquisition, consolidation, and retention of conditioned taste aversion (CTA) task, BDNF can reverse the CTA memory deficit caused by a protein synthesis inhibitor. Likewise, our research group have also shown that BDNF is required for the maintenance of CTA long-term memory. Here we evaluate the effects of the exposure to an enriched environment on the CTA memory strength, using a weak and strong version of this paradigm. The exposure to an EE for 21 days was able to attenuate the strong-CTA response through the restoration of BDNF levels in the IC of adult rats. These results provide evidence that environmental enrichment is capable of reducing the strength of an aversive memory trace, restoring the BDNF levels in a neocortical region of the adult brain.}, } @article {pmid35641228, year = {2022}, author = {Jung, AH and King, CT and Blonde, GD and King, M and Griggs, C and Hashimoto, K and Spector, AC and Schier, LA}, title = {A Subregion of Insular Cortex Is Required for Rapid Taste-Visceral Integration and Consequent Conditioned Taste Aversion and Avoidance Expression in Rats.}, journal = {eNeuro}, volume = {9}, number = {4}, pages = {}, pmid = {35641228}, issn = {2373-2822}, support = {R01 DC009821/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; *Avoidance Learning/physiology ; Cerebral Cortex/physiology ; Conditioning, Classical/physiology ; Insular Cortex ; Lithium Chloride/pharmacology ; Rats ; Sucrose ; *Taste/physiology ; }, abstract = {Postingestive signals are important for shaping appetitive and consummatory responses, but the brain mechanisms required to assimilate interoceptive events with those at the frontlines of ingestion (taste-guided) are poorly understood. Here, we investigated whether an insular cortex (IC) region, which receives viscerosensory input, including gustatory, is required to modify taste-elicited consummatory reactions in response to a real-time interoceptive change using a serial taste reactivity (TR) test where the rats' oromotor and somatic reactions to intraoral (IO) infusions of sucrose were periodically assessed over 45 min following lithium chloride (LiCl) administration. Results showed that neurally-intact rats shifted from an ingestive repertoire to an aversive one as LiCl took effect. Overall, this hedonic shift was delayed in rats with bilateral neurotoxic IC lesions. Rats with greater neuronal loss in posterior gustatory IC displayed fewer aversive reactions to sucrose following this initial LiCl injection. We further assessed whether the failure to integrate interoceptive feedback with ongoing taste-guided behavior impaired acquisition and/or expression of conditioned aversion and/or avoidance in these same rats. Although, as a group, LiCl-injected rats with IC lesions subsequently avoided the sugar in a 48-h two-bottle test, their preference for sucrose was significantly greater than that of the LiCl-injected neurally-intact rats. Overall lesion size, as well as proportion of the posterior gustatory and/or anterior visceral IC were each associated with impaired avoidance. These findings reveal new roles for the posterior gustatory and anterior visceral ICs in multisensory integrative function.}, } @article {pmid35558436, year = {2022}, author = {Nakai, J and Chikamoto, N and Fujimoto, K and Totani, Y and Hatakeyama, D and Dyakonova, VE and Ito, E}, title = {Insulin and Memory in Invertebrates.}, journal = {Frontiers in behavioral neuroscience}, volume = {16}, number = {}, pages = {882932}, pmid = {35558436}, issn = {1662-5153}, abstract = {Insulin and insulin-like peptides (ILP) help to maintain glucose homeostasis, whereas insulin-like growth factor (IGF) promotes the growth and differentiation of cells in both vertebrates and invertebrates. It is sometimes difficult to distinguish between ILP and IGF in invertebrates, however, because in some cases ILP has the same function as IGF. In the present review, therefore, we refer to these peptides as ILP/IGF signaling (IIS) in invertebrates, and discuss the role of IIS in memory formation after classical conditioning in invertebrates. In the arthropod Drosophila melanogaster, IIS is involved in aversive olfactory memory, and in the nematode Caenorhabditis elegans, IIS controls appetitive/aversive response to NaCl depending on the duration of starvation. In the mollusk Lymnaea stagnalis, IIS has a critical role in conditioned taste aversion. Insulin in mammals is also known to play an important role in cognitive function, and many studies in humans have focused on insulin as a potential treatment for Alzheimer's disease. Although analyses of tissue and cellular levels have progressed in mammals, the molecular mechanisms, such as transcriptional and translational levels, of IIS function in cognition have been far advanced in studies using invertebrates. We anticipate that the present review will help to pave the way for studying the effects of insulin, ILPs, and IGFs in cognitive function across phyla.}, } @article {pmid35501556, year = {2022}, author = {Bouton, ME and Michaud, NL}, title = {Partial reinforcement effects on acquisition and extinction of a conditioned taste aversion.}, journal = {Learning & behavior}, volume = {50}, number = {3}, pages = {360-371}, pmid = {35501556}, issn = {1543-4508}, support = {R01 DA033123/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; *Avoidance Learning ; Conditioning, Classical ; *Extinction, Psychological ; Humans ; Hylobates ; Lithium Chloride/pharmacology ; Rats ; Reinforcement, Psychology ; }, abstract = {Four experiments with rat subjects asked whether a partial reinforcement extinction effect (PREE) occurs in taste aversion learning. The question has received little attention in the literature, and to our knowledge no taste aversion experiment has previously demonstrated a PREE. In each of the present experiments, experimental groups received a taste mixed in drinking water for 20 min; such taste exposures were sometimes paired with a lithium chloride (LiCl) injection and sometimes not. Control groups received only taste-LiCl pairings. There was evidence that each reinforced and non-reinforced trial produced increments and decrements in aversion strength (respectively), and trials mattered more than accumulated time during the conditioned stimulus and during the background (as emphasized in time-accumulation models like those of Gallistel and Gibbon, Psychological Review, 107, 289-344, 2000, and Gibbon and Balsam, Autoshaping and conditioning theory, Academic Press, New York, pp. 219-235, 1981). In addition, a partial reinforcement extinction effect was observed when there was a relatively large number of conditioning trials. The results extend our understanding of extinction in taste aversion learning and provide more evidence that aversion learning might follow rules that are qualitatively similar to those of other forms of learning.}, } @article {pmid35500755, year = {2022}, author = {Haines, KM and Czachowski, CL}, title = {Evaluating habit formation across pairs of female and male selectively bred alcohol-preferring and non-preferring rats.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {102}, number = {}, pages = {11-22}, doi = {10.1016/j.alcohol.2022.04.003}, pmid = {35500755}, issn = {1873-6823}, support = {P60 AA007611/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking/genetics ; *Alcoholism/genetics ; Animals ; Conditioning, Classical ; *Ethanol ; Female ; Habits ; Male ; Rats ; }, abstract = {Some individuals with alcohol use disorder (AUD) continue to drink because they have developed a habit where they do not consider the consequences of their actions. Genetically selected lines of alcohol-preferring and non-preferring rats allow for exploration of how specific endophenotypes, such as tendency to form habits, may be risk factors that interact with a genetic predisposition of AUD. While high alcohol drinking (HAD) and alcohol-preferring (P) rats were selectively bred to consume high amounts of freely available ethanol, they exhibit differences in alcohol-seeking behaviors as well as impulsive behaviors, and may represent different behavioral models of AUD. The goal of the current study was to compare the tendency to develop habitual behaviors across female and male HAD1, HAD2, and P rats and their respective alcohol non-preferring counterparts. Alcohol-naïve rats were trained on a variable interval schedule using a non-ethanol reinforcer and were then tested in two extinction sessions, one prior to a reinforcer devaluation (conditioned taste aversion) procedure and one after. There were no differences in total lever presses between P and alcohol non-preferring (NP) rats, but there were differences between HAD and low-alcohol drinking (LAD) rats. All six strains decreased lever pressing after reinforcer devaluation. However, P and NP females did not increase latency to first lever press after devaluation, suggesting some inclination toward habitual behavior that was not apparent in either the HAD or LAD lines. Selective breeding for alcohol preference does not seem to influence the tendency to form habits, whereas background strain and sex may have an influence on this behavior.}, } @article {pmid35496768, year = {2022}, author = {Riley, AL and Manke, HN and Huang, S}, title = {Impact of the Aversive Effects of Drugs on Their Use and Abuse.}, journal = {Behavioural neurology}, volume = {2022}, number = {}, pages = {8634176}, pmid = {35496768}, issn = {1875-8584}, mesh = {Humans ; *Reward ; *Substance-Related Disorders/psychology ; Taste ; }, abstract = {Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential.}, } @article {pmid35456614, year = {2022}, author = {Lopalco, A and Manni, A and Keeley, A and Haider, S and Li, W and Lopedota, A and Altomare, CD and Denora, N and Tuleu, C}, title = {In Vivo Investigation of (2-Hydroxypropyl)-β-cyclodextrin-Based Formulation of Spironolactone in Aqueous Solution for Paediatric Use.}, journal = {Pharmaceutics}, volume = {14}, number = {4}, pages = {}, pmid = {35456614}, issn = {1999-4923}, abstract = {Spironolactone (SPL), a potent anti-aldosterone steroidal drug used to treat several diseases in paediatric patients (e.g., hypertension, primary aldosteronism, Bartter's syndrome, and congestive heart failure), is not available in child-friendly dosage forms, and spironolactone liquids have been reported to be unpalatable. Aiming to enhance SPL solubility in aqueous solution and overcome palatability, herein, the effects of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CyD) were thoroughly investigated on solubilisation in water and on masking the unpleasant taste of SPL in vivo. Although the complexation of SPL with HP-β-CyD was demonstrated through phase solubility studies, Job's plot, NMR and computational docking studies, our in vivo tests did not show significant effects on taste aversion. Our findings, on the one hand, suggest that the formation of an inclusion complex of SPL with HP-β-CyD itself is not necessarily a good indicator for an acceptable degree of palatability, whereas, on the other hand, they constitute the basis for investigating other cyclodextrin-based formulations of the poorly water-soluble steroidal drug, including solid dosage forms, such as spray-dried powders and orodispersible tablets.}, } @article {pmid35409269, year = {2022}, author = {Berríos-Cárcamo, P and Quezada, M and Santapau, D and Morales, P and Olivares, B and Ponce, C and Ávila, A and De Gregorio, C and Ezquer, M and Quintanilla, ME and Herrera-Marschitz, M and Israel, Y and Ezquer, F}, title = {A Novel Morphine Drinking Model of Opioid Dependence in Rats.}, journal = {International journal of molecular sciences}, volume = {23}, number = {7}, pages = {}, pmid = {35409269}, issn = {1422-0067}, mesh = {Animals ; Disease Models, Animal ; Morphine/pharmacology ; *Morphine Dependence ; *Opioid-Related Disorders/drug therapy ; Quinine/pharmacology/therapeutic use ; Rats ; Taste ; Water ; }, abstract = {An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants' presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.}, } @article {pmid35360496, year = {2022}, author = {Gil-Lievana, E and Ramírez-Mejía, G and Urrego-Morales, O and Luis-Islas, J and Gutierrez, R and Bermúdez-Rattoni, F}, title = {Photostimulation of Ventral Tegmental Area-Insular Cortex Dopaminergic Inputs Enhances the Salience to Consolidate Aversive Taste Recognition Memory via D1-Like Receptors.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {823220}, pmid = {35360496}, issn = {1662-5102}, abstract = {Taste memory involves storing information through plasticity changes in the neural network of taste, including the insular cortex (IC) and ventral tegmental area (VTA), a critical provider of dopamine. Although a VTA-IC dopaminergic pathway has been demonstrated, its role to consolidate taste recognition memory remains poorly understood. We found that photostimulation of dopaminergic neurons in the VTA or VTA-IC dopaminergic terminals of TH-Cre mice improves the salience to consolidate a subthreshold novel taste stimulus regardless of its hedonic value, without altering their taste palatability. Importantly, the inhibition of the D1-like receptor into the IC impairs the salience to facilitate consolidation of an aversive taste recognition memory. Finally, our results showed that VTA photostimulation improves the salience to consolidate a conditioned taste aversion memory through the D1-like receptor into the IC. It is concluded that the dopamine activity from the VTA into IC is required to increase the salience enabling the consolidation of a taste recognition memory. Notably, the D1-like receptor activity into the IC is required to consolidate both innate and learned aversive taste memories but not appetitive taste memory.}, } @article {pmid35318075, year = {2022}, author = {Salguero, A and Marengo, L and Portillo-Salido, E and Ruiz-Leyva, L and Cendán, CM and Morón, I and Marcos Pautassi, R}, title = {Administration of the sigma-1 receptor agonist PRE-084 at emerging adulthood, but not at early adolescence, attenuated ethanol-induced conditioned taste aversion in female rats.}, journal = {Neuroscience letters}, volume = {778}, number = {}, pages = {136585}, doi = {10.1016/j.neulet.2022.136585}, pmid = {35318075}, issn = {1872-7972}, mesh = {Alcohol Drinking ; Animals ; Avoidance Learning ; *Ethanol/pharmacology ; Female ; Morpholines ; Rats ; Rats, Wistar ; Receptors, sigma ; *Taste ; }, abstract = {Ethanol-induced conditioned taste aversion (CTA) is greater in late adolescence or young adulthood than in early adolescence. The role of the sigma receptor system in this age-related difference has not been extensively explored, particularly in female rats. This study assessed the effects of the activation of sigma-1 receptors (S1-R), via the selective S1-R agonist PRE-084, on ethanol-induced CTA at early or at terminal adolescence/emerging adulthood (28 or 56 days-old at the beginning of the procedures, respectively) in female Wistar rats. The modulation of binge-like ethanol intake by PRE-084 was assessed at terminal adolescence. S1-R activation at the acquisition of ethanol-induced CTA attenuated such learning at terminal but not at early adolescence. PRE-084 did not significantly affect ethanol binge drinking in the terminal adolescents. These results highlight the role of S1-R in ethanol-induced CTA and suggest that differential functionality of this transmitter system may underlie age-specific sensitivities to the aversive effects of ethanol.}, } @article {pmid35295904, year = {2022}, author = {Ramos, R and Wu, CH and Turrigiano, GG}, title = {Strong Aversive Conditioning Triggers a Long-Lasting Generalized Aversion.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {854315}, pmid = {35295904}, issn = {1662-5102}, abstract = {Generalization is an adaptive mnemonic process in which an animal can leverage past learning experiences to navigate future scenarios, but overgeneralization is a hallmark feature of anxiety disorders. Therefore, understanding the synaptic plasticity mechanisms that govern memory generalization and its persistence is an important goal. Here, we demonstrate that strong CTA conditioning results in a long-lasting generalized aversion that persists for at least 2 weeks. Using brain slice electrophysiology and activity-dependent labeling of the conditioning-active neuronal ensemble within the gustatory cortex, we find that strong CTA conditioning induces a long-lasting increase in synaptic strengths that occurs uniformly across superficial and deep layers of GC. Repeated exposure to salt, the generalized tastant, causes a rapid attenuation of the generalized aversion that correlates with a reversal of the CTA-induced increases in synaptic strength. Unlike the uniform strengthening that happens across layers, reversal of the generalized aversion results in a more pronounced depression of synaptic strengths in superficial layers. Finally, the generalized aversion and its reversal do not impact the acquisition and maintenance of the aversion to the conditioned tastant (saccharin). The strong correlation between the generalized aversion and synaptic strengthening, and the reversal of both in superficial layers by repeated salt exposure, strongly suggests that the synaptic changes in superficial layers contribute to the formation and reversal of the generalized aversion. In contrast, the persistence of synaptic strengthening in deep layers correlates with the persistence of CTA. Taken together, our data suggest that layer-specific synaptic plasticity mechanisms separately govern the persistence and generalization of CTA memory.}, } @article {pmid35256559, year = {2022}, author = {Pham, H and Seeley, SL and D'Souza, MS}, title = {Pharmacological activation of kappa opioid receptors in the nucleus accumbens core and ventral tegmental area increases the aversive effects of nicotine.}, journal = {Behavioural pharmacology}, volume = {33}, number = {4}, pages = {266-281}, doi = {10.1097/FBP.0000000000000675}, pmid = {35256559}, issn = {1473-5849}, mesh = {3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology ; Animals ; Nicotine/pharmacology ; Nucleus Accumbens/metabolism ; Rats ; Rats, Wistar ; Receptors, Opioid, kappa/metabolism ; *Tobacco Use Disorder ; *Ventral Tegmental Area ; }, abstract = {Aversive effects of nicotine play an important role in the development of nicotine dependence. However, neural substrates and/or brain regions that play a role in the aversive effects of nicotine have not been fully identified. Previous work done in our laboratory showed that systemic administration of kappa opioid receptors (KORs) agonist ±U50488 increased the aversive effects of nicotine. In this study, we assessed the effects of KOR activation in specific brain regions, namely, the nucleus accumbens (NAcc) core and ventral tegmental area (VTA) on the aversive effects of nicotine using the conditioned taste aversion model. Separate groups of Wistar rats were implanted with cannulae above either the NAcc core or the VTA. KOR agonist (±U50488) was bilaterally infused in the NAcc core (0, 0.3, and 3 ug/0.5 ul/side) or VTA (0, 0.3, 1.5, and 3 ug/0.5 ul/side) prior to receiving nicotine (0.4 mg/kg, base; s.c.) during conditioning. Bilateral infusion of the KOR agonist (3 ug/0.5 ul/side) in the NAcc core or the VTA increased the aversive effects of nicotine compared with respective saline controls. Together, these results suggest that pharmacological activation of the KORs in the NAcc core and VTA dose dependently modulate the aversive effects of nicotine. Because aversive effects of nicotine determine susceptibility to development of nicotine dependence, we can conclude that KOR activity in the NAcc and VTA after administration of nicotine may determine susceptibility to the development of nicotine dependence.}, } @article {pmid35255434, year = {2022}, author = {Han, F and Xu, F and Zhu, Q and Sun, P and Zhou, Y and Yu, M}, title = {Virus-mediated GHS-R1a expression in the basolateral amygdala blocks extinction of conditioned taste aversion memory in rats.}, journal = {Biochemical and biophysical research communications}, volume = {602}, number = {}, pages = {57-62}, doi = {10.1016/j.bbrc.2022.02.105}, pmid = {35255434}, issn = {1090-2104}, mesh = {Animals ; *Avoidance Learning ; *Basolateral Nuclear Complex/metabolism ; Feeding Behavior ; Ghrelin/pharmacology ; Rats ; *Receptors, Ghrelin/metabolism ; Taste/physiology ; }, abstract = {Ghrelin is an orexigenic gastric hormone that promotes feeding behaviors and regulating energy homeostasis in both humans and rodents. Our previous studies have shown that ghrelin, when locally infused into the basolateral amygdala (BLA), blocks both acquisition and extinction of conditioned taste aversion (CTA) memory in rats. In this study, we further investigated the effect of virus-mediated overexpression of ghrelin receptor growth hormone secretagogue receptor 1a (GHS-R1a) in BLA pyramidal neurons on CTA memory processes. We found that upregulation of GHS-R1a expression in BLA pyramidal neurons repressed CTA extinction while it had no effect on CTA acquisition. In addition, we reported that local infusion of the endogenous GHS-R1a antagonist, liver-expressed antimicrobial peptide 2 (LEAP2), in the BLA abolished the inhibitory effect of increased GHS-R1a on CTA memory extinction. Those findings provide new supportive evidence that ghrelin/GHS-R1a signaling in the BLA circuit shapes emotional memory processes.}, } @article {pmid35169271, year = {2022}, author = {Yu, M and Zhu, QQ and Niu, ML and Li, N and Ren, BQ and Yu, TB and Zhou, ZS and Guo, JD and Zhou, Y}, title = {Ghrelin infusion into the basolateral amygdala suppresses CTA memory formation in rats via the PI3K/Akt/mTOR and PLC/PKC signaling pathways.}, journal = {Acta pharmacologica Sinica}, volume = {43}, number = {9}, pages = {2242-2252}, pmid = {35169271}, issn = {1745-7254}, mesh = {Amygdala/physiology ; Animals ; Avoidance Learning ; *Basolateral Nuclear Complex/physiology ; Feeding Behavior ; Ghrelin/pharmacology/physiology ; Glycogen Synthase Kinase 3/pharmacology ; Humans ; Mice ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; Rats ; Signal Transduction ; TOR Serine-Threonine Kinases ; Type C Phospholipases/metabolism ; }, abstract = {Ghrelin is a circulating orexigenic hormone that promotes feeding behavior and regulates metabolism in humans and rodents. We previously reported that local infusion of ghrelin into the basolateral amygdala (BLA) blocked memory acquisition for conditioned taste aversion (CTA) by activating growth hormone secretagogue receptor 1a. In this study, we further explored the underlying mechanism and signaling pathways mediating ghrelin modulation of CTA memory in rats. Pharmacological agents targeting distinct signaling pathways were infused into the BLA during conditioning. We showed that preadministration of the PI3K inhibitor LY294002 abolished the repressive effect of ghrelin on CTA memory. Moreover, LY294002 pretreatment prevented ghrelin from inhibiting Arc and zif268 mRNA expression in the BLA triggered by CTA memory retrieval. Preadministration of rapamycin eliminated the repressive effect of ghrelin, while Gsk3 inhibitors failed to mimic ghrelin's effect. In addition, PLC and PKC inhibitors microinfused in the BLA blocked ghrelin's repression of CTA acquisition. These results demonstrate that ghrelin signaling in the BLA shapes CTA memory via the PI3K/Akt/mTOR and PLC/PKC pathways. We conducted in vivo multichannel recordings from mouse BLA neurons and found that microinjection of ghrelin (20 µM) suppressed intrinsic excitability. By means of whole-cell recordings from rat brain slices, we showed that bath application of ghrelin (200 nM) had no effect on basal synaptic transmission or synaptic plasticity of BLA pyramidal neurons. Together, this study reveals the mechanism underlying ghrelin-induced interference with CTA memory acquisition in rats, i.e., suppression of intrinsic excitability of BLA principal neurons via the PI3K/Akt/mTOR and PLC/PKC pathways.}, } @article {pmid35156560, year = {2022}, author = {Totani, Y and Nakai, J and Hatakeyama, D and Dyakonova, VE and Lukowiak, K and Ito, E}, title = {CNS serotonin content mediating food deprivation-enhanced learning is regulated by hemolymph tryptophan concentration and autophagic flux in the pond snail.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/1028415X.2022.2033045}, pmid = {35156560}, issn = {1476-8305}, abstract = {Nutritional status affects cognitive function in many types of organisms. In the pond snail Lymnaea stagnalis, 1 day of food deprivation enhances taste aversion learning ability by decreasing the serotonin (5-hydroxytryptamin; 5-HT) content in the central nervous system (CNS). On the other hand, after 5 days of food deprivation, learning ability and the CNS 5-HT concentration return to basal levels. How food deprivation leads to alterations of 5-HT levels in the CNS, however, is unknown. Here, we measured the concentration of the 5-HT precursor tryptophan in the hemolymph and CNS, and demonstrated that the CNS tryptophan concentration was higher in 5-day food-deprived snails than in non-food-deprived or 1-day food-deprived snails, whereas the hemolymph tryptophan concentration was not affected by the duration of food deprivation. This finding suggests the existence of a mediator of the CNS tryptophan concentration independent of food deprivation. To identify the mediator, we investigated autophagic flux in the CNS under different food deprivation conditions. We found that autophagic flux was significantly upregulated by inhibition of the tropomyosin receptor kinase (Trk)-Akt-mechanistic target of rapamycin complex 1 (MTORC1) pathway in the CNS of 5-day food-deprived snails. Moreover, when autophagy was inhibited, the CNS 5-HT content was significantly downregulated in 5-day food-deprived snails. Our results suggest that the hemolymph tryptophan concentration and autophagic flux in the CNS cooperatively regulate learning ability affected by different durations of food deprivation. This mechanism may underlie the selection of behaviors appropriate for animal survival depending on the degree of nutrition.}, } @article {pmid35091058, year = {2022}, author = {Boccia, L and Borner, T and Ghidewon, MY and Kulka, P and Piffaretti, C and Doebley, SA and De Jonghe, BC and Grill, HJ and Lutz, TA and Le Foll, C}, title = {Hypophagia induced by salmon calcitonin, but not by amylin, is partially driven by malaise and is mediated by CGRP neurons.}, journal = {Molecular metabolism}, volume = {58}, number = {}, pages = {101444}, pmid = {35091058}, issn = {2212-8778}, support = {R01 DK021397/DK/NIDDK NIH HHS/United States ; R01 DK112812/DK/NIDDK NIH HHS/United States ; R56 DK021397/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Anorexia/chemically induced ; *Appetite Depressants/adverse effects/metabolism ; Calcitonin ; Calcitonin Gene-Related Peptide/metabolism ; *Islet Amyloid Polypeptide/metabolism ; Mice ; Nausea/metabolism ; Neurons/metabolism ; Rats ; Vomiting ; }, abstract = {OBJECTIVE: The behavioral mechanisms and the neuronal pathways mediated by amylin and its long-acting analog sCT (salmon calcitonin) are not fully understood and it is unclear to what extent sCT and amylin engage overlapping or distinct neuronal subpopulations to reduce food intake. We here hypothesize that amylin and sCT recruit different neuronal population to mediate their anorectic effects.

METHODS: Viral approaches were used to inhibit calcitonin gene-related peptide (CGRP) lateral parabrachial nucleus (LPBN) neurons and assess their role in amylin's and sCT's ability to decrease food intake in mice. In addition, to test the involvement of LPBN CGRP neuropeptidergic signaling in the mediation of amylin and sCT's effects, a LPBN site-specific knockdown was performed in rats. To deeper investigate whether the greater anorectic effect of sCT compared to amylin is due do the recruitment of additional neuronal pathways related to malaise multiple and distinct animal models tested whether amylin and sCT induce conditioned avoidance, nausea, emesis, and conditioned affective taste aversion.

RESULTS: Our results indicate that permanent or transient inhibition of CGRP neurons in LPBN blunts sCT-, but not amylin-induced anorexia and neuronal activation. Importantly, sCT but not amylin induces behaviors indicative of malaise including conditioned affective aversion, nausea, emesis, and conditioned avoidance; the latter mediated by CGRP[LPBN] neurons.

CONCLUSIONS: Together, the present study highlights that although amylin and sCT comparably decrease food intake, sCT is distinctive from amylin in the activation of anorectic neuronal pathways associated with malaise.}, } @article {pmid35049318, year = {2022}, author = {Flores, VL and Tanner, B and Katz, DB and Lin, JY}, title = {Cortical taste processing evolves through benign taste exposures.}, journal = {Behavioral neuroscience}, volume = {136}, number = {2}, pages = {182-194}, pmid = {35049318}, issn = {1939-0084}, support = {R21 DC016706/DC/NIDCD NIH HHS/United States ; F31 DC015931/DC/NIDCD NIH HHS/United States ; R01 DC006666/DC/NIDCD NIH HHS/United States ; R01 DC007703/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Learning/physiology ; Neurons/physiology ; Rats ; Rats, Long-Evans ; *Taste/physiology ; *Taste Perception/physiology ; }, abstract = {Experience impacts learning and perception. Familiarity with stimuli that later become the conditioned stimulus (CS) in a learning paradigm, for instance, reduces the strength of that learning-a fact well documented in studies of conditioned taste aversion (CTA; De la Casa & Lubow, 1995; Lubow, 1973; Lubow & Moore, 1959). Recently, we have demonstrated that even experience with "incidental" (i.e., non-CS) stimuli influences CTA learning: Long Evans rats pre-exposed to salty and/or sour tastes later learn unusually strong aversions to novel sucrose (Flores et al., 2016), and exhibit enhanced sucrose-responsiveness after learning in gustatory cortex (GC; Flores et al., 2018). These findings suggest that incidental taste exposure (TE) may change spiking responses that have been shown to underlie the processing of tastes in GC. Here, we test this hypothesis, evaluating whether GC neuron spiking responses change across 3 days of taste exposure. Our results demonstrate that the discriminability of GC ensemble taste responses increases with this familiarization. Analysis of single-neuron responses recorded across multiple sessions reveals that taste exposure not only enriches identity and palatability information in taste-evoked activity but also enhances the discriminability of even novel tastes. These findings demonstrate that "mere" familiarization with incidental episodes of tasting changes the neural spiking responses of taste processing and provides specific insight into how such TE may impact later learning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).}, } @article {pmid35011797, year = {2021}, author = {Head, MA and McColl, LK and Klockars, A and Levine, AS and Olszewski, PK}, title = {Acute Hypophagia and Changes in c-Fos Immunoreactivity in Adolescent Rats Treated with Low Doses of Oxytocin and Naltrexone.}, journal = {Journal of clinical medicine}, volume = {11}, number = {1}, pages = {}, pmid = {35011797}, issn = {2077-0383}, abstract = {A recent case report has shown that an adjunctive oxytocin + naltrexone (OT + NTX) treatment promoted more robust hypophagia and body weight reduction than OT alone in an adolescent male with hypothalamic obesity after craniopharyngioma resection. Thus far, there has been no basic research in adolescent laboratory animals that would examine whether the benefit of OT + NTX on appetite extends onto adolescent individuals without surgically induced overeating. Thus, here we examined whether low doses of combined OT + NTX acutely affect post-deprivation intake of energy-dense, standard chow; intake of energy-dense and palatable high-fat high-sugar (HFHS) diet; or calorie-dilute, palaTable 10% sucrose solution without deprivation in adolescent male rats. We assessed whether OT + NTX decreases water intake after water deprivation or produces a conditioned taste aversion (CTA). Finally, by using c-Fos immunoreactivity, we determined changes in activity of feeding-related brain areas after OT + NTX. We found that individual subthreshold doses of OT and NTX decreased feeding induced by energy and by palatability. Significant c-Fos changes were noted in the arcuate and dorsomedial hypothalamic nuclei. The hypophagic doses of OT + NTX did not suppress water intake in thirsty rats and did not cause a CTA, which suggests that feeding reduction is not a secondary effect of gastrointestinal discomfort or changes in thirst processing. We conclude that OT + NTX is an effective drug combination to reduce appetite in adolescent male rats.}, } @article {pmid34916257, year = {2022}, author = {Arieli, E and Younis, N and Moran, A}, title = {Distinct Progressions of Neuronal Activity Changes Underlie the Formation and Consolidation of a Gustatory Associative Memory.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {42}, number = {5}, pages = {909-921}, pmid = {34916257}, issn = {1529-2401}, mesh = {Animals ; Association Learning ; Female ; Male ; *Memory Consolidation ; Neurons/*physiology ; Rats ; Rats, Long-Evans ; Sensorimotor Cortex/cytology/*physiology ; *Taste Perception ; }, abstract = {Acquiring new memories is a multistage process. Numerous studies have convincingly demonstrated that initially acquired memories are labile and are stabilized only by later consolidation processes. These multiple phases of memory formation are known to involve modification of both cellular excitability and synaptic connectivity, which in turn change neuronal activity at both the single neuron and ensemble levels. However, the specific mapping between the known phases of memory and the changes in neuronal activity at different organizational levels-the single-neuron, population representations, and ensemble-state dynamics-remains unknown. Here we address this issue in the context of conditioned taste aversion learning by continuously tracking gustatory cortex neuronal taste responses in alert male and female rats during the 24 h following a taste-malaise pairing. We found that the progression of activity changes depends on the neuronal organizational level: whereas the population response changed continuously, the population mean response amplitude and the number of taste-responsive neurons only increased during the acquisition and consolidation phases. In addition, the known quickening of the ensemble-state dynamics associated with the faster rejection of harmful foods appeared only after consolidation. Overall, these results demonstrate how complex dynamics in the different representational levels of cortical activity underlie the formation and stabilization of memory within the cortex.SIGNIFICANCE STATEMENT Memory formation is a multiphased process; early acquired memories are labile and consolidate to their stable forms over hours and days. The progression of memory is assumed to be supported by changes in neuronal activity, but the mapping between memory phases and neuronal activity changes remains elusive. Here we tracked cortical neuronal activity over 24 h as rats acquired and consolidated a taste-malaise association memory, and found specific differences between the progression at the single-neuron and populations levels. These results demonstrate how balanced changes on the single-neuron level lead to changes in the network-level representation and dynamics required for the stabilization of memories.}, } @article {pmid34907488, year = {2021}, author = {Boniatti, J and Tappin, MRR and da S Teixeira, RG and de A V Gandos, T and Rios, LPS and Ferreira, IAM and Oliveira, KC and Calil-Elias, S and Santana, AKM and da Fonseca, LB and Shimizu, FM and Carr, O and Oliveira, ON and Dantas, FML and Amendoeira, FC and Viçosa, AL}, title = {In Vivo and In Vitro Taste Assessment of Artesunate-Mefloquine, Praziquantel, and Benznidazole Drugs for Neglected Tropical Diseases and Pediatric Patients.}, journal = {AAPS PharmSciTech}, volume = {23}, number = {1}, pages = {22}, pmid = {34907488}, issn = {1530-9932}, mesh = {Animals ; Artesunate ; Child ; Humans ; *Mefloquine ; Nitroimidazoles ; *Praziquantel ; Rats ; Tablets ; Taste ; }, abstract = {The assessment of drug taste is crucial for pediatric treatments so that formulations can be developed to enhance their effectiveness. In this study, in vivo and in vitro methods were applied to evaluate the taste of tablets of three drugs administered to children without taste-masking excipients to treat tropical diseases, namely artesunate-mefloquine (ASMQ), praziquantel (PZQ), and benznidazole (BNZ). In the first method, a model of rat palatability was adapted with recirculation to ensure sample dispersion, and the data were analyzed using ANOVA (single factor, 95%). The taste assessment results (in vivo) indicated an aversion to the three medicines, denoted by the animals retracting themselves to the bottom of the box after the first contact with the drugs. For the placebo samples, the animals behaved normally, indicating that taste perception was acceptable. The second method was based on the in vitro analysis of capacitance data from a homemade impedimetric electronic tongue. Consistent with the in vivo taste assessment results, the data points obtained with PZQ, ASMQ, and BNZ were far away from those of their placebos in a map built with the multidimensional projection technique referred to as Interactive Document Mapping (IDMAP). A combined analysis of the results with the two methods allowed us to confirm the bitterness of the three drugs, also pointing to electronic tongues as a promising tool to replace in vivo palatability tests.}, } @article {pmid34898621, year = {2021}, author = {Bernanke, A and Burnette, E and Murphy, J and Hernandez, N and Zimmerman, S and Walker, QD and Wander, R and Sette, S and Reavis, Z and Francis, R and Armstrong, C and Risher, ML and Kuhn, C}, title = {Behavior and Fos activation reveal that male and female rats differentially assess affective valence during CTA learning and expression.}, journal = {PloS one}, volume = {16}, number = {12}, pages = {e0260577}, pmid = {34898621}, issn = {1932-6203}, mesh = {Acoustic Stimulation ; Amygdala/drug effects/metabolism ; Animals ; *Conditioning, Psychological/drug effects/radiation effects ; Female ; Lithium Chloride/pharmacology ; Male ; Proto-Oncogene Proteins c-fos/*metabolism ; Rats ; Sex Characteristics ; Ultrasonics ; }, abstract = {Females are more affected by psychiatric illnesses including eating disorders, depression, and post-traumatic stress disorder than males. However, the neural mechanisms mediating these sex differences are poorly understood. Animal models can be useful in exploring such neural mechanisms. Conditioned taste aversion (CTA) is a behavioral task that assesses how animals process the competition between associated reinforcing and aversive stimuli in subsequent task performance, a process critical to healthy behavior in many domains. The purpose of the present study was to identify sex differences in this behavior and associated neural responses. We hypothesized that females would value the rewarding stimulus (Boost®) relative to the aversive stimulus (LiCl) more than males in performing CTA. We evaluated behavior (Boost® intake, LiCl-induced behaviors, ultrasonic vocalizations (USVs), CTA performance) and Fos activation in relevant brain regions after the acute stimuli [acute Boost® (AB), acute LiCl (AL)] and the context-only task control (COT), Boost® only task (BOT) and Boost®-LiCl task (BLT). Acutely, females drank more Boost® than males but showed similar aversive behaviors after LiCl. Females and males performed CTA similarly. Both sexes produced 55 kHz USVs anticipating BOT and inhibited these calls in the BLT. However, more females emitted both 22 kHz and 55 kHz USVs in the BLT than males: the latter correlated with less CTA. Estrous cycle stage also influenced 55 kHz USVs. Fos responses were similar in males and females after AB or AL. Females engaged the gustatory cortex and ventral tegmental area (VTA) more than males during the BOT and males engaged the amygdala more than females in both the BOT and BLT. Network analysis of correlated Fos responses across brain regions identified two unique networks characterizing the BOT and BLT, in both of which the VTA played a central role. In situ hybridization with RNAscope identified a population of D1-receptor expressing cells in the CeA that responded to Boost® and D2 receptor-expressing cells that responded to LiCl. The present study suggests that males and females differentially process the affective valence of a stimulus to produce the same goal-directed behavior.}, } @article {pmid34856204, year = {2022}, author = {Shah, T and Dunning, JL and Contet, C}, title = {At the heart of the interoception network: Influence of the parasubthalamic nucleus on autonomic functions and motivated behaviors.}, journal = {Neuropharmacology}, volume = {204}, number = {}, pages = {108906}, pmid = {34856204}, issn = {1873-7064}, support = {P50 AA006420/AA/NIAAA NIH HHS/United States ; R01 AA026685/AA/NIAAA NIH HHS/United States ; R21 AA027372/AA/NIAAA NIH HHS/United States ; P60 AA006420/AA/NIAAA NIH HHS/United States ; R21 AA027636/AA/NIAAA NIH HHS/United States ; }, mesh = {Amygdala/physiology ; Animals ; Anorexia/physiopathology ; Appetite ; Avoidance Learning ; Behavior/*physiology ; Behavior, Addictive ; Corticotropin-Releasing Hormone/metabolism ; Eating/physiology ; Emotions/physiology ; Humans ; Impulsive Behavior ; Interoception/*physiology ; Motivation/*physiology ; Neurons/metabolism/physiology ; Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism ; Posterior Thalamic Nuclei/metabolism/*physiology ; Substance P/metabolism ; }, abstract = {The parasubthalamic nucleus (PSTN), a small nucleus located on the lateral edge of the posterior hypothalamus, has emerged in recent years as a highly interconnected node within the network of brain regions sensing and regulating autonomic function and homeostatic needs. Furthermore, the strong integration of the PSTN with extended amygdala circuits makes it ideally positioned to serve as an interface between interoception and emotions. While PSTN neurons are mostly glutamatergic, some of them also express neuropeptides that have been associated with stress-related affective and motivational dysfunction, including substance P, corticotropin-releasing factor, and pituitary adenylate-cyclase activating polypeptide. PSTN neurons respond to food ingestion and anorectic signals, as well as to arousing and distressing stimuli. Functional manipulation of defined pathways demonstrated that the PSTN serves as a central hub in multiple physiologically relevant networks and is notably implicated in appetite suppression, conditioned taste aversion, place avoidance, impulsive action, and fear-induced thermoregulation. We also discuss the putative role of the PSTN in interoceptive dysfunction and negative urgency. This review aims to synthesize the burgeoning preclinical literature dedicated to the PSTN and to stimulate interest in further investigating its influence on physiology and behavior.}, } @article {pmid34782401, year = {2021}, author = {Garr, E and Padovan-Hernandez, Y and Janak, PH and Delamater, AR}, title = {Maintained goal-directed control with overtraining on ratio schedules.}, journal = {Learning & memory (Cold Spring Harbor, N.Y.)}, volume = {28}, number = {12}, pages = {435-439}, pmid = {34782401}, issn = {1549-5485}, support = {R01 DA035943/DA/NIDA NIH HHS/United States ; SC1 DA034995/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Behavior, Animal ; *Conditioning, Operant ; *Goals ; Motivation ; Rats ; Reinforcement, Psychology ; }, abstract = {It is thought that goal-directed control of actions weakens or becomes masked by habits over time. We tested the opposing hypothesis that goal-directed control becomes stronger over time, and that this growth is modulated by the overall action-outcome contiguity. Despite group differences in action-outcome contiguity early in training, rats trained under random and fixed ratio schedules showed equivalent goal-directed control of lever pressing that appeared to grow over time. We confirmed that goal-directed control was maintained after extended training under another type of ratio schedule-continuous reinforcement-using specific satiety and taste aversion devaluation methods. These results add to the growing literature showing that extensive training does not reliably weaken goal-directed control and that it may strengthen it, or at least maintain it.}, } @article {pmid34768105, year = {2021}, author = {Smith, DW and Islam, M and Furst, KE and Mustaree, S and Crider, YS and Akter, N and Islam, SA and Sultana, S and Mahmud, ZH and Rahman, M and Mitch, WA and Davis, J}, title = {Chlorine taste can increase simulated exposure to both fecal contamination and disinfection byproducts in water supplies.}, journal = {Water research}, volume = {207}, number = {}, pages = {117806}, doi = {10.1016/j.watres.2021.117806}, pmid = {34768105}, issn = {1879-2448}, mesh = {Bangladesh ; Chlorine ; *Disinfectants ; Disinfection ; Escherichia coli ; Halogenation ; Humans ; Taste ; Trihalomethanes/analysis ; *Water Pollutants, Chemical/analysis ; *Water Purification ; Water Supply ; }, abstract = {Expanding drinking water chlorination could substantially reduce the burden of disease in low- and middle-income countries, but the taste of chlorinated water often impedes adoption. We developed a Monte Carlo simulation to estimate the effect of people's choice to accept or reject drinking water based on chlorine taste and their subsequent exposure to E. coli and trihalomethanes, a class of disinfection byproduct (DBP). The simulation used empirical data from Dhaka, Bangladesh, a megacity with endemic waterborne disease. We drew on published taste acceptability thresholds from Dhaka residents, measured residual chlorine and thermotolerant E. coli inactivation following the addition of six chlorine doses (0.25-3.0 mg/L as Cl2) to untreated piped water samples from 100 locations, and analyzed trihalomethane formation in 54 samples. A dose of 0.5 mg/L, 75% lower than the 2 mg/L dose typically recommended for household chlorination of low-turbidity waters, minimized overall exposure to E. coli. Doses of 1-2 mg/L maximized overall exposure to trihalomethanes. Accounting for chlorine taste aversion indicates that microbiological exposure increases and DBP exposure decreases above certain doses as a higher proportion of people reject chlorinated water in favor of untreated water. Taken together with findings from other modeling analyses, empirical studies, and field trials, our results suggest that taste acceptability should be a critical consideration in establishing chlorination dosing guidelines. Particularly when chlorination is first implemented in water supplies with low chlorine demand, lower doses than those generally recommended for household water treatment can help avoid taste-related objections while still meaningfully reducing contaminant exposure.}, } @article {pmid34744692, year = {2021}, author = {Shyu, BC and Gao, ZY and Wu, JJ and He, ABH and Cheng, CN and Huang, ACW}, title = {Methamphetamine and Modulation Functionality of the Prelimbic Cortex for Developing a Possible Treatment of Alzheimer's Disease in an Animal Model.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {751913}, pmid = {34744692}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition that causes cognitive impairment and other neuropsychiatric symptoms. Previously, little research has thus far investigated whether methamphetamine (MAMPH) can enhance cognitive function or ameliorate AD symptoms. This study examined whether a low dose of MAMPH can induce conditioned taste aversion (CTA) learning, or can increase plasma corticosterone levels, neural activity, and neural plasticity in the medial prefrontal cortex (mPFC) (responsible for cognitive function), the nucleus accumbens (NAc) and the amygdala (related to rewarding and aversive emotion), and the hippocampus (responsible for spatial learning). Furthermore, the excitations or lesions of the prelimbic cortex (PrL) can affect MAMPH-induced CTA learning, plasma corticosterone levels, and neural activity or plasticity in the mPFC [i.e., PrL, infralimbic cortex (IL), cingulate cortex 1 (Cg1)], the NAc, the amygdala [i.e., basolateral amygdala (BLA) and central amygdala (CeA)], and the hippocampus [i.e., CA1, CA2, CA3, and dentate gyrus (DG)]. In the experimental procedure, the rats were administered either saline or NMDA solutions, which were injected into the PrL to excite or destroy PrL neurons. Additionally, rats received 0.1% saccharin solution for 15 min, followed by intraperitoneal injections of either normal saline or 1 mg/kg MAMPH to induce CTA. A one-way ANOVA was performed to analyze the effects of saccharin intake on CTA, plasma corticosterone levels, and the expression of c-Fos and p-ERK. The results showed that the MAMPH induced CTA learning and increased plasma corticosterone levels. The mPFC, and particularly the PrL and IL and the DG of the hippocampus, appeared to show increased neural activity in c-Fos expression or neural plasticity in p-ERK expression. The excitation of the PrL neurons upregulated neural activity in c-Fos expression and neural plasticity in p-ERK expression in the PrL and IL. In summary, MAMPH may be able to improve cognitive and executive function in the brain and reduce AD symptoms. Moreover, the excitatory modulation of the PrL with MAMPH administration can facilitate MAMPH-induced neural activity and plasticity in the PrL and IL of the mPFC. The present data provide clinical implications for developing a possible treatment for AD in an animal model.}, } @article {pmid34652631, year = {2021}, author = {Zheng, Y and Chen, ZY and Ma, WJ and Wang, QZ and Liang, H and Ma, AG}, title = {B Vitamins Supplementation Can Improve Cognitive Functions and May Relate to the Enhancement of Transketolase Activity in A Rat Model of Cognitive Impairment Associated with High-fat Diets.}, journal = {Current medical science}, volume = {41}, number = {5}, pages = {847-856}, pmid = {34652631}, issn = {2523-899X}, mesh = {Animals ; Cognitive Dysfunction/chemically induced/*drug therapy/enzymology ; Diet, High-Fat/*adverse effects ; Dietary Supplements ; Disease Models, Animal ; Folic Acid/administration & dosage/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Male ; Morris Water Maze Test/drug effects ; Niacin/administration & dosage/pharmacology ; Pyridoxine/administration & dosage/pharmacology ; Rats ; Riboflavin/administration & dosage/pharmacology ; Thiamine/administration & dosage/pharmacology ; Transketolase/*metabolism ; Vitamin B 12/administration & dosage/pharmacology ; Vitamin B Complex/*administration & dosage/pharmacology ; }, abstract = {OBJECTIVE: To determine whether B vitamin treatment was sufficient to reduce cognitive impairment associated with high-fat diets in rats and to modulate transketolase (TK) expression and activity.

METHODS: To test this, we separated 50 rats into five groups that were either fed a standard chow diet (controls) or a high-fat diet (experimental groups H0, H1, H2, and H3). H0 group animals received no additional dietary supplementation, while H1 group animals were administered 100 mg/kg body weight (BW) thiamine, 100 mg/kg BW riboflavin, and 250 mg/kg BW niacin each day, and group H2 animals received daily doses of 100 mg/kg BW pyridoxine, 100 mg/kg BW cobalamin, and 5 mg/kg BW folate. Animals in the H3 group received the B vitamin regimens administered to both H1 and H2 each day.

RESULTS: Over time, group H0 exhibited greater increases in BW and fat mass relative to other groups. When spatial and memory capabilities in these animals were evaluated via conditioned taste aversion (CTA) and Morris Water Maze (MWM), we found B vitamin treatment was associated with significant improvements relative to untreated H0 controls. Similarly, B vitamin supplementation was associated with elevated TK expression in erythrocytes and hypothalamus of treated animals relative to those in H0 (P<0.05).

CONCLUSION: Together, these findings suggest B vitamin can modulate hypothalamic TK activity to reduce the severity of cognitive deficits in a rat model of obesity. As such, B vitamin supplementation may be a beneficial method for reducing cognitive dysfunction in clinical settings associated with high-fat diets.}, } @article {pmid34589798, year = {2021}, author = {Strekalova, T and Svirin, E and Veniaminova, E and Kopeikina, E and Veremeyko, T and Yung, AWY and Proshin, A and Walitza, S and Anthony, DC and Lim, LW and Lesch, KP and Ponomarev, ED}, title = {ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5.}, journal = {Brain, behavior, & immunity - health}, volume = {16}, number = {}, pages = {100306}, pmid = {34589798}, issn = {2666-3546}, abstract = {Gangliosides are glycosphingolipids, which are abundant in brain, are known to modulate ion channels and cell-to-cell communication. Deficiencies can result in aberrant myelination and altered immune responses, which can give rise to neurodevelopmental psychiatric disorders. However, to date, little mechanistic data is available on how ganglioside deficiencies contribute to the behavioural disorders. In humans, the loss of lactosylceramide-alpha-2,3-sialyltransferase (ST3Gal5) leads to a severe neuropathology, but in ST3Gal5 knock-out (St3gal5-/-) mice the absence of GM3 and associated a-, b- and c-series gangliosides is partially compensated by 0-series gangliosides and there is no overt behavioural phenotype. Here, we sought to examine the behavioural and molecular consequences of GM3 loss more closely. Mutants of both sexes exhibited impaired conditioned taste aversion in an inhibitory learning task and anxiety-like behaviours in the open field, moderate motor deficits, abnormal social interactions, excessive grooming and rearing behaviours. Taken together, the aberrant behaviours are suggestive of an autism spectrum disorder (ASD)-like syndrome. Molecular analysis showed decreased gene and protein expression of proteolipid protein-1 (Plp1) and over expression of proinflammatory cytokines, which has been associated with ASD-like syndromes. The inflammatory and behavioural responses to lipopolysaccharide (LPS) were also altered in the St3gal5-/- mice compared to wild-type, which is indicative of the importance of GM3 gangliosides in regulating immune responses. Together, the St3gal5-/- mice display ASD-like behavioural features, altered response to systemic inflammation, signs of hypomyelination and neuroinflammation, which suggests that deficiency in a- and b-series gangliosides could contribute to the development of an ASD-like pathology in humans.}, } @article {pmid34553981, year = {2021}, author = {Angulo, R and Arévalo-Romero, CA}, title = {Sexual dimorphism in classical conditioning? Sex differences in neophobia, latent inhibition, generalization, and extinction for rats (Rattus norvegicus) in a conditioned taste aversion preparation irrespective of housing conditions.}, journal = {Journal of comparative psychology (Washington, D.C. : 1983)}, volume = {135}, number = {3}, pages = {315-326}, doi = {10.1037/com0000275}, pmid = {34553981}, issn = {1939-2087}, mesh = {Animals ; Avoidance Learning ; *Conditioning, Classical ; Female ; Housing ; Male ; Rats ; *Sex Characteristics ; Taste ; }, abstract = {This study aimed to assess possible sex differences and a potential impact of social housing conditions for some Pavlovian conditioning effects in a conditioned taste aversion preparation with rats. The results of Experiment 1 suggest sex differences in neophobia, latent inhibition, and generalization. Specifically, for females, neophobia, and generalization appeared to be stronger while latent inhibition seemed to be attenuated. Experiment 2 confirmed these sex differences in neophobia and generalization, while also revealing slower extinction in males. Experiment 3 provided evidence for the same sex differences in neophobia and generalization, even when a perceptual learning effect was in operation following pre-exposures to the test stimulus. No effects of social housing conditions were found in either Experiment 1 or Experiment 2. In general, these findings appear to support the hypothesis of sexual dimorphism in Pavlovian conditioning, encouraging a systematic approach to the topic by means of further research. (PsycInfo Database Record (c) 2021 APA, all rights reserved).}, } @article {pmid34547331, year = {2021}, author = {Dornellas, APS and Burnham, NW and Luhn, KL and Petruzzi, MV and Thiele, TE and Navarro, M}, title = {Activation of locus coeruleus to rostromedial tegmental nucleus (RMTg) noradrenergic pathway blunts binge-like ethanol drinking and induces aversive responses in mice.}, journal = {Neuropharmacology}, volume = {199}, number = {}, pages = {108797}, pmid = {34547331}, issn = {1873-7064}, support = {R01 AA022048/AA/NIAAA NIH HHS/United States ; R01 AA025809/AA/NIAAA NIH HHS/United States ; R37 AA013573/AA/NIAAA NIH HHS/United States ; T32 DA007244/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/drug effects/physiology ; Behavior, Animal/*physiology ; Binge Drinking/*physiopathology/*therapy ; Disease Models, Animal ; Female ; Locus Coeruleus/*physiology ; Male ; Mice ; Mice, Transgenic ; Norepinephrine/*physiology ; Signal Transduction/physiology ; Ventral Tegmental Area/*physiology ; Vocalization, Animal/drug effects/physiology ; }, abstract = {There is strong evidence that ethanol entails aversive effects that can act as a deterrent to overconsumption. We have found that in doses that support the development of a conditioned taste aversion ethanol increases the activity of tyrosine hydroxylase (TH) positive neurons in the locus coeruleus (LC), a primary source of norepinephrine (NE). Using cre-inducible AAV8-ChR2 viruses in TH-ires-cre mice we found that the LC provides NE projections that innervate the rostromedial tegmental nucleus (RMTg), a brain region that has been implicated in the aversive properties of drugs. Because the neurocircuitry underlying the aversive effects of ethanol is poorly understood, we characterized the role of the LC to RMTg circuit in modulating aversive unconditioned responses and binge-like ethanol intake. Here, both male and female TH-ires-cre mice were cannulated in the RMTg and injected in the LC with rAVV viruses that encode for a Gq-expressing designer receptor exclusively activated by designer drugs (DREADDs) virus, or its control virus, to directly control the activity of NE neurons. A Latin Square paradigm was used to analyze both 20% ethanol and 3% sucrose consumption using the "drinking-in-the-dark" (DID) paradigm. Chemogenetic activation of the LC to RMTg pathway significantly blunted the binge-ethanol drinking, with no effect on the sucrose consumption, increased the emission of mid-frequency vocalizations and induced malaise-like behaviors in mice. The present findings indicate an important involvement of the LC to RMTg pathway in reducing ethanol consumption, and characterize unconditioned aversive reactions induced by activation of this noradrenergic pathway.}, } @article {pmid34545750, year = {2021}, author = {Simões, S and Almeida, AJ and Marto, J}, title = {Palatability of pediatric formulations: do rats predict aversiveness?.}, journal = {Drug development and industrial pharmacy}, volume = {47}, number = {7}, pages = {1121-1126}, doi = {10.1080/03639045.2021.1984519}, pmid = {34545750}, issn = {1520-5762}, mesh = {Animals ; Child ; Drug Compounding ; Flavoring Agents ; Humans ; Quinine ; Rats ; *Sweetening Agents ; *Taste ; }, abstract = {BACKGROUND: The brief-access taste aversion (BATA) model has been used as an alternative taste assessment tool to human taste panels and became an important element of pharmaceutical drug development, especially regarding pediatric patient's compliance. This model has been validated, demonstrating a concentration-dependent sensitivity to drug aversiveness, as well as the capacity to evaluate the taste-masking effects of cyclodextrins. In the BATA model, samples are presented randomly to rodents in numerous sipper tubes and a lickometer is used for the electronic record of licks in a sophisticated approach.

OBJECTIVES: The aim of this study was to test possible drug taste-masking strategies. Additionally, we have used an alternative approach to measure the animal lick number in the presence of different compounds, non-simultaneously.

RESULTS: In the present work we show for the first time the licking profile of different compounds during the time course of the experiment, with each animal being exposed to only one bottle of testing product. To validate the experiments, quinine hydrochloride dihydrate (QHD) was used as a bitter reference compound.

CONCLUSION: The results obtained using this simple approach showed that aversiveness is dependent on the assay duration, and that it is possible to predict the aversiveness just by measuring the mass of the tested substance consumption. Moreover, some taste-masking strategies, such as those used in pediatric formulations and corresponding to the addition of sweeteners or flavors, cannot be predicted from rodents BATA model.}, } @article {pmid34516195, year = {2021}, author = {Bouton, ME and Allan, SM and Tavakkoli, A and Steinfeld, MR and Thrailkill, EA}, title = {Effect of context on the instrumental reinforcer devaluation effect produced by taste-aversion learning.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {47}, number = {4}, pages = {476-489}, pmid = {34516195}, issn = {2329-8464}, support = {K01 DA044456/DA/NIDA NIH HHS/United States ; R01 DA033123/DA/NIDA NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Animals ; Conditioning, Classical ; Conditioning, Operant ; *Extinction, Psychological ; Learning ; Rats ; *Taste ; }, abstract = {Four experiments manipulated the context in which taste-aversion conditioning occurred when the reinforcer was devalued after instrumental learning. In all experiments, rats learned to lever press in an operant conditioning chamber and then had an aversion to the food-pellet reinforcer conditioned by pairing it with lithium chloride (LiCl) in either that context or a different context. Lever pressing was then tested in extinction to assess its status as a goal-directed action. In Experiment 1, aversion conditioning in the operant conditioning chamber suppressed lever-pressing during the test, but aversion conditioning in the home cage did not. Exposure to the averted pellet in the operant conditioning chamber after conditioning in the home cage did not change this effect (Experiment 2). The same pattern was observed when the different context was a second operant-style chamber (counterbalanced), exposure to the contexts was controlled, and pellets were presented in them in the same manner (Experiment 3). The greater effect of aversion conditioning in the instrumental context was not merely due to potentiated contextual conditioning (Experiment 4). Importantly, consumption tests revealed that the aversion conditioned in the different context had transferred to the test context. Thus, when reinforcer devaluation occurred in a different context, the rats lever pressed in extinction for a reinforcer they would otherwise reject. The results suggest that animals encode contextual information about the reinforcer during instrumental learning and suggest caution in making inferences about action versus habit learning when the reinforcer is devalued in a different context. (PsycInfo Database Record (c) 2021 APA, all rights reserved).}, } @article {pmid34428526, year = {2021}, author = {Nakajima, S}, title = {Food avoidance learning based on entirely voluntary wheel running in laboratory mice (Mus musculus).}, journal = {Behavioural processes}, volume = {192}, number = {}, pages = {104484}, doi = {10.1016/j.beproc.2021.104484}, pmid = {34428526}, issn = {1872-8308}, mesh = {Animals ; *Avoidance Learning ; Conditioning, Classical ; Food ; Mice ; *Motor Activity ; Taste ; }, abstract = {Previous studies (Nakajima, 2019a,b) demonstrated food avoidance learning based on wheel running in laboratory mice: Consumption of a target snack becomes suppressed if it is repeatedly paired with an opportunity to run in an activity wheel. This is a kind of Pavlovian conditioning, because the avoidance is specific to the paired snack. For example, in an experiment, mice were initially trained to run in closed wheels. Then, access to one of the two kinds of snacks (cheese or raisins, counterbalanced) was followed by confinement in a large pet cage with an open wheel, while access to the other snack was not. After several repetitions of these two types of trials, differentiation in consumption between the two snacks emerged: The intake of the unpaired snack increased gradually over days, while the increase was attenuated for the running-paired snack. The present study replicated this food avoidance learning without the pretraining of running in a closed wheel, emphasizing the intrinsic capacity of running to establish food avoidance. The results somewhat suggest that pretraining in open wheels facilitates running-based food avoidance, but this effect was too weak in the present study to draw a clear conclusion.}, } @article {pmid34376756, year = {2021}, author = {Zajdel, J and Sköld, J and Jaarola, M and Singh, AK and Engblom, D}, title = {Calcitonin gene related peptide α is dispensable for many danger-related motivational responses.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {16204}, pmid = {34376756}, issn = {2045-2322}, mesh = {Amygdala/metabolism/pathology ; Animals ; Anorexia/*physiopathology ; Avoidant Restrictive Food Intake Disorder ; *Behavior, Animal ; Calcitonin Gene-Related Peptide/*physiology ; Conditioning, Classical/*physiology ; Eating ; Fear/*psychology ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motivation ; Neurons/metabolism/*pathology ; Nociception ; Pain/metabolism/*pathology ; Parabrachial Nucleus/metabolism/pathology ; }, abstract = {Calcitonin gene related peptide (CGRP) expressing neurons in the parabrachial nucleus have been shown to encode danger. Through projections to the amygdala and other forebrain structures, they regulate food intake and trigger adaptive behaviors in response to threats like inflammation, intoxication, tumors and pain. Despite the fact that this danger-encoding neuronal population has been defined based on its CGRP expression, it is not clear if CGRP is critical for its function. It is also not clear if CGRP in other neuronal structures is involved in danger-encoding. To examine the role of CGRP in danger-related motivational responses, we used male and female mice lacking αCGRP, which is the main form of CGRP in the brain. These mice had no, or only very weak, CGRP expression. Despite this, they did not behave differently compared to wildtype mice when they were tested for a battery of danger-related responses known to be mediated by CGRP neurons in the parabrachial nucleus. Mice lacking αCGRP and wildtype mice showed similar inflammation-induced anorexia, conditioned taste aversion, aversion to thermal pain and pain-induced escape behavior, although it should be pointed out that the study was not powered to detect any possible differences that were minor or sex-specific. Collectively, our findings suggest that αCGRP is not necessary for many threat-related responses, including some that are known to be mediated by CGRP neurons in the parabrachial nucleus.}, } @article {pmid34361981, year = {2021}, author = {Yu, Y and He, AB and Liou, M and Ou, C and Kozłowska, A and Chen, P and Huang, AC}, title = {The Paradoxical Effect Hypothesis of Abused Drugs in a Rat Model of Chronic Morphine Administration.}, journal = {Journal of clinical medicine}, volume = {10}, number = {15}, pages = {}, pmid = {34361981}, issn = {2077-0383}, abstract = {A growing body of studies has recently shown that abused drugs could simultaneously induce the paradoxical effect in reward and aversion to influence drug addiction. However, whether morphine induces reward and aversion, and which neural substrates are involved in morphine's reward and aversion remains unclear. The present study first examined which doses of morphine can simultaneously produce reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA) in rats. Furthermore, the aversive dose of morphine was determined. Moreover, using the aversive dose of 10 mg/kg morphine tested plasma corticosterone (CORT) levels and examined which neural substrates were involved in the aversive morphine-induced CTA on conditioning, extinction, and reinstatement. Further, we analyzed c-Fos and p-ERK expression to demonstrate the paradoxical effect-reward and aversion and nonhomeostasis or disturbance by morphine-induced CTA. The results showed that a dose of more than 20 mg/kg morphine simultaneously induced reward in CPP and aversion in CTA. A dose of 10 mg/kg morphine only induced the aversive CTA, and it produced higher plasma CORT levels in conditioning and reacquisition but not extinction. High plasma CORT secretions by 10 mg/kg morphine-induced CTA most likely resulted from stress-related aversion but were not a rewarding property of morphine. For assessments of c-Fos and p-ERK expression, the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) were involved in the morphine-induced CTA, and resulted from the aversive effect of morphine on conditioning and reinstatement. The c-Fos data showed fewer neural substrates (e.g., PrL, IL, and LH) on extinction to be hyperactive. In the context of previous drug addiction data, the evidence suggests that morphine injections may induce hyperactivity in many neural substrates, which mediate reward and/or aversion due to disturbance and nonhomeostasis in the brain. The results support the paradoxical effect hypothesis of abused drugs. Insight from the findings could be used in the clinical treatment of drug addiction.}, } @article {pmid34327337, year = {2021}, author = {Dantzer, R}, title = {Love and fear in the times of sickness.}, journal = {Comprehensive psychoneuroendocrinology}, volume = {6}, number = {}, pages = {}, pmid = {34327337}, issn = {2666-4976}, support = {R01 CA193522/CA/NCI NIH HHS/United States ; R01 NS073939/NS/NINDS NIH HHS/United States ; }, abstract = {Sickness induced by gastrointestinal malaise or by microbial pathogens is more than a private experience. Sick individuals share their illness within their social environment by communicating their sickness to others. In turn, recipients of the communication respond with appropriate behavioral adaptations. Avoidance of sick individuals and the events associated with their sickness is advantageous for members of the group. However, these responses can conflict with the need for comfort or social support expressed by sick individuals. There is evidence that the relationship between the sick individual and its social environment involves neurobiological mechanisms that are similar to those that mediate social bonding. Despite their commonality the feelings of love and fear/disgust that are associated with the sociality of sickness have thus far been neglected by mainstream affective neuroscience.}, } @article {pmid34323519, year = {2021}, author = {Wu, CW and Ou, CY and Yu, YH and Yu, YC and Shyu, BC and Huang, ACW}, title = {Involvement of the ventral tegmental area but not periaqueductal gray matter in the paradoxical rewarding and aversive effects of morphine.}, journal = {Behavioral neuroscience}, volume = {135}, number = {6}, pages = {762-770}, doi = {10.1037/bne0000483}, pmid = {34323519}, issn = {1939-0084}, mesh = {Conditioning, Classical ; *Morphine/pharmacology ; Periaqueductal Gray ; Reward ; *Ventral Tegmental Area ; }, abstract = {The paradoxical effects of reward and aversion with abused drugs may interact to produce drug addiction, which is the so-called paradoxical effect hypothesis of abused drugs. However, there is no research examining how the ventral tegmental area (VTA) or periaqueductal gray matter (PAG) regulates morphine's paradoxical effect of reward and aversion. The present study addresses this issue, utilizing a high concentration of N-methyl-D-aspartic acid (NMDA) via injections to destroy the VTA or the PAG. Moreover, the study employed the new "pre- and postassociation" experimental paradigm (2010) to test whether the simultaneous rewarding and aversive effects of morphine can be affected by an NMDA lesion in the VTA or the PAG. The results indicated that the NMDA lesion of the VTA simultaneously reduced morphine-induced conditioned suppression of saccharin solution intake in conditioned taste aversion (CTA) and morphine-induced spent time in the preference compartment in conditioned place preference (CPP), whereas the PAG lesion did not change either measure. Thus, the VTA, but not the PAG, appears to contribute to the paradoxical effect reward in CPP and aversion in CTA induced by morphine. The VTA's involvement in morphine-induced CTA aversion and CPP reward supports the paradoxical effect hypothesis of abused drugs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).}, } @article {pmid34153368, year = {2021}, author = {Wang, YC and Chiu, WC and Cheng, CN and Lee, C and Chih Wei Huang, A}, title = {Examination of neuroinflammatory cytokine interleukin-1 beta expression in the medial prefrontal cortex, amygdala, and hippocampus for the paradoxical effects of reward and aversion induced by morphine.}, journal = {Neuroscience letters}, volume = {760}, number = {}, pages = {136076}, doi = {10.1016/j.neulet.2021.136076}, pmid = {34153368}, issn = {1872-7972}, mesh = {Amygdala/metabolism/pathology/physiopathology ; Animals ; Conditioning, Operant ; Disease Models, Animal ; Hippocampus/metabolism/pathology/physiopathology ; Humans ; Interleukin-1beta/*metabolism ; Male ; Morphine/administration & dosage/*adverse effects ; Morphine Dependence/*immunology/pathology/physiopathology ; Neuroinflammatory Diseases/*immunology/pathology/physiopathology ; Prefrontal Cortex/metabolism/pathology/physiopathology ; Rats ; *Reward ; Saccharin/administration & dosage ; Signal Transduction/immunology ; }, abstract = {A growing body of evidence has shown that abused drugs could simultaneously induce the paradoxical effect-reward and aversion. Moreover, the medial prefrontal cortex (mPFC), amygdala, and hippocampus were involved in this paradoxical effect by abused drugs. However, no research examined whether neuroinflammatory changes in the mPFC [including cingulate cortex area 1 (Cg1); prelimbic cortex (PrL); infralimbic cortex (IL)], basolateral amygdala, and hippocampus [e.g., CA1, CA2, CA3, and dentate gyrus (DG)] after morphine-induced reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA). The results showed that after morphine administration, the consumption of a 0.1% saccharin solution decreased; the mean time spent in the morphine-paired side compartment of the CPP box increased, indicating that morphine simultaneously induced the paradoxical effects of reward and aversion. The PrL and IL of the mPFC, the BLA of the amygdala, the CA1, CA2, CA3, and DG of the hippocampus but not the Cg1 presented hyperactive IL-1β expression in response to morphine's aversion and reward. The mPFC, amygdala, and hippocampus may appear neuroinflammation activity following morphine-induced paradoxical effect-reward in CPP and aversion in CTA. The present data may provide a better understanding of the relationship between neuroinflammation and morphine addiction.}, } @article {pmid34052874, year = {2021}, author = {Rivi, V and Batabyal, A and Juego, K and Kakadiya, M and Benatti, C and Blom, JMC and Lukowiak, K}, title = {To eat or not to eat: a Garcia effect in pond snails (Lymnaea stagnalis).}, journal = {Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology}, volume = {207}, number = {4}, pages = {479-495}, pmid = {34052874}, issn = {1432-1351}, mesh = {Animals ; Avoidance Learning/*physiology ; Conditioning, Classical ; Feeding Behavior/*physiology ; HSP40 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Response/physiology ; Lymnaea/*physiology ; Memory, Long-Term/*physiology ; Taste/*physiology ; }, abstract = {Taste aversion learning is universal. In animals, a single presentation of a novel food substance followed hours later by visceral illness causes animals to avoid that taste. This is known as bait-shyness or the Garcia effect. Humans demonstrate this by avoiding a certain food following the development of nausea after ingesting that food ('Sauce Bearnaise effect'). Here, we show that the pond snail Lymnaea stagnalis is capable of the Garcia effect. A single 'pairing' of a novel taste, a carrot slurry followed hours later by a heat shock stressor (HS) is sufficient to suppress feeding response elicited by carrot for at least 24 h. Other food tastes are not suppressed. If snails had previously been exposed to carrot as their food source, the Garcia-like effect does not occur when carrot is 'paired' with the HS. The HS up-regulates two heat shock proteins (HSPs), HSP70 and HSP40. Blocking the up-regulation of the HSPs by a flavonoid, quercetin, before the heat shock, prevented the Garcia effect in the snails. Finally, we found that snails exhibit Garcia effect following a period of food deprivation but the long-term memory (LTM) phenotype can be observed only if the animals are tested in a food satiated state.}, } @article {pmid33995059, year = {2021}, author = {Zhong, W and Darmani, NA}, title = {The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva).}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {647021}, pmid = {33995059}, issn = {1663-9812}, abstract = {Subtypes (1-4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in the central and peripheral nervous systems, as well as the cells of smooth muscles in many organs. They mainly serve to regulate cellular excitability in these tissues. The HCN channel blocker ZD7288 has been shown to reduce apomorphine-induced conditioned taste aversion on saccharin preference in rats suggesting potential antinausea/antiemetic effects. Currently, in the least shew model of emesis we find that ZD7288 induces vomiting in a dose-dependent manner, with maximal efficacies of 100% at 1 mg/kg (i.p.) and 83.3% at 10 µg (i.c.v.). HCN channel subtype (1-4) expression was assessed using immunohistochemistry in the least shrew brainstem dorsal vagal complex (DVC) containing the emetic nuclei (area postrema (AP), nucleus tractus solitarius and dorsal motor nucleus of the vagus). Highly enriched HCN1 and HCN4 subtypes are present in the AP. A 1 mg/kg (i.p.) dose of ZD7288 strongly evoked c-Fos expression and ERK1/2 phosphorylation in the shrew brainstem DVC, but not in the in the enteric nervous system in the jejunum, suggesting a central contribution to the evoked vomiting. The ZD7288-evoked c-Fos expression exclusively occurred in tryptophan hydroxylase 2-positive serotonin neurons of the dorsal vagal complex, indicating activation of serotonin neurons may contribute to ZD7288-induced vomiting. To reveal its mechanism(s) of emetic action, we evaluated the efficacy of diverse antiemetics against ZD7288-evoked vomiting including the antagonists/inhibitors of: ERK1/2 (U0126), L-type Ca[2+] channel (nifedipine); store-operated Ca[2+] entry (MRS 1845); T-type Ca[2+] channel (Z944), IP3R (2-APB), RyR receptor (dantrolene); the serotoninergic type 3 receptor (palonosetron); neurokinin 1 receptor (netupitant), dopamine type 2 receptor (sulpride), and the transient receptor potential vanilloid 1 receptor agonist, resiniferatoxin. All tested antiemetics except sulpride attenuated ZD7288-evoked vomiting to varying degrees. In sum, ZD7288 has emetic potential mainly via central mechanisms, a process which involves Ca[2+] signaling and several emetic receptors. HCN channel blockers have been reported to have emetic potential in the clinic since they are currently used/investigated as therapeutic candidates for cancer therapy related- or unrelated-heart failure, pain, and cognitive impairment.}, } @article {pmid33932558, year = {2021}, author = {Har-Paz, I and Arieli, E and Moran, A}, title = {ApoE4 attenuates cortical neuronal activity in young behaving apoE4 rats.}, journal = {Neurobiology of disease}, volume = {155}, number = {}, pages = {105373}, doi = {10.1016/j.nbd.2021.105373}, pmid = {33932558}, issn = {1095-953X}, mesh = {Action Potentials/*physiology ; Animals ; Apolipoprotein E4/*genetics ; Avoidance Learning/*physiology ; Cerebral Cortex/*physiology ; Female ; Humans ; Neurons/*physiology ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; }, abstract = {The E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD-related neuropathology. Understanding these primary dysfunctions is vital for the early detection of AD and the development of therapeutic strategies. Recently we reported impaired extra-hippocampal memory in young apoE4 mice, a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we tested the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 (hApoE4) and wildtype rats expressing rat apoE (rAE), before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young hApoE4 rats showed impaired CTA learning, consistent with our previous results in target-replacement apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Further taste coding analyses at the single neuron and ensemble levels revealed that GC neurons of the hApoE4 group correctly classified tastes, but were unable to undergo plasticity to support learning. These results suggest that apoE4 impacts brain excitability and plasticity early in life that may act as an initiator for later AD pathologies.}, } @article {pmid33930301, year = {2021}, author = {Yiannakas, A and Kolatt Chandran, S and Kayyal, H and Gould, N and Khamaisy, M and Rosenblum, K}, title = {Parvalbumin interneuron inhibition onto anterior insula neurons projecting to the basolateral amygdala drives aversive taste memory retrieval.}, journal = {Current biology : CB}, volume = {31}, number = {13}, pages = {2770-2784.e6}, doi = {10.1016/j.cub.2021.04.010}, pmid = {33930301}, issn = {1879-0445}, mesh = {Animals ; Avoidance Learning/physiology ; *Basolateral Nuclear Complex ; Interneurons ; Mammals ; Neurons/physiology ; Parvalbumins ; Taste/physiology ; }, abstract = {Memory retrieval refers to the fundamental ability of organisms to make use of acquired, sometimes inconsistent, information about the world. Although memory acquisition has been studied extensively, the neurobiological mechanisms underlying memory retrieval remain largely unknown. Conditioned taste aversion (CTA) is a robust associative paradigm, through which animals can be trained to express aversion toward innately appetitive tastants. The anterior insula (aIC) is indispensable in the ability of mammals to retrieve associative information regarding tastants that have been previously linked with gastric malaise. Here, we show that CTA memory retrieval promotes cell-type-specific activation in the aIC. Using chemogenetic tools in the aIC, we found that CTA memory acquisition requires activation of excitatory neurons and inhibition of inhibitory neurons, whereas retrieval necessitates activation of both excitatory and inhibitory aIC circuits. CTA memory retrieval at the aIC activates parvalbumin (PV) interneurons and increases synaptic inhibition onto activated pyramidal neurons projecting to the basolateral amygdala (aIC-BLA). Unlike innately appetitive taste memory retrieval, CTA retrieval increases synaptic inhibition onto aIC-BLA-projecting neurons that is dependent on activity in aIC PV interneurons. PV aIC interneurons coordinate CTA memory retrieval and are necessary for its dominance when conflicting internal representations are encountered over time. The reinstatement of CTA memories following extinction is also dependent on activation of aIC PV interneurons, which increase the frequency of inhibition onto aIC-BLA-projecting neurons. This newly described interaction of PV and a subset of excitatory neurons can explain the coherency of aversive memory retrieval, an evolutionary pre-requisite for animal survival.}, } @article {pmid33915300, year = {2021}, author = {Urrieta, E and Escobar, ML}, title = {Metaplastic regulation of neocortical long-term depression in vivo is sensitive to distinct phases of conditioned taste aversion.}, journal = {Neurobiology of learning and memory}, volume = {182}, number = {}, pages = {107449}, doi = {10.1016/j.nlm.2021.107449}, pmid = {33915300}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*physiology ; Basolateral Nuclear Complex/*physiology ; Extinction, Psychological/physiology ; Insular Cortex/*physiology ; Long-Term Synaptic Depression/*physiology ; Neocortex/physiology ; Neural Pathways/physiology ; Neuronal Plasticity/physiology ; Rats ; *Taste ; }, abstract = {Metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Accumulated evidence has proposed that metaplasticity contributes to network function and cognitive processes such as learning and memory. In this regard, it has been observed that training in several behavioral tasks modifies the possibility to induce subsequent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). For instance, our previous studies have shown that conditioned taste aversion (CTA) training prevents the induction of in vivo LTP in the projection from the basolateral nucleus of the amygdala to the insular cortex (BLA-IC). Likewise, we reported that extinction of CTA allows induction but not maintenance of LTP in the same pathway. Besides, we showed that it is possible to express in vivo low-frequency stimulation LTD in the BLA-IC projection and that its induction prior to CTA training facilitates the extinction of this task. However, until now, little is known about the participation of LTD on metaplastic processes. The present study aimed to analyze whether CTA training modifies the expression of in vivo LTD in the BLA-IC projection. To do so, animals received low-frequency stimulation to induce IC-LTD 48 h after CTA training. Our results show that CTA training occludes the subsequent induction of LTD in the BLA-IC pathway in a retrieval-dependent manner. These findings reveal that CTA elicits a metaplastic regulation of long-lasting changes in the IC synaptic strength, as well as that specific phases of learning differentially take part in adjusting the expression of synaptic plasticity in neocortical regions.}, } @article {pmid33872755, year = {2021}, author = {de Brugada, I and González, F and Cándido, A and Hall, G}, title = {Contextual control of the retardation of flavour aversion learning by preexposure to the unconditioned stimulus: Acquisition or retrieval deficit?.}, journal = {Behavioural processes}, volume = {188}, number = {}, pages = {104394}, doi = {10.1016/j.beproc.2021.104394}, pmid = {33872755}, issn = {1872-8308}, mesh = {Animals ; *Avoidance Learning ; *Conditioning, Classical ; Conditioning, Operant ; Cues ; Lithium Chloride/pharmacology ; Rats ; Taste ; }, abstract = {Two experiments, using rats as the subjects, and flavour aversion learning with an injection of lithium chloride (LiCl) as the unconditioned stimulus (US), examined the effects of a context shift between phases of the procedure on the retardation of learning produced by preexposure to the US. Experiment 1 showed that the US-preexposure effect (the reduction in the size of the conditioned aversion) was not attenuated when the animals were given both preexposure to the US and the conditioning procedure in a novel context but received the test phase in a different context (the home cages). Experiment 2 showed that, after degrading the injection cues-illness association by interpolating saline injections between LiCl preexposures, the US-preexposure effect was attenuated when there was a context shift between preexposure and conditioning, but that the context shift was without effect when it occurred between conditioning and test. These results are consistent with the proposal that US preexposure obtained in this procedure has its effect by interfering with the formation of the target association; they provide no support for the suggestion that the effect depends on interference at the test stage.}, } @article {pmid33831511, year = {2021}, author = {Osorio-Gómez, D and Bermúdez-Rattoni, F and Guzmán-Ramos, KR}, title = {Cortical neurochemical signaling of gustatory stimuli and their visceral consequences during the acquisition and consolidation of taste aversion memory.}, journal = {Neurobiology of learning and memory}, volume = {181}, number = {}, pages = {107437}, doi = {10.1016/j.nlm.2021.107437}, pmid = {33831511}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*physiology ; Brain/metabolism ; Cerebral Cortex/metabolism ; Dopamine/*metabolism ; Glutamic Acid/*metabolism ; Injections, Intraperitoneal ; Insular Cortex/*metabolism ; Interoception/physiology ; Lithium Chloride/adverse effects ; Norepinephrine/*metabolism ; Physical Stimulation ; Rats ; Receptors, Dopamine D1/metabolism ; Receptors, Dopamine D5/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Recognition, Psychology/*physiology ; Taste ; }, abstract = {The insular cortex (IC) has a crucial role in taste recognition memory, including conditioned taste aversion (CTA). CTA is a learning paradigm in which a novel taste stimulus (CS) is associated with gastric malaise (US), inducing aversion to the CS in future encounters. The role of the IC in CTA memory formation has been extensively studied. However, the functional significance of neurotransmitter release during the presentation of taste stimuli and gastric malaise-inducing agents remains unclear. Using microdialysis in free-moving animals, we evaluated simultaneous changes in glutamate, norepinephrine and dopamine release in response to the presentation of an innate appetitive or aversive gustatory novel stimulus, as well as after i.p. administration of isotonic or hypertonic gastric malaise-inducing solutions. Our results demonstrate that the presentation of novel stimuli, regardless of their innate valence, induces an elevation of norepinephrine and dopamine. Administration of a gastric malaise inducing agent (LiCl) promotes an elevation of glutamate regardless of its concentration. In comparison, norepinephrine release is related to the LiCl concentration and its equimolar NaCl control. Additionally, we evaluated their functional role on short and long-term taste aversion memory. Results indicate that the blockade of noradrenergic β1,2 receptors in the IC spares CTA acquisition and memory consolidation. In contrast, blockade of dopamine D1/D5 receptors impaired CTA consolidation, whereas the NMDA receptor blockade impedes both acquisition and consolidation of CTA. These results suggest that dopaminergic and noradrenergic release are related to the salience of conditioned taste stimuli. However, only cortical D1/D5 dopaminergic activity, but not the noradrenergic β1,2 activity, is involved in the acquisition and consolidation of taste memory formation. Additionally, glutamatergic activity signals visceral distress caused by LiCl administration and activates NMDA receptors necessary for the acquisition and consolidation of long-lasting taste aversion memory.}, } @article {pmid33809564, year = {2021}, author = {Kotańska, M and Mika, K and Szafarz, M and Kubacka, M and Müller, CE and Sapa, J and Kieć-Kononowicz, K}, title = {Effects of GPR18 Ligands on Body Weight and Metabolic Parameters in a Female Rat Model of Excessive Eating.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {3}, pages = {}, pmid = {33809564}, issn = {1424-8247}, abstract = {GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass and the development of metabolic disorders commonly accompanying obesity. Experiments were carried out on female Wistar rats. In order to determine the anorectic activity of the investigated ligands, their effect on food and water intake in a model of excessive eating was assessed. Lipid profile, glucose and insulin levels as well as alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activity in plasma were also evaluated. Potential side effects were examined in rat models of pica behavior and conditioned taste aversion. Animals treated with different ligands gained significantly less weight than rats from the obese control group. Effects of GPR18 antagonists on food intake and body weight were specific and unrelated to visceral illness, stress or changes in spontaneous activity. However, the GPR18 agonist is likely to affect body weight by inducing gastrointestinal disorders such as nausea. The presented preliminary data support the idea that the search for selective GPR18 antagonists for the treatment of obesity might be promising.}, } @article {pmid33804920, year = {2021}, author = {Calder, AN and Yu, T and Dahir, NS and Sun, Y and Gilbertson, TA}, title = {Ghrelin Receptors Enhance Fat Taste Responsiveness in Female Mice.}, journal = {Nutrients}, volume = {13}, number = {4}, pages = {}, pmid = {33804920}, issn = {2072-6643}, support = {R01 DC013318/DC/NIDCD NIH HHS/United States ; R21 DC013194/DC/NIDCD NIH HHS/United States ; R01DC013318, R21DC013194/NH/NIH HHS/United States ; }, mesh = {Animal Feed ; Animals ; Appetite/*physiology ; Fats/*administration & dosage ; Feeding Behavior/*physiology ; Female ; Mice ; Mice, Transgenic ; Models, Animal ; Receptors, Ghrelin/*metabolism ; Taste/*physiology ; }, abstract = {Ghrelin is a major appetite-stimulating neuropeptide found in circulation. While its role in increasing food intake is well known, its role in affecting taste perception, if any, remains unclear. In this study, we investigated the role of the growth hormone secretagogue receptor's (GHS-R; a ghrelin receptor) activity in the peripheral taste system using feeding studies and conditioned taste aversion assays by comparing wild-type and GHS-R-knockout models. Using transgenic mice expressing enhanced green fluorescent protein (GFP), we demonstrated GHS-R expression in the taste system in relation phospholipase C ß2 isotype (PLCβ2; type II taste cell marker)- and glutamate decarboxylase type 67 (GAD67; type III taste cell marker)-expressing cells using immunohistochemistry. We observed high levels of co-localization between PLCβ2 and GHS-R within the taste system, while GHS-R rarely co-localized in GAD67-expressing cells. Additionally, following 6 weeks of 60% high-fat diet, female Ghsr[-/-] mice exhibited reduced responsiveness to linoleic acid (LA) compared to their wild-type (WT) counterparts, while no such differences were observed in male Ghsr[-/-] and WT mice. Overall, our results are consistent with the interpretation that ghrelin in the taste system is involved in the complex sensing and recognition of fat compounds. Ghrelin-GHS-R signaling may play a critical role in the recognition of fatty acids in female mice, and this differential regulation may contribute to their distinct ingestive behaviors.}, } @article {pmid33798429, year = {2021}, author = {Wu, CH and Ramos, R and Katz, DB and Turrigiano, GG}, title = {Homeostatic synaptic scaling establishes the specificity of an associative memory.}, journal = {Current biology : CB}, volume = {31}, number = {11}, pages = {2274-2285.e5}, pmid = {33798429}, issn = {1879-0445}, support = {R01 EY025613/EY/NEI NIH HHS/United States ; T32 MH019929/MH/NIMH NIH HHS/United States ; F31 NS108506/NS/NINDS NIH HHS/United States ; R01 DC006666/DC/NIDCD NIH HHS/United States ; R35 NS111562/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/drug effects ; *Conditioning, Classical/drug effects ; Female ; *Homeostasis/drug effects ; Insular Cortex/*physiology ; Male ; *Memory/drug effects ; *Neuronal Plasticity/drug effects ; Rats ; Saccharin/*administration & dosage ; Synapses/drug effects/*metabolism ; }, abstract = {Correlation-based (Hebbian) forms of synaptic plasticity are crucial for the initial encoding of associative memories but likely insufficient to enable the stable storage of multiple specific memories within neural circuits. Theoretical studies have suggested that homeostatic synaptic normalization rules provide an essential countervailing force that can stabilize and expand memory storage capacity. Although such homeostatic mechanisms have been identified and studied for decades, experimental evidence that they play an important role in associative memory is lacking. Here, we show that synaptic scaling, a widely studied form of homeostatic synaptic plasticity that globally renormalizes synaptic strengths, is dispensable for initial associative memory formation but crucial for the establishment of memory specificity. We used conditioned taste aversion (CTA) learning, a form of associative learning that relies on Hebbian mechanisms within gustatory cortex (GC), to show that animals conditioned to avoid saccharin initially generalized this aversion to other novel tastants. Specificity of the aversion to saccharin emerged slowly over a time course of many hours and was associated with synaptic scaling down of excitatory synapses onto conditioning-active neuronal ensembles within gustatory cortex. Blocking synaptic scaling down in the gustatory cortex enhanced the persistence of synaptic strength increases induced by conditioning and prolonged the duration of memory generalization. Taken together, these findings demonstrate that synaptic scaling is crucial for sculpting the specificity of an associative memory and suggest that the relative strengths of Hebbian and homeostatic plasticity can modulate the balance between stable memory formation and memory generalization.}, } @article {pmid33693689, year = {2021}, author = {Igarashi, A and Ogasawara, S and Takagi, R and Okada, K and Ito, YM and Hara, H and Hira, T}, title = {Acute Oral Calcium Suppresses Food Intake Through Enhanced Peptide-YY Secretion Mediated by the Calcium-Sensing Receptor in Rats.}, journal = {The Journal of nutrition}, volume = {151}, number = {5}, pages = {1320-1328}, doi = {10.1093/jn/nxab013}, pmid = {33693689}, issn = {1541-6100}, mesh = {Administration, Oral ; Animals ; *Appetite Regulation ; Calcium/administration & dosage/*pharmacology ; Calcium Chloride/pharmacology ; Calcium, Dietary/administration & dosage/*pharmacology ; Eating/*drug effects ; Energy Intake/drug effects ; Fasting ; Male ; Peptide YY/*blood ; Postprandial Period ; Rats, Sprague-Dawley ; Receptors, Calcium-Sensing/*blood ; Receptors, Gastrointestinal Hormone/metabolism ; Satiation ; Satiety Response/*drug effects ; }, abstract = {BACKGROUND: Dietary calcium has been proposed to reduce appetite in human studies. Postprandial satiety is mainly controlled by gut hormones. However, the effect of calcium on appetite and the role of gut hormones remain unclear.

OBJECTIVES: We examined whether oral administration of calcium reduces food intake in rats and investigated the underlying mechanism.

METHODS: Male Sprague Dawley rats (8-12 wk old) were used after an overnight fastifffng. In a series of 2 trials with 1-wk interval between challenges, food intake was measured 0.5-24 h after oral gavage of a vehicle (saline containing 1.5% carboxymethyl cellulose) as the control treatment, or the vehicle containing various calcium compounds [calcium chloride (CaCl2), calcium carbonate, calcium lactate, in a random order] at 150 mg calcium/kg dose. A conditional taste aversion test was conducted. In separate experiments, plasma calcium and gut hormone concentrations were measured 15 or 30 min after oral administration of the calcium compounds. In anesthetized rats, portal peptide-YY (PYY) concentrations were measured after intraluminal administration of a liquid meal with or without additional calcium.

RESULTS: Oral CaCl2 reduced food intake acutely (30 min, ∼20%, P < 0.05) compared with control rats, without taste aversion. Plasma PYY concentration was higher (100%, P < 0.05) in CaCl2-preloaded rats than in control rats, 15 min after administration. In anesthetized rats, luminal meal + CaCl2 induced a 4-fold higher increase in plasma PYY than the control treatment did. Oral administration of a calcium-sensing receptor (CaSR) agonist suppressed food intake (∼30%, P < 0.05), but CaCl2 and CaSR agonist did not suppress food intake under treatment with a PYY receptor antagonist. Furthermore, the CaSR antagonist attenuated the effect of CaCl2 on food intake.

CONCLUSIONS: CaCl2 suppresses food intake partly by increasing CaSR-mediated PYY secretion in rats. Our findings could at least partially explain the satiating effect of calcium.}, } @article {pmid33605825, year = {2021}, author = {Karavasili, C and Gkaragkounis, A and Fatouros, DG}, title = {Patent landscape of pediatric-friendly oral dosage forms and administration devices.}, journal = {Expert opinion on therapeutic patents}, volume = {31}, number = {7}, pages = {663-686}, doi = {10.1080/13543776.2021.1893691}, pmid = {33605825}, issn = {1744-7674}, mesh = {Administration, Oral ; Chemistry, Pharmaceutical/*methods ; Child ; *Dosage Forms ; Drug Industry/methods ; Excipients/chemistry ; Humans ; Patents as Topic ; Pharmaceutical Preparations/administration & dosage/chemistry ; Taste ; Technology, Pharmaceutical/*methods ; }, abstract = {INTRODUCTION: The current availability of dosage forms designed specifically for children is limited, constituting common practice the use of unlicensed or off-labeled medicines and extemporaneous preparations. Swallowing difficulties and taste aversion are the primary reasons for medicine rejection; therefore, enhancing palatability and ease of administration are the most common approaches adopted to overcome these issues.

AREAS COVERED: A search of patents was performed for pediatric dosage forms and devices. The review aims to provide an overview on new formulation approaches and technologies adopted to develop pediatric-friendly dosage forms and devices, as well as on the regulatory efforts aiming to support the pediatrics market.

EXPERT OPINION: Children deserve medicines of the same efficacy, quality and safety as adults. The present review highlights the momentum developed by pharmaceutical industries in the field of pediatrics, since more than 60 patents have been published in the last 5 years. An increasing interest, especially in mini-tablets, orodispersible, and chewable dosage forms, as well as on excipients and methods, to achieve sufficient taste-masking was identified, recognizing also the need for coordinated research networks and sustainable collaborations across the public and private sectors to provide better medicines for children.}, } @article {pmid33593916, year = {2021}, author = {Sabatini, PV and Frikke-Schmidt, H and Arthurs, J and Gordian, D and Patel, A and Rupp, AC and Adams, JM and Wang, J and Beck Jørgensen, S and Olson, DP and Palmiter, RD and Myers, MG and Seeley, RJ}, title = {GFRAL-expressing neurons suppress food intake via aversive pathways.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {8}, pages = {}, pmid = {33593916}, issn = {1091-6490}, support = {T32 DK071212/DK/NIDDK NIH HHS/United States ; T32 DK101357/DK/NIDDK NIH HHS/United States ; P30 DK089503/DK/NIDDK NIH HHS/United States ; P30 DK034933/DK/NIDDK NIH HHS/United States ; R01 DA024908/DA/NIDA NIH HHS/United States ; P30 DK020572/DK/NIDDK NIH HHS/United States ; R01 DK119188/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*drug effects ; Body Weight ; Eating/*drug effects ; Feeding Behavior/*drug effects ; Female ; Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics/*metabolism ; Growth Differentiation Factor 15/*pharmacology ; Male ; Mice ; Neurons/drug effects/*physiology ; Parabrachial Nucleus/drug effects/*physiology ; Rats ; Rats, Long-Evans ; }, abstract = {The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated Gfral[Cre] and conditional Gfral[CreERT] mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating Gfral[Cre] -expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRP[PBN]) neurons. Silencing CGRP[PBN] neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.}, } @article {pmid33511630, year = {2021}, author = {Dannenhoffer, CA and Werner, DF and Varlinskaya, EI and Spear, LP}, title = {Adolescent intermittent ethanol exposure does not alter responsiveness to ifenprodil or expression of vesicular GABA and glutamate transporters.}, journal = {Developmental psychobiology}, volume = {63}, number = {5}, pages = {903-914}, pmid = {33511630}, issn = {1098-2302}, support = {T32 AA025606/AA/NIAAA NIH HHS/United States ; U01 AA019972/AA/NIAAA NIH HHS/United States ; }, mesh = {*Amino Acid Transport System X-AG ; Animals ; *Ethanol/pharmacology ; Female ; Glutamates ; Male ; Piperidines ; Rats ; gamma-Aminobutyric Acid ; }, abstract = {Adolescent intermittent ethanol (AIE) exposure in the rat results in a retention of adolescent-like responsiveness to ethanol into adulthood characterized by enhanced sensitivity to socially facilitating and decreased sensitivity to socially suppressing and aversive effects. Similar pattern of responsiveness to social and aversive effects of the selective glutamate NMDA NR2B receptor antagonist ifenprodil is evident in adolescent rats, suggesting that AIE would also retain this pattern of ifenprodil sensitivity into adulthood. Social (Experiment 1) and aversive (measured via conditioned taste aversion; Experiment 2) effects of ifenprodil were assessed in adult male and female rats following AIE exposure. Sensitivity to the social and aversive effects of ifenprodil was not affected by AIE exposure. Experiment 3 assessed protein expression of vesicular transporters of GABA (vGAT) and glutamate (vGlut2) within the prelimbic cortex and nucleus accumbens in adolescents versus adults and in AIE adults versus controls. vGlut2 expression was higher in adolescents relative to adults within the PrL, but lower in the NAc. AIE adults did not retain these adolescent-typical ratios. These findings suggest that AIE is not associated with the retention of adolescent-typical sensitivity to NR2B receptor antagonism, along with no AIE-induced shift in vGlut2 to vGAT ratios.}, } @article {pmid33502048, year = {2021}, author = {Indigo, NL and Jolly, CJ and Kelly, E and Smith, J and Webb, JK and Phillips, BL}, title = {Effects of learning and adaptation on population viability.}, journal = {Conservation biology : the journal of the Society for Conservation Biology}, volume = {35}, number = {4}, pages = {1245-1255}, doi = {10.1111/cobi.13691}, pmid = {33502048}, issn = {1523-1739}, mesh = {Animals ; Biological Evolution ; Bufo marinus ; *Conservation of Natural Resources ; Humans ; *Marsupialia ; Phenotype ; }, abstract = {Cultural adaptation is one means by which conservationists may help populations adapt to threats. A learned behavior may protect an individual from a threat, and the behavior can be transmitted horizontally (within generations) and vertically (between generations), rapidly conferring population-level protection. Although possible in theory, it remains unclear whether such manipulations work in a conservation setting; what conditions are required for them to work; and how they might affect the evolutionary process. We examined models in which a population can adapt through both genetic and cultural mechanisms. Our work was motivated by the invasion of highly toxic cane toads (Rhinella marina) across northern Australia and the resultant declines of endangered northern quolls (Dasyurus hallucatus), which attack and are fatally poisoned by the toxic toads. We examined whether a novel management strategy in which wild quolls are trained to avoid toads can reduce extinction probability. We used a simulation model tailored to quoll life history. Within simulations, individuals were trained and a continuous evolving trait determined innate tendency to attack toads. We applied this model in a population viability setting. The strategy reduced extinction probability only when heritability of innate aversion was low (<20%) and when trained mothers trained >70% of their young to avoid toads. When these conditions were met, genetic adaptation was slower, but rapid cultural adaptation kept the population extant while genetic adaptation was completed. To gain insight into the evolutionary dynamics (in which we saw a transitory peak in cultural adaptation over time), we also developed a simple analytical model of evolutionary dynamics. This model showed that the strength of natural selection declined as the cultural transmission rate increased and that adaptation proceeded only when the rate of cultural transmission was below a critical value determined by the relative levels of protection conferred by genetic versus cultural mechanisms. Together, our models showed that cultural adaptation can play a powerful role in preventing extinction, but that rates of cultural transmission need to be high for this to occur.}, } @article {pmid33443041, year = {2021}, author = {Itoh, A and Komatsuzaki, Y and Lukowiak, K and Saito, M}, title = {Epicatechin increases the persistence of long-term memory formed by conditioned taste aversion in Lymnaea.}, journal = {The Journal of experimental biology}, volume = {224}, number = {Pt 3}, pages = {}, doi = {10.1242/jeb.238055}, pmid = {33443041}, issn = {1477-9145}, mesh = {Animals ; *Catechin ; Conditioning, Operant ; Feeding Behavior ; *Lymnaea ; Memory, Long-Term ; Taste ; }, abstract = {We examined the effects of epicatechin (Epi), a flavonoid abundant in green tea and cocoa, on long-term memory (LTM) formed following conditioned taste aversion (CTA) training in Lymnaeastagnalis In CTA training, the snails learnt to avoid a food that initially they liked (i.e. sucrose). Twenty-four hours after CTA training, 67% of the trained snails showed a significant decrease in the feeding behaviour elicited by sucrose. Placing snails in the Epi solution in CTA training did not alter the percentage of snails exhibiting LTM, but it significantly increased LTM persistence. We also examined changes following Epi exposure in spontaneous activity of the cerebral giant cells (CGCs) that modulate feeding behaviour and are necessary for CTA-LTM. Our data suggest that Epi causes a decrease in CGC activity and increases LTM persistence, possibly via a GABAergic mechanism.}, } @article {pmid33383859, year = {2020}, author = {Toyoda, H and Katagiri, A and Kato, T and Sato, H}, title = {Intranasal Administration of Rotenone Reduces GABAergic Inhibition in the Mouse Insular Cortex Leading to Impairment of LTD and Conditioned Taste Aversion Memory.}, journal = {International journal of molecular sciences}, volume = {22}, number = {1}, pages = {}, pmid = {33383859}, issn = {1422-0067}, mesh = {Administration, Intranasal ; Animals ; Cerebral Cortex/cytology/*drug effects/*metabolism ; GABAergic Neurons/*drug effects/*metabolism ; Long-Term Potentiation/*drug effects ; *Memory ; Mice ; Pyramidal Cells/drug effects/metabolism ; Receptors, GABA-A/metabolism ; Rotenone/*administration & dosage ; Taste Perception/*drug effects/genetics ; }, abstract = {The pesticide rotenone inhibits mitochondrial complex I and is thought to cause neurological disorders such as Parkinson's disease and cognitive disorders. However, little is known about the effects of rotenone on conditioned taste aversion memory. In the present study, we investigated whether intranasal administration of rotenone affects conditioned taste aversion memory in mice. We also examined how the intranasal administration of rotenone modulates synaptic transmission and plasticity in layer V pyramidal neurons of the mouse insular cortex that is critical for conditioned taste aversion memory. We found that the intranasal administration of rotenone impaired conditioned taste aversion memory to bitter taste. Regarding its cellular mechanisms, long-term depression (LTD) but not long-term potentiation (LTP) was impaired in rotenone-treated mice. Furthermore, spontaneous inhibitory synaptic currents and tonic GABA currents were decreased in layer V pyramidal neurons of rotenone-treated mice compared to the control mice. The impaired LTD observed in pyramidal neurons of rotenone-treated mice was restored by a GABAA receptor agonist muscimol. These results suggest that intranasal administration of rotenone decreases GABAergic synaptic transmission in layer V pyramidal neurons of the mouse insular cortex, the result of which leads to impairment of LTD and conditioned taste aversion memory.}, } @article {pmid33357702, year = {2021}, author = {Kawabata, F and Yoshida, Y and Inoue, Y and Kawabata, Y and Nishimura, S and Tabata, S}, title = {Research Note: Behavioral preference and conditioned taste aversion to oleic acid solution in chickens.}, journal = {Poultry science}, volume = {100}, number = {1}, pages = {372-376}, pmid = {33357702}, issn = {1525-3171}, mesh = {Animals ; *Avoidance Learning/drug effects ; *Chickens ; *Feeding Behavior/drug effects ; Female ; Oleic Acid/pharmacology ; *Taste ; }, abstract = {A functional fatty acid taste receptor, GPR120, is present in chicken oral tissues, and chickens show a preference for lipid in feed. However, it remains unclear whether chickens can detect fatty acids. To address this issue, we adopted 2 behavioral paradigms: a one-bowl drinking test to evaluate the preference for oleic acid solution and a conditioned taste aversion test to investigate the role of gustation in chickens' ability to detect oleic acid. In the one-bowl drinking test, chickens did not show any preference for solution containing 0.001, 0.01, 0.03, 0.1, or 30 mmol/L oleic acid although 30 mmol/L oleic acid was enough to fully activate GPR120, confirmed by Ca[2+] imaging. On the other hand, chickens conditioned to avoid 30 mmol/L oleic acid solution also learned to avoid the solution. These results suggested that chickens have a gustatory perception of oleic acid solution but do not have a preference for it. The present results support the idea that chickens prefer lipid in feed, not only by a postingestive effect but also by sensing the taste of fatty acid.}, } @article {pmid33352200, year = {2021}, author = {Wyszogrodzka, E and Dyr, W and Siwińska-Ziółkowska, A and Mierzejewski, P}, title = {Higher sensitivity to ethanol's aversive properties in WLP (Warsaw Low Preferring) vs. WHP (Warsaw High Preferring) rats.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {90}, number = {}, pages = {67-73}, doi = {10.1016/j.alcohol.2020.12.002}, pmid = {33352200}, issn = {1873-6823}, mesh = {*Alcohol Drinking ; Animals ; Anxiety ; *Avoidance Learning ; *Conditioning, Classical ; Ethanol/administration & dosage ; Rats ; }, abstract = {Ethanol can have both an aversive and rewarding effect, which may have a significant relationship to its individual preference. So far, the reasons for the high and low ethanol preference in the WHP (Warsaw High Preferring) and WLP (Warsaw Low Preferring) lines have not been found. WHP rats spontaneously drink over 5 g/kg/day of ethanol, while WLP rats drink under 2 g/kg/day. The purpose of the work was to study the sensitivity of WHP and WLP rats to the aversive effects of ethanol at doses of 1.5 g/kg and 2.0 g/kg in the conditioned taste aversion (CTA) procedure. Lower doses (0.5 and 1.0 g/kg, i.p. [intraperitoneally]) were tested earlier and only 1.0 g/kg produced a slight aversion in WLP rats. The secondary aim was to check the additional potential factors (blood ethanol concentration, pain sensitivity, anxiety-related behavior, learning, and memory) that may constitute an important differentiating feature of the WHP and WLP lines. For this purpose, the following tests were conducted: blood ethanol concentration, novel object recognition (NOR), flinch-jump, hot-plate, and elevated plus maze (EPM). The 1.5 g/kg i.p. dose of ethanol caused the development of an aversion only in WLP rats and the aversion extinguished in the post-conditioning phase. The 2.0 g/kg i.p. dose of ethanol resulted in the development of an aversion in both the tested groups, with the aversion being maintained throughout the whole post-conditioning period only in the WLP rats. There were no differences between the lines in terms of the blood ethanol concentration and the EPM tests. WHP rats had a higher pain sensitivity compared to WLP rats in flinch-jump and hot-plate tests. WLP rats showed a shorter exploration time for both objects compared to WHP in the NOR test. In conclusion, WHP and WLP rats differ in sensitivity to the aversive effects of ethanol. This difference may partially explain their opposite ethanol preference.}, } @article {pmid33333877, year = {2020}, author = {Robinson, SL and Dornellas, APS and Burnham, NW and Houck, CA and Luhn, KL and Bendrath, SC and Companion, MA and Brewton, HW and Thomas, RD and Navarro, M and Thiele, TE}, title = {Distinct and Overlapping Patterns of Acute Ethanol-Induced C-Fos Activation in Two Inbred Replicate Lines of Mice Selected for Drinking to High Blood Ethanol Concentrations.}, journal = {Brain sciences}, volume = {10}, number = {12}, pages = {}, pmid = {33333877}, issn = {2076-3425}, support = {AA022048/AA/NIAAA NIH HHS/United States ; R37 AA013573/AA/NIAAA NIH HHS/United States ; T32 DA007244/DA/NIDA NIH HHS/United States ; AA013573/AA/NIAAA NIH HHS/United States ; AA025811/AA/NIAAA NIH HHS/United States ; R01 AA025809/AA/NIAAA NIH HHS/United States ; AA025809/AA/NIAAA NIH HHS/United States ; }, abstract = {UNLABELLED: The inbred high drinking in the dark (iHDID1 and iHDID2) strains are two replicate lines bred from the parent HS/Npt (HS) line for achieving binge levels of blood ethanol concentration (≥80 mg/dL BEC) in a four-hour period. In this work, we sought to evaluate differences in baseline and ethanol-induced c-Fos activation between the HS, iHDID1, and iHDID2 genetic lines in brain regions known to process the aversive properties of ethanol.

METHODS: Male and female HS, iHDID1, and iHDID2 mice underwent an IP saline 2 3 g/kg ethanol injection. Brain sections were then stained for c-Fos expression in the basolateral/central amygdala (BLA/CeA), bed nucleus of the stria terminals (BNST), A2, locus coeruleus (LC), parabrachial nucleus (PBN), lateral/medial habenula (LHb/MHb), paraventricular nucleus of the thalamus (PVT), periaqueductal gray (PAG), Edinger-Westphal nuclei (EW), and rostromedial tegmental nucleus (RMTg).

RESULTS: The iHDID1 and iHDID2 lines showed similar and distinct patterns of regional c-Fos; however, in no region did the two both significantly differ from the HS line together.

CONCLUSIONS: These data lend further support to altered baseline or ethanol-induced activation in brain regions associated with processing the aversive properties of ethanol in the iHDID1 and iHDID2 genetic lines.}, } @article {pmid33290705, year = {2020}, author = {Stensmyr, MC and Caron, SJC}, title = {Neuroscience: The Secret of Sauce Béarnaise Syndrome Is in the Circuit.}, journal = {Current biology : CB}, volume = {30}, number = {23}, pages = {R1413-R1415}, doi = {10.1016/j.cub.2020.09.085}, pmid = {33290705}, issn = {1879-0445}, mesh = {Animals ; *Avoidance Learning ; Cues ; Eating ; *Mushroom Bodies ; Taste ; }, abstract = {During conditioned food aversion - a.k.a. sauce béarnaise syndrome - the ingestion of a spoiled food item leads to a lasting aversion towards cues reminiscent of the item. A new study finds that, in Drosophila, taste aversion depends on the immune system and the mushroom body.}, } @article {pmid33256267, year = {2020}, author = {Nakai, J and Totani, Y and Hatakeyama, D and Dyakonova, VE and Ito, E}, title = {Another Example of Conditioned Taste Aversion: Case of Snails.}, journal = {Biology}, volume = {9}, number = {12}, pages = {}, pmid = {33256267}, issn = {2079-7737}, abstract = {Conditioned taste aversion (CTA) in mammals has several specific characteristics: (1) emergence of a negative symptom in subjects due to selective association with a taste-related stimulus, (2) robust long-term memory that is resistant to extinction induced by repeated presentation of the conditioned stimulus (CS), (3) a very-long-delay presentation of the unconditioned stimulus (US), and (4) single-trial learning. The pond snail, Lymnaea stagnalis, can also form a CTA. Although the negative symptoms, like nausea, in humans cannot be easily observed in invertebrate animal models of CTA, all the other characteristics of CTA seem to be present in snails. Selective associability was confirmed using a sweet sucrose solution and a bitter KCl solution. Once snails form a CTA, repeated presentation of the CS does not extinguish the CTA. A long interstimulus interval between the CS and US, like in trace conditioning, still results in the formation of a CTA in snails. Lastly, even single-trial learning has been demonstrated with a certain probability. In the present review, we compare, in detail, CTA in mammals and snails, and discuss the possible molecular events in CTA.}, } @article {pmid33169666, year = {2020}, author = {Haley, MS and Bruno, S and Fontanini, A and Maffei, A}, title = {LTD at amygdalocortical synapses as a novel mechanism for hedonic learning.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, pmid = {33169666}, issn = {2050-084X}, support = {NS115779//NIH Blueprint for Neuroscience Research/International ; DC013770//NIH Blueprint for Neuroscience Research/International ; R01 DC015234/DC/NIDCD NIH HHS/United States ; R01 DC013770/DC/NIDCD NIH HHS/United States ; DC015234//NIH Blueprint for Neuroscience Research/International ; UF1 NS115779/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*physiology ; Basolateral Nuclear Complex/*physiology ; Cerebral Cortex/*physiology ; Conditioning, Classical/*physiology ; Female ; Male ; *Models, Neurological ; Neuronal Plasticity/physiology ; Optogenetics ; Rats ; Synapses/*physiology ; Taste Perception ; }, abstract = {A novel, pleasant taste stimulus becomes aversive if associated with gastric malaise, a form of learning known as conditioned taste aversion (CTA). CTA is common to vertebrates and invertebrates and is an important survival response: eating the wrong food may be deadly. CTA depends on the gustatory portion of the insular cortex (GC) and the basolateral nucleus of the amygdala (BLA) however, its synaptic underpinnings are unknown. Here we report that CTA was associated with decreased expression of immediate early genes in rat GC of both sexes, and with reduced amplitude of BLA-GC synaptic responses, pointing to long-term depression (LTD) as a mechanism for learning. Indeed, association of a novel tastant with induction of LTD at the BLA-GC input in vivo was sufficient to change the hedonic value of a taste stimulus. Our results demonstrate a direct role for amygdalocortical LTD in taste aversion learning.}, } @article {pmid33152457, year = {2021}, author = {Morin, JP and Rodríguez-Nava, E and Torres-García, VM and Contreras-Vázquez, OA and Castellanos-Pérez, CA and Tovar-Díaz, J and Roldán-Roldán, G}, title = {Muscarinic receptor signaling in the amygdala is required for conditioned taste aversion.}, journal = {Neuroscience letters}, volume = {740}, number = {}, pages = {135466}, doi = {10.1016/j.neulet.2020.135466}, pmid = {33152457}, issn = {1872-7972}, mesh = {Amygdala/drug effects/*physiology ; Animals ; Avoidance Learning/drug effects/*physiology ; Emotions ; Male ; Memory Consolidation/drug effects ; Mental Recall/drug effects ; Microinjections ; Muscarinic Antagonists/administration & dosage/pharmacology ; Parasympathetic Nervous System/drug effects/physiology ; Rats ; Rats, Wistar ; Receptors, Muscarinic/drug effects/*physiology ; Scopolamine/administration & dosage/pharmacology ; Signal Transduction/drug effects/*physiology ; Taste/drug effects/*physiology ; }, abstract = {The sense of taste provides information regarding the nutrient content, safety or potential toxicity of an edible. This is accomplished via a combination of innate and learned taste preferences. In conditioned taste aversion (CTA), rats learn to avoid ingesting a taste that has previously been paired with gastric malaise. Recent evidence points to a role of cholinergic muscarinic signaling in the amygdala for the learning and storage of emotional memories. The present study tested the participation of muscarinic receptors in the amygdala during the formation of CTA by infusing the non-specific antagonist scopolamine into the basolateral or central subnuclei before or after conditioning, as well as before retrieval. Our data show that regardless of the site of infusion, pre-conditioning administration of scopolamine impaired CTA acquisition whereas post-conditioning infusion did not affect its storage. Also, infusions into the basolateral but not in the central amygdala before retrieval test partially reduced the expression of CTA. Our results indicate that muscarinic receptors activity is required for acquisition but not consolidation of CTA. In addition, our data add to recent evidence pointing to a role of cholinergic signaling in peri-hippocampal structures in the process of memory retrieval.}, } @article {pmid33119327, year = {2021}, author = {Steinfeld, MR and Bouton, ME}, title = {Renewal of goal direction with a context change after habit learning.}, journal = {Behavioral neuroscience}, volume = {135}, number = {1}, pages = {79-87}, pmid = {33119327}, issn = {1939-0084}, support = {R01 DA033123/DA/NIDA NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Animals ; Extinction, Psychological ; Female ; *Goals ; *Habits ; *Learning ; Motivation ; Rats ; }, abstract = {An instrumental action can be goal-directed after a moderate amount of practice and then convert to habit after more extensive practice. Recent evidence suggests, however, that habits can return to action status after different environmental manipulations. The present experiments therefore asked whether habit learning interferes with goal direction in a context-dependent manner like other types of retroactive interference (e.g., extinction, punishment, counterconditioning). In Experiment 1, rats were given a moderate amount of instrumental training to form an action in one context (Context A) and then more extended training of the same response to form a habit in another context (Context B). We then performed reinforcer devaluation with taste aversion conditioning in both contexts, and tested the response in both contexts. The response remained habitual in Context B, but was goal-directed in Context A, indicating renewal of goal direction after habit learning. Experiment 2 expanded on Experiment 1 by testing the response in a third context (Context C). It found that the habitual response also renewed as action in this context. Together, the results establish a parallel between habit and extinction learning: Conversion to habit does not destroy action knowledge, but interferes with it in a context-specific way. They are also consistent with other results suggesting that habit is specific to the context in which it is learned, whereas goal-direction can transfer between contexts. (PsycInfo Database Record (c) 2021 APA, all rights reserved).}, } @article {pmid33077494, year = {2020}, author = {Fonseca, E and Sandoval-Herrera, V and Simon, SA and Gutierrez, R}, title = {Behavioral Disassociation of Perceived Sweet Taste Intensity and Hedonically Positive Palatability.}, journal = {eNeuro}, volume = {7}, number = {5}, pages = {}, pmid = {33077494}, issn = {2373-2822}, mesh = {Animals ; Conditioning, Classical ; Food Preferences ; Rats ; Sucrose ; *Taste ; *Taste Perception ; }, abstract = {The intensity of sucrose (its perceived concentration) and its palatability (positive hedonic valence associated with ingestion) are two taste attributes that increase its attractiveness and overconsumption. Although both sensory attributes covary, in that increases in sucrose concentration leads to similar increases in its palatability, this covariation does not imply that they are part of the same process or whether they represent separate processes. Both these possibilities are considered in the literature. For this reason, we tested whether sucrose's perceived intensity could be separated from its hedonically positive palatability. To address this issue, rats were trained in a sucrose intensity task to report the perceived intensity of a range of sucrose concentrations before and after its palatability was changed using a conditioned taste aversion (CTA) protocol. We found that the subjects' performance remained essentially unchanged, although its palatability was changed from hedonically positive to negative. Overall, these data demonstrate that sucrose's perceived intensity and its positive palatability can be dissociated, meaning that changes of one taste attribute render the other mostly unaffected. Thus, the intensity attribute is sufficient to inform the perceptual judgments of sucrose's concentrations.}, } @article {pmid33065316, year = {2020}, author = {Sato, T and Hirai, Y and Su, S and Zimo, W and Yasuura, N and Inui, T and Funahashi, M}, title = {Involvement of the area postrema and the nucleus tractus solitarius in the emetogenic action of emetine in rats.}, journal = {Journal of oral biosciences}, volume = {62}, number = {4}, pages = {310-314}, doi = {10.1016/j.job.2020.10.001}, pmid = {33065316}, issn = {1880-3865}, mesh = {Animals ; *Area Postrema ; Emetics ; Emetine ; Nausea ; Rats ; *Solitary Nucleus ; }, abstract = {OBJECTIVES: The aim of the present study was to demonstrate the effective dose of emetine for inducing nausea and/or emesis, and the effects of emetine on the excitability of central neurons in the area postrema (AP) and the nucleus tractus solitarius (NTS).

METHODS: Rats were used as experimental animals. We measured the conditioned taste aversion (CTA) induced by the intraperitoneal administration of emetine solution (0.03, 0.1, 0.3, 0.5, and 1.0 mM in saline) and that of only saline. We also performed immunohistochemical analyses of c-Fos expression in the area postrema and the NTS, to examine changes in the excitability of brainstem neurons that may be responsible for emetine-induced nausea and/or emesis.

RESULTS: The emetine-induced CTA occurred in a dose-dependent manner. The half maximal inhibitory concentration (IC50) of emetine on the saccharin preference was calculated to be 0.348 mM using the Hill equation. In the animals injected with emetine (0.5 and 1.0 mM), many c-Fos-like immunoreactive (Fos-ir) cells were observed in the area postrema and the NTS, while few Fos-ir cells were identified in the animals injected with saline. The average number of Fos-ir cells in the area postrema and the NTS was significantly larger in animals injected with emetine than in animals injected with saline.

CONCLUSIONS: The present study demonstrated a dose-responsive manner of emetine effects and emetine-induced upregulation of neuronal excitability in the area postrema and the NTS that form a part of the induction mechanisms of emetine-induced nausea and/or emesis.}, } @article {pmid33011270, year = {2020}, author = {Tobajas, J and Ruiz-Aguilera, MJ and López-Bao, JV and Ferreras, P and Mateo, R}, title = {The effectiveness of conditioned aversion in wolves: Insights from experimental tests.}, journal = {Behavioural processes}, volume = {181}, number = {}, pages = {104259}, doi = {10.1016/j.beproc.2020.104259}, pmid = {33011270}, issn = {1872-8308}, mesh = {Animals ; Livestock ; Odorants ; Predatory Behavior ; Taste ; *Wolves ; }, abstract = {It has been suggested that conditioned food aversion (CFA) could be a potential non-lethal intervention by which to deter attacks on livestock by large carnivores. CFA occurs when an animal associates the characteristics of a food with an illness, thus rejecting that food in subsequent encounters. CFA can be associated with an artificial odour during conditioning. Despite the debate surrounding the use of this intervention, more studies evaluating the effectiveness of CFA are necessary. We experimentally evaluated the potential of microgranulated levamisole + a vanilla odour cue to induce CFA in captive Iberian wolves (Canis lupus signatus). Four out of the five wolves treated showed an aversion to the meat for a minimum of one month after conditioning. The microgranulated presentation masked the flavour and smell of the levamisole but increased its volume, which may have facilitated its detection by the wolves. We also observed that the strength of the odour played an important role in the aversion extinction. The use of microgranulated levamisole + an odour cue has the potential to be used as an intervention by which to induce aversive conditioning in wolves in the wild, although rigorous field tests are required. We discuss the potential of CFA to deter attacks on livestock by large carnivores.}, } @article {pmid32994339, year = {2020}, author = {Fukabori, R and Iguchi, Y and Kato, S and Takahashi, K and Eifuku, S and Tsuji, S and Hazama, A and Uchigashima, M and Watanabe, M and Mizuma, H and Cui, Y and Onoe, H and Hikishima, K and Yasoshima, Y and Osanai, M and Inagaki, R and Fukunaga, K and Nishijo, T and Momiyama, T and Benton, R and Kobayashi, K}, title = {Enhanced Retrieval of Taste Associative Memory by Chemogenetic Activation of Locus Coeruleus Norepinephrine Neurons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {40}, number = {43}, pages = {8367-8385}, pmid = {32994339}, issn = {1529-2401}, mesh = {Animals ; Arousal/physiology ; Drosophila melanogaster ; Electrophysiological Phenomena ; Humans ; Locus Coeruleus/cytology/*drug effects ; Memory/drug effects/*physiology ; Mental Recall/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/physiology ; Norepinephrine/*physiology ; Phenylacetates/pharmacology ; Receptors, Adrenergic/drug effects/*physiology ; Receptors, Odorant/physiology ; Sensory Receptor Cells/drug effects/*physiology ; Taste/drug effects/genetics/*physiology ; }, abstract = {The ability of animals to retrieve memories stored in response to the environment is essential for behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. Here, we developed a novel chemogenetic activation strategy exploiting insect olfactory ionotropic receptors (IRs), termed "IR-mediated neuronal activation," and used it for selective stimulation of NE neurons in the locus coeruleus (LC). Drosophila melanogaster IR84a and IR8a subunits were expressed in LC NE neurons in transgenic mice. Application of phenylacetic acid (a specific ligand for the IR84a/IR8a complex) at appropriate doses induced excitatory responses of NE neurons expressing the receptors in both slice preparations and in vivo electrophysiological conditions, resulting in a marked increase of NE release in the LC nerve terminal regions (male and female). Ligand-induced activation of LC NE neurons enhanced the retrieval process of conditioned taste aversion without affecting taste sensitivity, general arousal state, and locomotor activity. This enhancing effect on taste memory retrieval was mediated, in part, through α1- and β-adrenergic receptors in the basolateral nucleus of the amygdala (BLA; male). Pharmacological inhibition of LC NE neurons confirmed the facilitative role of these neurons in memory retrieval via adrenergic receptors in the BLA (male). Our findings indicate that the LC NE system, through projections to the BLA, controls the retrieval process of taste associative memory.SIGNIFICANCE STATEMENT Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation, but the role of the NE system in memory retrieval remains unclear. We developed a chemogenetic activation system based on insect olfactory ionotropic receptors and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons enhanced the retrieval of conditioned taste aversion, which was mediated, in part, through adrenoceptors in the basolateral amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdala pathway plays an important role in the recall of taste associative memory.}, } @article {pmid32991926, year = {2021}, author = {Grijalva, LE and Miranda, MI and Paredes, RG}, title = {Differential changes in GAP-43 or synaptophysin during appetitive and aversive taste memory formation.}, journal = {Behavioural brain research}, volume = {397}, number = {}, pages = {112937}, doi = {10.1016/j.bbr.2020.112937}, pmid = {32991926}, issn = {1872-7549}, mesh = {Animals ; Appetitive Behavior/*physiology ; Avoidance Learning/*physiology ; Basolateral Nuclear Complex/*metabolism ; Central Amygdaloid Nucleus/*metabolism ; Cerebral Cortex/*metabolism ; Frontal Lobe/metabolism ; GAP-43 Protein/*metabolism ; Male ; Neuronal Plasticity/*physiology ; Rats ; Rats, Wistar ; Synaptophysin/*metabolism ; Taste Perception/*physiology ; }, abstract = {Association between events in time and space is a major mechanism for all animals, including humans, which allows them to learn about the world and potentially change their behavior in the future to adapt to different environments. Conditioning taste aversion (CTA) is a single-trial learning paradigm where animals are trained to avoid a novel flavor which is associated with malaise. Many variables can be analyzed with this model and the circuits involved are well described. Thus, the amygdala and the gustatory cortex (GC) are some of the most relevant structures involved in CTA. In the present study we focused in plastic changes that occur during appetitive and/or aversive taste memory formation. Previous studies have demonstrated that memory consolidation, in hippocampal dependent paradigms, induces plastic changes like increase in the concentration of proteins considered as markers of neuronal plasticity, such as the growth associated protein 43 (GAP-43) and synaptophysin (SYN). In the present experiment in male rats we evaluated changes in GAP-43 and SYN expression, using immunofluorescence, induce by the formation of aversive and appetitive taste memory. We found that taste aversive memory formation can induce an increase in GAP-43 in the granular layer of the GC. Furthermore, we also found an increase in SYN expression in both layers of the GC, the basolateral amygdala (BLA) and the central amygdala (CeA). These results suggest that aversive memory representation induces a new circuitry (inferred from an increase in GAP 43). On the other hand, an appetitive taste learning increased SYN expression in the GC (both layers), the BLA and the CeA without any changes in GAP 43. Together these results indicate that aversive memory formation induces structural and synaptic changes, while appetitive memory formation induces synaptic changes; suggesting that aversive and appetitive memories require a different set of cortical and amygdala plastic changes.}, } @article {pmid32981845, year = {2020}, author = {Heyes, C and Chater, N and Dwyer, DM}, title = {Sinking In: The Peripheral Baldwinisation of Human Cognition.}, journal = {Trends in cognitive sciences}, volume = {24}, number = {11}, pages = {884-899}, doi = {10.1016/j.tics.2020.08.006}, pmid = {32981845}, issn = {1879-307X}, mesh = {Adaptation, Biological ; *Cognition ; Fear ; Humans ; Language ; *Learning ; }, abstract = {The Baldwin effect is a hypothetical process in which a learned response to environmental change evolves a genetic basis. Modelling has shown that the Baldwin effect offers a plausible and elegant explanation for the emergence of complex behavioural traits, but there is little direct empirical evidence for its occurrence. We highlight experimental evidence of the Baldwin effect and argue that it acts preferentially on peripheral rather than on central cognitive processes. Careful scrutiny of research on taste-aversion and fear learning, language, and imitation indicates that their efficiency depends on adaptively specialised input and output processes: analogues of scanner and printer interfaces that feed information to core inference processes and structure their behavioural expression.}, } @article {pmid32936829, year = {2020}, author = {Galistu, A and D'Aquila, PS}, title = {Memantine effects on ingestion microstructure and the effect of administration time: A within-subject study.}, journal = {PloS one}, volume = {15}, number = {9}, pages = {e0239270}, pmid = {32936829}, issn = {1932-6203}, mesh = {Animals ; Conditioning, Classical/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drinking Behavior/drug effects ; Eating ; Feeding Behavior/*drug effects ; Humans ; Memantine/adverse effects/*pharmacology ; Memory/*drug effects/physiology ; Rats ; Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/genetics ; }, abstract = {In a between-subject comparison of two memantine administration schedules we observed that treatment with the NMDA receptor antagonist memantine before testing sessions reduced ingestion of a 10% sucrose solution in rats, due to reduced licking burst size, thus suggesting a blunted hedonic response. Conversely, daily post-session administration reduced burst number, indicating a reduced level of behavioural activation, likely due to the development of conditioned taste aversion (CTA). In this study, the effect of pre-session and post-session memantine administration was investigated within-subjects. Memantine was administered in daily intraperitoneal injections for 13 days, on alternate days, either 1-h before-"before testing" sessions-or immediately after a 30-min session-"after testing" sessions. The effects on the microstructure of licking for a 10% sucrose solution were examined in the course of treatment and for 21 days after treatment discontinuation. The results show reduced burst size in the "before testing" sessions, without effects on the intra-burst lick rate, an index of motoric effects. Moreover, burst number was reduced since the third session of both administration conditions until the end of treatment. Interestingly, the effect of memantine of reducing the activation of ingestive behaviour was less pronounced in this study with respect to that observed with the previous study post-session administration schedule, in spite of the longer treatment. This apparent paradox might be explained if one considers these effects as instances of a memory-related effect, such as the development of CTA. In the framework of this hypothesis, the "before testing" sessions, not being followed by memantine administration, can be considered as extinction sessions performed every other day. Moreover, the animals treated with memantine at the highest dose failed to recover to pre-treatment ingestion levels 21 days after treatment discontinuation, while the animals treated after testing sessions in the previously published study showed a complete recovery well before the 15th day test. Within the same interpretative framework, this might depend by the reduced number and frequency of the extinction trials-i.e. the number of the sessions run after treatment discontinuation-in the present study. These results provide further support to the conclusion that memantine administration before sessions reduce burst size, an effect which is likely due to blockade of NMDA receptors occurring during behavioural testing. The observation that this effect can be obtained even in absence of a reduced intra-burst lick rate, which rules out the involvement of motor impairment, provides an important piece of evidence in support to the interpretation of this effect as a blunted hedonic response. Moreover, these results provide further evidence that burst number reduction is due to a memory-related effect induced by memantine administration after sessions.}, } @article {pmid32857870, year = {2020}, author = {Arieli, E and Gerbi, R and Shein-Idelson, M and Moran, A}, title = {Temporally-precise basolateral amygdala activation is required for the formation of taste memories in gustatory cortex.}, journal = {The Journal of physiology}, volume = {598}, number = {23}, pages = {5505-5522}, doi = {10.1113/JP280213}, pmid = {32857870}, issn = {1469-7793}, mesh = {Amygdala ; Animals ; Avoidance Learning ; *Basolateral Nuclear Complex ; Cerebral Cortex ; Memory ; Rats ; Taste ; }, abstract = {KEY POINTS: The basolateral amygdala (BLA), the nucleus basalis magnocellularis (NBM), and the gustatory cortex (GC) are involved in taste processing, taste memory formation and conditioned taste aversion (CTA) learning, but their fine-temporal interactions that support these cognitive functions are not well understood. We found that the formation of novel-taste and CTA memories in the GC depend on a distinct late response (700-3000 ms) of BLA projection neurons. In contrast, BLA activity was not essential for palatability-related behaviour and coding in the GC prior to CTA. We identified the BLA→NBM pathway as a potential pathway for the transmission of taste novelty information, required for the formation of taste and CTA memories in the GC. Our results demonstrate how neuronal dynamics across multiple brain regions support long-term memory formation.

ABSTRACT: Learning to associate malaise with the intake of novel food is critical for survival. Since food poisoning may take hours to take effect, animals developed brain circuits to transform the current novel taste experience into a taste memory trace (TMT) and bridge this time lag. Ample studies showed that the basolateral amygdala (BLA), the nucleus basalis magnocellularis (NBM) and the gustatory cortex (GC) are involved in TMT formation and taste-malaise association. However, how dynamic activity across these brain regions during novel taste experience promotes the formation of these memories is currently unknown. We used the conditioned taste aversion (CTA) learning paradigm in combination with short-term optogenetics and electrophysiological recording in rats to test the hypothesis that temporally specific activation of BLA projection neurons is essential for TMT formation in the GC, and consequently CTA. We found that a short late epoch (LE, 700-3000 ms), but not the early epoch (EE, 0-500 ms), of BLA activation during novel taste experience is essential for normal CTA, for early c-Fos expression in the GC (a marker of TMT formation) and for the post-CTA changes in GC ensemble palatability coding. Interestingly, BLA activity was not required for intact taste identity or palatability perceptions before CTA. We further show that BLA-LE information is transmitted to GC through the BLA→NBM pathway where it affects the formation of taste memories. These results expose the dependence of long-term memory formation on specific temporal windows during sensory responses and the distributed circuits supporting this dependence.}, } @article {pmid32779566, year = {2020}, author = {Levitan, D and Liu, C and Yang, T and Shima, Y and Lin, JY and Wachutka, J and Marrero, Y and Ali Marandi Ghoddousi, R and Veiga Beltrame, ED and Richter, TA and Katz, DB and Nelson, SB}, title = {Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, pmid = {32779566}, issn = {2050-084X}, support = {R21 DC016706/DC/NIDCD NIH HHS/United States ; R01 NS109916/NS/NINDS NIH HHS/United States ; T90 DA032435/DA/NIDA NIH HHS/United States ; DC006666/DC/NIDCD NIH HHS/United States ; NS109916/NS/NINDS NIH HHS/United States ; R90 DA033463/DA/NIDA NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases ; Animals ; *Basolateral Nuclear Complex/chemistry/cytology/metabolism ; Conditioning, Classical/*physiology ; Female ; Gene Knockout Techniques ; Male ; Memory, Long-Term/*physiology ; Mice ; Neurons/chemistry/metabolism ; *Protein Serine-Threonine Kinases/genetics/metabolism ; *Proto-Oncogene Proteins c-fos/genetics/metabolism ; Taste/physiology ; }, abstract = {Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms remain poorly understood. RNAseq from BLApn identified changes in multiple candidate learning-related transcripts including the expected immediate early gene Fos and Stk11, a master kinase of the AMP-related kinase pathway with important roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 in BLApn blocked memory prior to training, but not following it and increased neuronal excitability. Conversely, BLApn had reduced excitability following CTA. BLApn knockout of a second learning-related gene, Fos, also increased excitability and impaired learning. Independently increasing BLApn excitability chemogenetically during CTA also impaired memory. STK11 and C-FOS activation were independent of one another. These data suggest key roles for Stk11 and Fos in CTA long-term memory formation, dependent at least partly through convergent action on BLApn intrinsic excitability.}, } @article {pmid32727819, year = {2020}, author = {Hurley, SW and Carelli, RM}, title = {Activation of Infralimbic to Nucleus Accumbens Shell Pathway Suppresses Conditioned Aversion in Male But Not Female Rats.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {40}, number = {36}, pages = {6888-6895}, pmid = {32727819}, issn = {1529-2401}, support = {F32 MH115653/MH/NIMH NIH HHS/United States ; R01 DA014339/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Aversive Agents ; *Conditioning, Classical ; Female ; Limbic System/*physiology ; Male ; Neural Pathways/physiology ; Nucleus Accumbens/*physiology ; Quinine ; Rats ; Rats, Sprague-Dawley ; Sex Factors ; *Taste Perception ; }, abstract = {Hedonic processing plays an integral role in directing appropriate behavior, but disrupted hedonic processing is associated with psychiatric disorders such as depression. The infralimbic cortex (IL) is a key structure in affective processing in rodents and activation of its human homolog, the ventromedial prefrontal cortex, has been implicated in suppressing aversive states. Here, we tested whether optogenetic activation of glutamatergic projections from the IL to the nucleus accumbens shell (NAcSh) suppresses the aversive impact of sucrose devalued using the conditioned taste aversion paradigm in males and female rats. In naive rats, no significant differences in appetitive or aversive taste reactivity (TR) to sucrose was observed indicating that initial sucrose palatability was equivalent across sex. However, we found that optical activation of the IL-NAcSh pathway during intraoral infusion of devalued sucrose inhibited aversive TR in male but not female rats. Interestingly, when allowed to freely ingest water and sucrose in a two-bottle test both males and females with a history of IL-NAcSh stimulation exhibited greater preference for sucrose. Optical pathway activation failed to alter TR to innately bitter quinine in either sex. Finally, both sexes lever pressed to self-stimulate the IL-NAcSh pathway. These results indicate that the IL-NAcSh pathway plays an important role in suppressing learned aversive states selectively in males but spares hedonic processing of innately aversive tastants. Further, pathway activation is reinforcing in both sexes, indicating that suppression of conditioned aversive TR can be dissociable from the effects of unconditioned rewarding properties of IL-NAcSh pathway activation.SIGNIFICANCE STATEMENT Negative emotional states contribute to psychiatric disorders including depression and substance use disorders. In this study, we examined whether brain circuitry previously implicated in suppressing negative emotional states in humans can inhibit learned aversion in male and female rats. We found that optical activation of the infralimbic to nucleus accumbens shell pathway attenuates learned aversive responses in male but not female rats, indicating an important sex difference in the function of this brain pathway. Furthermore, we found that pathway stimulation was reinforcing in both sexes. Collectively, these findings support the role of the infralimbic cortex and its projection to the nucleus accumbens shell in suppressing learned negative emotional states and highlight an important sex-specific function of this pathway.}, } @article {pmid32723372, year = {2020}, author = {Abe, K and Kuroda, M and Narumi, Y and Kobayashi, Y and Itohara, S and Furuichi, T and Sano, Y}, title = {Cortico-amygdala interaction determines the insular cortical neurons involved in taste memory retrieval.}, journal = {Molecular brain}, volume = {13}, number = {1}, pages = {107}, pmid = {32723372}, issn = {1756-6606}, mesh = {Amygdala/*physiology ; Animals ; Avoidance Learning/physiology ; Cerebral Cortex/*physiology ; Conditioning, Classical ; Learning ; Male ; Mental Recall/*physiology ; Mice, Inbred C57BL ; Nerve Net ; Neurons/*physiology ; Taste/*physiology ; }, abstract = {The insular cortex (IC) is the primary gustatory cortex, and it is a critical structure for encoding and retrieving the conditioned taste aversion (CTA) memory. In the CTA, consumption of an appetitive tastant is associated with aversive experience such as visceral malaise, which results in avoidance of consuming a learned tastant. Previously, we showed that levels of the cyclic-AMP-response-element-binding protein (CREB) determine the insular cortical neurons that proceed to encode a conditioned taste memory. In the amygdala and hippocampus, it is shown that CREB and neuronal activity regulate memory allocation and the neuronal mechanism that determines the specific neurons in a neural network that will store a given memory. However, cellular mechanism of memory allocation in the insular cortex is not fully understood. In the current study, we manipulated the neuronal activity in a subset of insular cortical and/or basolateral amygdala (BLA) neurons in mice, at the time of learning; for this purpose, we used an hM3Dq designer receptor exclusively activated by a designer drug system (DREADD). Subsequently, we examined whether the neuronal population whose activity is increased during learning, is reactivated by memory retrieval, using the expression of immediate early gene c-fos. When an hM3Dq receptor was activated only in a subset of IC neurons, c-fos expression following memory retrieval was not significantly observed in hM3Dq-positive neurons. Interestingly, the probability of c-fos expression in hM3Dq-positive IC neurons after retrieval was significantly increased when the IC and BLA were co-activated during conditioning. Our findings suggest that functional interactions between the IC and BLA regulates CTA memory allocation in the insular cortex, which shed light on understanding the mechanism of memory allocation regulated by interaction between relevant brain areas.}, } @article {pmid32712137, year = {2020}, author = {Angulo, R and Bustamante, J and Arévalo-Romero, CA}, title = {Age, sex and pre-exposure effects on acquisition and generalization of conditioned taste aversion in rats.}, journal = {Behavioural brain research}, volume = {394}, number = {}, pages = {112813}, doi = {10.1016/j.bbr.2020.112813}, pmid = {32712137}, issn = {1872-7549}, mesh = {Aging/*psychology ; Animals ; *Avoidance Learning ; Female ; *Generalization, Psychological ; Male ; Rats, Sprague-Dawley ; *Sex Characteristics ; Sex Factors ; *Taste ; }, abstract = {The main aim of the present study was to assess the effect of sex and aging in two pre-exposure learning effects, latent inhibition (LI) and perceptual learning (PL), with a conditioned taste aversion paradigm. Young adult (90 days) and aged (more than 18 months) males and females received 8 pre-exposure trials either with stimulus AX (LI conditions) or BX (PL conditions). Then, all animals received a conditioning trial with AX and two test trials, one with AX and other with BX. The level of generalization between AX and BX was assessed by means of the absolute level of consumption of BX and by the difference in consumption between both stimuli. The results showed an attenuation of latent inhibition as well a stronger generalization of conditioned taste aversion in females when generalization is inferred from the BX consumption. A facilitation of conditioning for the aged animals was also found regardless of the pre-exposed stimulus. Pre-exposures to BX resulted in little generalization, but pre-exposures to AX resulted in a very similar consumption of both compounds, indicating a strong generalization between them. Overall, the study provided novel evidence about the effect of sex and aging on taste aversion, raising at the same time some relevant questions about perceptual learning and how such pre-exposure effect has been typically assessed.}, } @article {pmid32681199, year = {2021}, author = {Miranda, MI and Rangel-Hernández, A and Vera-Rivera, G and Cortes, C and Eguibar, JR}, title = {Taste association capabilities differ in high- and low-yawning rats versus outbred Sprague-Dawley rats after prolonged sugar consumption.}, journal = {Animal cognition}, volume = {24}, number = {1}, pages = {41-52}, pmid = {32681199}, issn = {1435-9456}, mesh = {Animals ; Avoidance Learning ; Dietary Sugars ; Rats ; Rats, Sprague-Dawley ; Sugars ; *Taste ; *Yawning ; }, abstract = {Yawning is a stereotypical behavior pattern commonly associated with other behaviors such as grooming, sleepiness, and arousal. Several differences in behavioral and neurochemical characteristics have been described in high-yawning (HY) and low-yawning (LY) sublines from Sprague-Dawley (SD) rats that support they had changes in the neural mechanism between sublines. Differences in behavior and neurochemistry observed in yawning sublines could also overlap in processes needed during taste learning, particularly during conditioned taste aversion (CTA) and its latent inhibition. Therefore, the aim of this study was to analyze taste memory differences, after familiarization to novel or highly sweet stimuli, between yawning sublines and compare them with outbred SD rats. First, we evaluated changes in appetitive response during long-term sugar consumption for 14 days. Then, we evaluated the latent inhibition of CTA strength induced by this long pre-exposure, and we also measured aversive memory extinction rate. The results showed that SD rats and the two sublines developed similar CTA for novel sugar and significantly stronger appetitive memory after long-term sugar exposure. However, after 14 days of sugar exposure, HY and LY sublines were unable to develop latent inhibition of CTA after two acquisition trials and had a slower aversive memory extinction rate than outbreed rats. Thus, the inability of the HY and LY sublines to develop latent inhibition of CTA after long-term sugar exposure could be related to the time/context processes involved in long-term appetitive re-learning, and in the strong inbreeding that characterizes the behavioral traits of these sublines, suggesting that inbreeding affects associative learning, particularly after long-term exposure to sweet stimuli which reflects high familiarization.}, } @article {pmid32655385, year = {2020}, author = {Angulo, R and Bustamante, J and Estades, V and Ramírez, V and Jorquera, B}, title = {Sex Differences in Cue Competition Effects With a Conditioned Taste Aversion Preparation.}, journal = {Frontiers in behavioral neuroscience}, volume = {14}, number = {}, pages = {107}, pmid = {32655385}, issn = {1662-5153}, abstract = {This study aimed to test whether male and female rats might show differences in cue competition effects in a conditioned taste aversion (CTA) model. Experiment 1 tested for sex differences in overshadowing. After conditioning of a flavored compound AB or only one simple flavor A (being A and B a solution of sugar 10% and salt 1%, counterbalanced), consumption of the A solution at test was larger in the former than in the latter case only in males. Thus, the usual effect of overshadowing was observed in males but not in females. Experiment 2 examined sex differences in blocking with the same stimuli used in Experiment 1. After conditioning of AB, the consumption of B was larger for the animals that previously received a single conditioning trial with A than for those that received unpaired presentations of A and the illness. As observed in Experiment 1, the typical blocking effect appeared only in males but not in females. The present findings thus support the hypothesis that sex dimorphism might be expressed in classical conditioning, or at least, in cue competition effects such as overshadowing and blocking with a taste aversion model.}, } @article {pmid32652234, year = {2020}, author = {Lai, Y and Despouy, E and Sandoz, JC and Su, S and de Brito Sanchez, MG and Giurfa, M}, title = {Degradation of an appetitive olfactory memory via devaluation of sugar reward is mediated by 5-HT signaling in the honey bee.}, journal = {Neurobiology of learning and memory}, volume = {173}, number = {}, pages = {107278}, doi = {10.1016/j.nlm.2020.107278}, pmid = {32652234}, issn = {1095-9564}, mesh = {Animals ; Bees ; Memory/*drug effects/physiology ; *Odorants ; *Reward ; Serotonin/*metabolism ; Signal Transduction/*drug effects/physiology ; Sugars/pharmacology ; }, abstract = {Conditioned taste aversion (CTA) learning induces the devaluation of a preferred food through its pairing with a stimulus inducing internal illness. In invertebrates, it is still unclear how this aversive learning impairs the memories of stimuli that had been associated with the appetitive food prior to its devaluation. Here we studied this phenomenon in the honey bee and characterized its neural underpinnings. We first trained bees to associate an odorant (conditioned stimulus, CS) with appetitive fructose solution (unconditioned stimulus, US) using a Pavlovian olfactory conditioning. We then subjected the bees that learned the association to a CTA training during which the antennal taste of fructose solution was contingent or not to the ingestion of quinine solution, which induces malaise a few hours after ingestion. Only the group experiencing contingent fructose stimulation and quinine-based malaise exhibited a decrease in responses to the fructose and a concomitant decrease in odor-specific retention in tests performed 23 h after the original odor conditioning. Furthermore, injection of dopamine- and serotonin-receptor antagonists after CTA learning revealed that this long-term decrease was mediated by serotonergic signaling as its blockade rescued both the responses to fructose and the odor-specific memory 23 h after conditioning. The impairment of a prior CS memory by subsequent CTA conditioning confirms that bees retrieve a devaluated US representation when presented with the CS. Our findings further highlight the importance of serotonergic signaling in aversive learning in the bee and uncover mechanisms underlying aversive memories induced by internal illness in invertebrates.}, } @article {pmid32650432, year = {2020}, author = {Molero-Chamizo, A and Rivera-Urbina, GN}, title = {Taste Processing: Insights from Animal Models.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {14}, pages = {}, pmid = {32650432}, issn = {1420-3049}, mesh = {Amygdala/*physiology ; Animals ; Avoidance Learning/*physiology ; Brain Mapping ; Conditioning, Psychological/*physiology ; Humans ; *Models, Neurological ; Olfactory Perception/*physiology ; Taste Perception/*physiology ; }, abstract = {Taste processing is an adaptive mechanism involving complex physiological, motivational and cognitive processes. Animal models have provided relevant data about the neuroanatomical and neurobiological components of taste processing. From these models, two important domains of taste responses are described in this review. The first part focuses on the neuroanatomical and neurophysiological bases of olfactory and taste processing. The second part describes the biological and behavioral characteristics of taste learning, with an emphasis on conditioned taste aversion as a key process for the survival and health of many species, including humans.}, } @article {pmid32604471, year = {2021}, author = {Blednov, YA and Da Costa, A and Mayfield, J and Harris, RA and Messing, RO}, title = {Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice.}, journal = {Addiction biology}, volume = {26}, number = {2}, pages = {e12932}, pmid = {32604471}, issn = {1369-1600}, support = {U24 AA025479/AA/NIAAA NIH HHS/United States ; U01 AA013520/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Diazepam/pharmacology ; Drug Tolerance/*genetics ; Ethanol/*pharmacology ; Isoxazoles/pharmacology ; Male ; Mice ; Mice, Knockout ; Myeloid Differentiation Factor 88/*genetics ; Sex Factors ; Substance Withdrawal Syndrome ; Toll-Like Receptor 3/*genetics ; gamma-Aminobutyric Acid/drug effects ; }, abstract = {Pharmacological studies implicate toll-like receptor 3 (TLR3) signaling in alcohol drinking. We examined the role of TLR3 in behavioral responses to alcohol and GABAergic drugs by studying Tlr3 [-/-] mice. Because of opposing signaling between TLR3 and MyD88 pathways, we also evaluated Myd88 [-/-] mice. Ethanol consumption and preference decreased in male but not in female Tlr3 [-/-] mice during two-bottle choice every-other-day (2BC-EOD) drinking. There were no genotype differences in either sex during continuous or limited-access drinking. Null mutations in Tlr3 or Myd88 did not alter conditioned taste aversion to alcohol and had small or no effects on conditioned place preference. The Tlr3 null mutation did not alter acute alcohol withdrawal. Male, but not female, Tlr3 [-/-] mice took longer than wild-type littermates to recover from ataxia by ethanol or diazepam and longer to recover from sedative-hypnotic effects of ethanol or gaboxadol, indicating regulation of GABAergic signaling by TLR3. Acute functional tolerance (AFT) to alcohol-induced ataxia was decreased in Tlr3 [-/-] mice but was increased in Myd88 [-/-] mice. Thus, MyD88 and TLR3 pathways coordinately regulate alcohol consumption and tolerance to intoxicating doses of alcohol and GABAergic drugs. Despite similar alcohol metabolism and similar amounts of total alcohol consumed during 2BC and 2BC-EOD procedures in C57BL/6J mice, only 2BC-EOD drinking induced tolerance to alcohol-induced ataxia. Ataxia recovery was inversely correlated with level of drinking in wild-type and Tlr3 [-/-] littermates. Thus, deleting Tlr3 reduces alcohol consumption by reducing AFT to alcohol and not by altering tolerance induced by 2BC-EOD drinking.}, } @article {pmid32603778, year = {2020}, author = {Yamamura, T and Nakamura, F and Yasuo, T and Suwabe, T and Sako, N}, title = {Effect of the duration of a conditioned stimulus on component recognition in binary taste mixtures in rats.}, journal = {Journal of oral biosciences}, volume = {62}, number = {3}, pages = {267-271}, doi = {10.1016/j.job.2020.06.001}, pmid = {32603778}, issn = {1880-3865}, mesh = {Animals ; *Avoidance Learning ; Conditioning, Classical ; Conditioning, Operant ; Conditioning, Psychological ; Rats ; *Taste ; }, abstract = {OBJECTIVES: The aim of this behavioral study was to investigate the duration of a conditioned stimulus (CS-duration) necessary for rats to recognize the components of a binary taste mixture in a conditioned taste aversion (CTA) paradigm as well as the relationship between CS-duration and their spontaneous recovery.

METHODS: The experimental rats were categorized under conditioned and control groups and further divided into three groups according to the CS-duration: 10, 30, and 60 s. As the test stimuli, a mixture of 100 mM sucrose (S) + 30 μM quinine hydrochloride (Q) and its components were used.

RESULTS: On day 1 of the CTA test, the number of licks (NL) for S + Q and S in all conditioned groups was significantly lower than that of the control group presented with CS for 60 s (CON-60), which was the representative control group determined by the initial CTA test. For Q, there was no significant difference between NL of the CTA group presented with CS for 10 s and that of CON-60; however, NL in the other two CTA groups, i.e., CTA-30 and CTA-60, was significantly lower than that of CON-60. When the rats were presented with a shorter CS-duration, they showed spontaneous recovery earlier depending on the CS-duration.

CONCLUSIONS: These results suggest that rats can recognize a binary taste mixture and its components using a CS-duration of more than 30 s and that spontaneous recovery from CTA learning depends on the CS- duration.}, } @article {pmid32602851, year = {2020}, author = {Molero-Chamizo, A and Rivera-Urbina, GN}, title = {Temporal specificity of latent inhibition in rats with daily water restriction prior to taste conditioning.}, journal = {Acta neurobiologiae experimentalis}, volume = {80}, number = {2}, pages = {99-107}, pmid = {32602851}, issn = {1689-0035}, mesh = {Animals ; Avoidance Learning/physiology ; Conditioning, Psychological/*physiology ; *Inhibition, Psychological ; Male ; Memory/physiology ; Rats, Wistar ; Taste/*physiology ; *Water ; }, abstract = {Temporal specificity of latent inhibition of conditioned taste aversion (CTA) has been demonstrated after prolonged habituation to temporal contexts in the stages preceding conditioning, and it has been eliminated by restricting consumption during conditioning. However, it is not known if latent inhibition of CTA is still dependent on the temporal context when fluid consumption is limited in the stages prior to conditioning. We tested temporal specificity of latent inhibition in rats with (different time of day for the conditioning stage) and without (same time of day for pre-exposure and conditioning stages) temporal changes on the conditioning day. All animals had limited access to water in the morning sessions of the stages prior to the conditioning day and 15 min of free access to fluid in the evening sessions of these stages. Compared to animals without temporal changes between stages, animals with a different temporal context during conditioning did not show evidence of latent inhibition. Unlike the effects observed after taste stimulus restrictions during conditioning, these results suggest that the temporal specificity of latent inhibition of CTA is not abolished when access to water is limited in the stages preceding conditioning.}, } @article {pmid32565406, year = {2020}, author = {Hao, L and Kshatriya, D and Li, X and Badrinath, A and Szmacinski, Z and Goedken, MJ and Polunas, M and Bello, NT}, title = {Acute feeding suppression and toxicity of raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] in mice.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {143}, number = {}, pages = {111512}, pmid = {32565406}, issn = {1873-6351}, support = {R01 AT008933/AT/NCCIH NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Butanones/administration & dosage/*toxicity ; Feeding Behavior/*drug effects ; Female ; Male ; Mice ; Mice, Inbred C57BL ; }, abstract = {Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is used by the food and cosmetic industry as a flavoring agent. RK is also marketed as a dietary supplement for weight maintenance and appetite control. The purpose of the study was to characterize the acute feeding suppression with RK (64-640 mg/kg) by oral gavage in male and female C57BL/6J mice. Cumulative 24 h food intake was reduced at 200 mg/kg (24% feeding suppression) in males and reliably reduced at 640 mg/kg (49-77% feeding suppression). Feeding suppression was not associated with pica behavior over the range of doses or conditioned taste aversion. In a separate experiment, a single oral gavage of RK (640 mg/kg) resulted in approximate 43% mortality rate (6 out 14 male mice) within 2 days. Atrophy of white adipose tissue, splenic abnormalities, and thymus involution were noted after 2-4 days after oral gavage RK. Total white blood cell count, lymphocytes, monocytes, eosinophils were significantly lower, while mean red blood cells, hemoglobin, and hematocrit were significantly higher with RK treatment. Our findings indicated a dose-dependent feeding suppression with acute RK, but doses that reliable suppress food intake are associated with pathological changes.}, } @article {pmid32472169, year = {2020}, author = {Csikós, V and Varró, P and Bódi, V and Oláh, S and Világi, I and Dobolyi, A}, title = {The mycotoxin deoxynivalenol activates GABAergic neurons in the reward system and inhibits feeding and maternal behaviours.}, journal = {Archives of toxicology}, volume = {94}, number = {9}, pages = {3297-3313}, pmid = {32472169}, issn = {1432-0738}, mesh = {Animal Feed/microbiology ; Animals ; Feeding Behavior/*drug effects ; Food Contamination ; GABAergic Neurons/drug effects/*physiology ; Maternal Behavior/*drug effects ; Mice ; Mycotoxins/*toxicity ; Rats ; Trichothecenes/*toxicity ; }, abstract = {Deoxynivalenol (DON) or vomitoxin, is a trichothecene mycotoxin produced mainly by Fusarium graminearum and culmorum. Mycotoxins or secondary metabolic products of mold fungi are micro-pollutants, which may affect human and animal health. The neuronal and behavioural actions of DON were analysed in the present study. To address, which neurons can be affected by DON, the neuronal activation pattern following intraperitoneal injection of DON (1 mg/kg) was investigated in adult male rats and the results were confirmed in mice, too. DON-induced neuronal activation was assessed by c-Fos immunohistochemistry. DON injection resulted in profound c-Fos activation in only the elements of the reward system, such as the accumbens nucleus, the medial prefrontal cortex, and the ventral tegmental area. Further double labelling studies suggested that GABAergic neurons were activated by DON treatment. To study the behavioural relevance of this activation, we examined the effect of DON on feed intake as an example of reward-driven behaviours. Following DON injection, feed consumption was markedly reduced but returned to normal the following day suggesting an inhibitory action of DON on feed intake without forming taste-aversion. To further test how general the effect of DON on goal-directed behaviours is, its actions on maternal behaviour was also examined. Pup retrieval latencies were markedly increased by DON administration, and DON-treated mother rats spent less time with nursing suggesting reduced maternal motivation. In a supplementary control experiment, DON did not induce conditioned place preference arguing against its addictive or aversive actions. The results imply that acute uptake of the mycotoxin DON can influence the reward circuit of the brain and exert inhibitory actions on goal-directed, reward-driven behaviours. In addition, the results also suggest that DON exposure of mothers may have specific implications.}, } @article {pmid32407964, year = {2020}, author = {Huang, ACW and Yu, YH and He, ABH and Ou, CY}, title = {Interactions between prelimbic cortex and basolateral amygdala contribute to morphine-induced conditioned taste aversion in conditioning and extinction.}, journal = {Neurobiology of learning and memory}, volume = {172}, number = {}, pages = {107248}, doi = {10.1016/j.nlm.2020.107248}, pmid = {32407964}, issn = {1095-9564}, mesh = {Analgesics, Opioid/*administration & dosage ; Animals ; Basolateral Nuclear Complex/drug effects/*physiology ; Conditioning, Classical/*drug effects/*physiology ; Corticosterone/blood ; Extinction, Psychological/*drug effects/*physiology ; Male ; Morphine/*administration & dosage ; Neurons/drug effects/physiology ; Prefrontal Cortex/drug effects/*physiology ; Rats, Wistar ; Signal Transduction ; }, abstract = {The consequences of exciting or destroying the prelimbic cortex (PrL) or the basolateral amygdala (BLA) remain unclear, including the effects on morphine-induced conditioned taste aversion (CTA) in the conditioning and extinction phases, plasma corticosterone (CORT) levels, and c-Fos/p-ERK expressions in the subareas of the medial prefrontal cortex (i.e., PrL, infralimbic cortex [IL], cingulate cortex 1 [Cg1]), basolateral amygdala (BLA), central amygdala (CeA), hippocampus (i.e., CA1, CA2, CA3, and dentate gyrus [DG]), nucleus accumbens (NAc), lateral hypothalamus (LH), and piriform cortex (PC). During conditioning, excitation of the PrL glutamate neurons via NMDA injections disrupted morphine-induced CTA and decreased plasma CORT levels; moreover, c-Fos and p-ERK expression was hyperactive in the PrL and IL but hypoactive in the Cg1 and BLA. In conditioning, excitation of the BLA glutamate neurons via NMDA injections facilitated morphine-induced CTA and increased plasma CORT levels. The expression of c-Fos and p-ERK was hypoactive in the PrL and IL but hyperactive in the BLA. During extinction, lesion of the PrL glutamate neurons via NMDA injections impaired morphine-induced CTA extinction and enhanced plasma CORT levels. The expression of c-Fos and p-ERK was hypoactive in the PrL and IL but hyperactive in the BLA. In extinction, excitation of the PrL glutamatergic neurons via NMDA injections facilitated morphine-induced CTA extinction and did not affect plasma CORT levels; moreover, the expression of c-Fos and p-ERK was hypoactive in the Cg1, PrL, and IL but hyperactive in the BLA. Altogether, the interaction between the PrL and BLA plays a balancing role in morphine-induced CTA conditioning and extinction. During conditioning, the activity of the PrL correlated negatively with plasma CORT secretions, whereas the activity of the BLA correlated positively with the plasma CORT levels. During extinction, the activity of the PrL correlated negatively with plasma CORT secretions; however, the activity of the BLA may be negatively associated with the plasma CORT levels. The data presented here provide some implications for morphine addiction and dependence.}, } @article {pmid32385589, year = {2020}, author = {Nakai, J and Totani, Y and Kojima, S and Sakakibara, M and Ito, E}, title = {Features of behavioral changes underlying conditioned taste aversion in the pond snail Lymnaea stagnalis.}, journal = {Invertebrate neuroscience : IN}, volume = {20}, number = {2}, pages = {8}, doi = {10.1007/s10158-020-00241-7}, pmid = {32385589}, issn = {1439-1104}, mesh = {Animals ; Avoidance Learning/physiology ; Behavior, Animal/*physiology ; Conditioning, Classical/*physiology ; Lymnaea/*physiology ; Memory Consolidation/*physiology ; Taste/*physiology ; }, abstract = {Conditioned taste aversion (CTA) in the freshwater pulmonate Lymnaea stagnalis can be formed by presenting ten pairings of sucrose as the conditioned stimulus (CS) and KCl as the unconditioned stimulus (US). The CTA is consolidated to long-term memory (LTM) lasting longer than a month. In the present study, we examined the time course of protein synthesis-dependent period during the consolidation of Lymnaea CTA to LTM by pharmacological inhibition of transcription or translation. The robustness for CTA-LTM was then examined by extinction trials, i.e., repeated presentations of the CS alone. Furthermore, we evaluated the effects of the interstimulus interval (ISI) between the presentation of the CS and US. Our findings indicated that the protein synthesis-dependent period coincides with the CTA training. Repeated presentations of the CS alone after establishment of CTA did not extinguish the CTA, demonstrating the robustness of the CTA-LTM. The ISI ranged from 10 s to a few minutes, and there was no inverted U-shaped function between the ISI and the conditioned response (i.e., suppression of feeding). Thus, CTA still formed even when the presentation of the US was delayed. These features of Lymnaea CTA complement the knowledge for mammalian CTA.}, } @article {pmid32378909, year = {2020}, author = {Steinfeld, MR and Bouton, ME}, title = {Context and renewal of habits and goal-directed actions after extinction.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {46}, number = {4}, pages = {408-421}, pmid = {32378909}, issn = {2329-8464}, support = {R01 DA033123/DA/NIDA NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Animals ; Behavior, Animal/*physiology ; Conditioning, Operant/*physiology ; Extinction, Psychological/*physiology ; Female ; *Goals ; *Habits ; Motor Activity/*physiology ; Psychomotor Performance/*physiology ; Rats, Wistar ; }, abstract = {Instrumental behaviors that are goal-directed actions after moderate amounts of training can become habits after more extended training. Little research has asked how actions and habits are affected by retroactive interference treatments like extinction. The present experiments begin to fill this gap in the literature. In Experiments 1a and 1b, lever pressing in rats was minimally trained (1a) or extensively trained (1b) in one context (Context A), extinguished in a second context (Context B), and then tested in the acquisition context (Context A). Exposure to both contexts was equated and controlled throughout, and the status of the behavior as action or habit was determined by reinforcer devaluation methods (taste aversion conditioning). Results confirmed that action (1a) and habit (1b) renewed with action or habit status, respectively, when they were returned to Context A. Experiments 2a and 2b then similarly tested action and habit after extinction in an ABC renewal paradigm. Here, lever pressing that was trained in Context A and extinguished in Context B renewed as action in Context C regardless of whether it had been an action or habit before extinction. The apparent conversion of habit to action during renewal testing in Context C was consistent with other results suggesting that habits converted to action when the context was changed at the start of extinction. Together, the results suggest that extinction in a second context inhibits instrumental behaviors trained as either actions or habits in a context-specific manner. They also expand on prior findings suggesting that actions transfer across contexts, and that habits do not. A change of context may be sufficient to convert a habit to goal-directed action. (PsycInfo Database Record (c) 2020 APA, all rights reserved).}, } @article {pmid32316692, year = {2020}, author = {Keating, AV and Soto, J and Forbes, C and Zhao, M and Craig, DQM and Tuleu, C}, title = {Multi-Methodological Quantitative Taste Assessment of Anti-Tuberculosis Drugs to Support the Development of Palatable Paediatric Dosage Forms.}, journal = {Pharmaceutics}, volume = {12}, number = {4}, pages = {}, pmid = {32316692}, issn = {1999-4923}, abstract = {The unpalatability of antituberculosis drugs is often cited as a major cause of non-adherence in children, yet limited quantitative taste assessment data are available. The aim of this research was to quantify the bitterness of isoniazid, rifampicin, pyrazinamide, and ethambutol dihydrochloride using two in vivo (a human taste panel and a rat brief-access taste aversion (BATA) model) and one in vitro (sensor) method. The response of the Insent TS-5000Z electronic tongue was compared to the in vivo drug concentration found to elicit and suppress half the maximum taste response (EC50 in human and IC50 in rats). Using dose-relevant concentrations, an overarching rank order of bitterness was derived (rifampicin > ethambutol > pyrazinamid~isoniazid). In vitro, only ethambutol exhibited a linear response for all sensors/concentrations. Based on the EC50/IC50 generated, a 'taste index' was proposed to allow for anticipation of the likelihood of taste issues in practice, taking in account the saturability in the saliva and therapeutic doses; ethambutol and isoniazid were found to be the worst tasting using this measure. The study presents the first quantitative taste analysis of these life-saving drugs and has allowed for a comparison of three methods of obtaining such data. Such information allows the operator to identify and prioritise the drugs requiring taste masking to produce palatable formulations.}, } @article {pmid32315693, year = {2020}, author = {Sandoval-Sánchez, AR and Cedillo Zavaleta, LN and Jiménez, JC and Ruíz-García, I and Miranda, F}, title = {Administration of low doses of the 5-HT1A receptor agonist 8-OH-DPAT attenuates the discriminative signal of amphetamine in the conditioned taste aversion procedure.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {193}, number = {}, pages = {172932}, doi = {10.1016/j.pbb.2020.172932}, pmid = {32315693}, issn = {1873-5177}, mesh = {8-Hydroxy-2-(di-n-propylamino)tetralin/*administration & dosage ; Amphetamine/*administration & dosage ; Animals ; Aversive Agents/*administration & dosage ; Central Nervous System Stimulants/*administration & dosage ; Dopamine/metabolism ; Extracellular Space/metabolism ; Male ; Microdialysis ; Nucleus Accumbens/metabolism ; Raphe Nuclei/metabolism ; Rats ; Rats, Wistar ; Receptor, Serotonin, 5-HT1A ; Receptors, Presynaptic/metabolism ; Serotonin 5-HT1 Receptor Agonists/*administration & dosage ; Serotonin 5-HT1 Receptor Antagonists/administration & dosage ; Signal Transduction/drug effects ; Taste/*drug effects ; Ventral Tegmental Area/metabolism ; gamma-Aminobutyric Acid/metabolism ; }, abstract = {Several studies have reported that low doses of the 5-HT1A receptor agonist 8-OH-DPAT reduce cocaine-induced locomotor activity. However, it has also been reported that high doses of 8-OH-DPAT do not substitute for or alter the discriminative signal of cocaine (COC) or amphetamine (AMPH). This study aimed to evaluate the effects of low and high doses of the 5-HT1A agonist 8-OH-DPAT on the discriminative signal of AMPH using conditioned taste aversion as a drug discrimination procedure. Additionally, to establish a correlation between the behavioral effects in drug discrimination and changes in dopamine (DA) and gamma-aminobutyric acid (GABA) concentrations, we evaluated the effect of systemic administration of low or high doses of the 5-HT1A receptor agonist 8-OH-DPAT and of the 5-HT1A receptor antagonist WAY100135 on DA and GABA extracellular concentrations in the nucleus accumbens (nAcc) and ventral tegmental area (VTA), respectively, using cerebral microdialysis. The behavioral results showed that low but not high doses of 8-OH-DPAT produced a reduction in the AMPH-induced discriminative signal, while WAY100135 administration prevented such effects. The microdialysis results showed that a low dose of 8-OH-DPAT decreased extracellular DA concentrations in the nAcc and increased GABA concentrations in the VTA. Pretreatment with WAY100135 prevented these effects. These data support the hypothesis that 5-HT1A receptors modulate the behavioral effects of psychostimulant drugs, such as AMPH, through somatodendritic 5-HT1A autoreceptors in the raphe nucleus indicating that 5-HT1A receptors may be an important target for the development of pharmacological treatments for psychostimulant addiction.}, } @article {pmid32297780, year = {2020}, author = {Nakajima, S}, title = {Effect of pretrial running on running-based taste aversion learning in rats.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {46}, number = {3}, pages = {273-285}, doi = {10.1037/xan0000243}, pmid = {32297780}, issn = {2329-8464}, mesh = {Animals ; Avoidance Learning/*physiology ; Behavior, Animal/*physiology ; Conditioning, Classical/*physiology ; Male ; Rats ; Rats, Wistar ; Running/*physiology ; Taste Perception/*physiology ; }, abstract = {Voluntary wheel running works as an effective unconditioned stimulus (US) to establish conditioned taste aversion (CTA) in rats with a preceding taste solution as a conditioned stimulus (CS): repeated CS-US pairings evoke avoidance of the CS in the two-choice (CS vs. tap water) test administered at the end of the training. Experiment 1 demonstrated that exposure to running immediately before each CS-US trial alleviates CTA. Subsequent two experiments explored the characteristics of the proximal US-preexposure effect: the alleviation of CTA by the pretrial running was not affected by changing the background contexts between the pretrial and the trial running (Experiment 2) or by signaling the pretrial running via another taste cue (Experiment 3). These results indicate the robustness of the proximal US-preexposure effect and fit well with the predictions of Wagner's (1976, 1978) priming theory. (PsycInfo Database Record (c) 2020 APA, all rights reserved).}, } @article {pmid32291265, year = {2020}, author = {Totani, Y and Nakai, J and Dyakonova, VE and Lukowiak, K and Sakakibara, M and Ito, E}, title = {Induction of LTM following an Insulin Injection.}, journal = {eNeuro}, volume = {7}, number = {2}, pages = {}, pmid = {32291265}, issn = {2373-2822}, mesh = {Animals ; *Avoidance Learning ; Conditioning, Operant ; *Insulin ; Lymnaea ; Memory, Long-Term ; Taste ; }, abstract = {The pond snail Lymnaea stagnalis learns conditioned taste aversion (CTA) and consolidates it into long-term memory (LTM). One-day food-deprived snails (day 1 snails) show the best CTA learning and memory, whereas more severely food-deprived snails (5 d) do not express good memory. However, previous studies showed that CTA-LTM was indeed formed in 5-d food-deprived snails (day 5 snails), but its recall was prevented by the effects of food deprivation. CTA-LTM recall in day 5 snails was expressed following 7 d of feeding and then 1 d of food deprivation (day 13 snails). In the present study, we thus hypothesized that memory recall occurs because day 13 snails are in an optimal internal state. One day of food deprivation before the memory test in day 13 snails increased the mRNA level of molluscan insulin-related peptide (MIP) in the CNS. Thus, we further hypothesized that an injection of insulin into day 5 snails following seven additional days with access to food (day 12 snails) activates CTA neurons and mimics the food deprivation state before the memory test in day 13 snails. Day 12 snails injected with insulin could recall the memory. In addition, the simultaneous injection of an anti-insulin receptor antibody and insulin into day 12 snails did not allow memory recall. Insulin injection also decreased the hemolymph glucose concentration. Together, the results suggest that an optimal internal state (i.e., a spike in insulin release and specific glucose levels) are necessary for LTM recall following CTA training in snails.}, } @article {pmid32179656, year = {2020}, author = {Amaya, KA and Stott, JJ and Smith, KS}, title = {Sign-tracking behavior is sensitive to outcome devaluation in a devaluation context-dependent manner: implications for analyzing habitual behavior.}, journal = {Learning & memory (Cold Spring Harbor, N.Y.)}, volume = {27}, number = {4}, pages = {136-149}, pmid = {32179656}, issn = {1549-5485}, support = {F99 NS115270/NS/NINDS NIH HHS/United States ; R01 DA044199/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Behavior, Animal/*physiology ; Conditioning, Classical/*physiology ; Conditioning, Operant/physiology ; Cues ; *Habits ; Male ; Motivation/*physiology ; Rats ; Rats, Long-Evans ; Reinforcement, Psychology ; *Reward ; Taste Perception/physiology ; }, abstract = {Motivationally attractive cues can draw in behavior in a phenomenon termed incentive salience. Incentive cue attraction is an important model for animal models of drug seeking and relapse. One question of interest is the extent to which the pursuit of motivationally attractive cues is related to the value of the paired outcome or can become unrelated and habitual. We studied this question using a sign-tracking (ST) paradigm in rats, in which a lever stimulus preceding food reward comes to elicit conditioned lever-interaction behavior. We asked whether reinforcer devaluation by means of conditioned taste aversion, a classic test of habitual behavior, can modify ST to incentive cues, and whether this depends upon the manner in which reinforcer devaluation takes place. In contrast to several recent reports, we conclude that ST is indeed sensitive to reinforcer devaluation. However, this effect depends critically upon the congruence between the context in which taste aversion is learned and the context in which it is tested. When the taste aversion successfully transfers to the testing context, outcome value strongly influences ST behavior, both when the outcome is withheld (in extinction) and when animals can learn from outcome feedback (reacquisition). When taste aversion does not transfer to the testing context, ST remains high. In total, the extent to which ST persists after outcome devaluation is closely related to the extent to which that outcome is truly devalued in the task context. We believe this effect of context on devaluation can reconcile contradictory findings about the flexibility/inflexibility of ST. We discuss this literature and relate our findings to the study of habits generally.}, } @article {pmid32165443, year = {2020}, author = {Xu, LH and Yang, Y and Liu, HX and Xiao, SF and Qiu, WX and Wang, JX and Zhao, CC and Gui, YH and Liu, GZ and Peng, B and Li, X and Wang, GH and Zhou, X and Jiang, ZL}, title = {Inner Ear Arginine Vasopressin-Vasopressin Receptor 2-Aquaporin 2 Signaling Pathway Is Involved in the Induction of Motion Sickness.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {373}, number = {2}, pages = {248-260}, doi = {10.1124/jpet.119.264390}, pmid = {32165443}, issn = {1521-0103}, mesh = {Animals ; Antidiuretic Hormone Receptor Antagonists/therapeutic use ; Aquaporin 2/*physiology ; Arginine Vasopressin/blood/*physiology ; Benzazepines/therapeutic use ; Cells, Cultured ; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors ; Dogs ; Ear, Inner/*physiology ; Female ; Male ; Motion Sickness/drug therapy/*etiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Vasopressin/*physiology ; Signal Transduction/physiology ; }, abstract = {It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus- or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness.}, } @article {pmid32032742, year = {2020}, author = {László, BR and Hormay, E and Szabó, I and Mintál, K and Nagy, B and László, K and Péczely, L and Ollmann, T and Lénárd, L and Karádi, Z}, title = {Disturbance of taste reactivity and other behavioral alterations after bilateral interleukin-1β microinjection into the cingulate cortex of the rat.}, journal = {Behavioural brain research}, volume = {383}, number = {}, pages = {112537}, doi = {10.1016/j.bbr.2020.112537}, pmid = {32032742}, issn = {1872-7549}, mesh = {Animals ; Behavior, Animal/*drug effects ; Conditioning, Psychological ; Drinking/drug effects ; Drinking Behavior/*drug effects ; Eating/drug effects ; Exploratory Behavior/drug effects ; Feeding Behavior/*drug effects ; *Gyrus Cinguli ; Interleukin-1beta/*pharmacology ; Locomotion/drug effects ; Microinjections ; Motivation ; Rats ; Taste Perception/*drug effects ; }, abstract = {The anterior cingulate cortex (ACC), is known to be intimately involved in food-related motivational processes and their behavioral organization, primarily by evaluating hedonic properties of the relevant stimuli. In the present study, the involvement of cingulate cortical interleukin-1β (IL-1β) mediated mechanisms in a) gustation associated facial and somato-motor behavioral patterns of Wistar rats were examined in taste reactivity test (TR). In addition, b) conditioned taste aversion (CTA) paradigm was performed to investigate the role of these cytokine mechanisms in taste sensation associated learning processes, c) the general locomotor activity of the animals was observed in open field test (OPF), and d) the potentially negative reinforcing effect of IL-1β was examined in conditioned place preference test (CPP). During the TR test, species specific behavioral patterns in response to the five basic tastes were analyzed. Response rates of ingestive and aversive patterns of the cytokine treated and the control groups differed significantly in case of the weaker bitter (QHCl, 0.03 mM), and the stronger umami (MSG, 0.5 M) tastes. IL-1β itself did not elicit CTA, it did not interfere with the acquisition of LiCl induced CTA, and it also failed to cause place preference or aversion in the CPP test. In the OPF paradigm, however, significant differences were found between the cytokine treated and the control groups in the rearing and grooming, the number of crossings, and in the distance moved. Our results indicate the involvement of cingulate cortical IL-1β mechanisms in the control of taste perception and other relevant behavioral processes.}, } @article {pmid31990947, year = {2020}, author = {Chia, J and Scott, K}, title = {Activation of specific mushroom body output neurons inhibits proboscis extension and sucrose consumption.}, journal = {PloS one}, volume = {15}, number = {1}, pages = {e0223034}, pmid = {31990947}, issn = {1932-6203}, support = {R01 DC013280/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Appetitive Behavior/physiology ; Avoidance Learning/*physiology ; Dendrites/physiology ; Drosophila/physiology ; Light ; Mushroom Bodies/*physiology ; Neurons/drug effects/*metabolism/physiology ; Odorants/analysis ; Smell/physiology ; Sucrose/*metabolism ; Taste/physiology ; }, abstract = {The ability to modify behavior based on prior experience is essential to an animal's survival. For example, animals may become attracted to a previously neutral odor or reject a previously appetitive food source based on previous encounters. In Drosophila, the mushroom bodies (MBs) are critical for olfactory associative learning and conditioned taste aversion, but how the output of the MBs affects specific behavioral responses is unresolved. In conditioned taste aversion, Drosophila shows a specific behavioral change upon learning: proboscis extension to sugar is reduced after a sugar stimulus is paired with an aversive stimulus. While studies have identified MB output neurons (MBONs) that drive approach or avoidance behavior, whether the same MBONs impact innate proboscis extension behavior is unknown. Here, we tested the role of MB pathways in altering proboscis extension and identified MBONs that synapse onto multiple MB compartments that upon activation significantly decreased proboscis extension to sugar. Activating several of these lines also decreased sugar consumption, revealing that these MBONs have a general role in modifying feeding behavior beyond proboscis extension. The MBONs that decreased proboscis extension and ingestion are different from those that drive avoidance behavior in another context. These studies provide insight into how activation of MB output neurons decreases proboscis extension to taste compounds.}, } @article {pmid31980843, year = {2020}, author = {Derman, RC and Bass, CE and Ferrario, CR}, title = {Effects of hM4Di activation in CamKII basolateral amygdala neurons and CNO treatment on sensory-specific vs. general PIT: refining PIT circuits and considerations for using CNO.}, journal = {Psychopharmacology}, volume = {237}, number = {5}, pages = {1249-1266}, pmid = {31980843}, issn = {1432-2072}, support = {R21DA043190/DA/NIDA NIH HHS/United States ; R01DK115526/DK/NIDDK NIH HHS/United States ; R01 DK115526/DK/NIDDK NIH HHS/United States ; F31 DK111194/DK/NIDDK NIH HHS/United States ; R01DK106188/DK/NIDDK NIH HHS/United States ; R01 DK106188/DK/NIDDK NIH HHS/United States ; P30 DK020572/DK/NIDDK NIH HHS/United States ; R21 DA043190/DA/NIDA NIH HHS/United States ; 1F31-DK111194-01/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Basolateral Nuclear Complex/drug effects/*metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism ; Clozapine/administration & dosage/*analogs & derivatives ; Conditioning, Classical/drug effects/*physiology ; Feeding Behavior/drug effects/physiology/psychology ; Female ; Male ; Motivation/drug effects/physiology ; Neurons/drug effects/*metabolism ; Piperazines/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Pavlovian stimuli can influence instrumental behaviors via phenomena such as Pavlovian-to-instrumental transfer (PIT). PIT arises via dissociable processes as sensory-specific PIT (SS-PIT) and general PIT. The basolateral amygdala (BLA) mediates SS-PIT, but not general PIT. However, the specific BLA neuronal populations involved are unknown.

AIMS: To determine the contribution of glutamatergic BLA neurons to the expression of SS-PIT and to the recall of sensory-specific properties of stimulus-outcome associations.

METHODS: BLA neurons were transduced with virus containing either GFP or hM4Di, driven by the CamKII promoter. Rats were then tested for SS and general PIT and subsequently for expression of Pavlovian outcome devaluation effects and conditioned taste aversion following injections of vehicle or clozapine-N-oxide (CNO, the hM4Di agonist).

RESULTS: CNO selectively blocked SS-PIT in the hM4Di-expressing group, but not controls, without altering expression of Pavlovian outcome devaluation or sensory-specific taste aversion in either group. Unexpectedly, CNO disrupted general PIT in both groups.

CONCLUSIONS: CamKII BLA neurons mediate the expression of SS-PIT by enabling Pavlovian stimuli to trigger recall of the correct action-outcome associations rather than by mediating recall of the sensory-specific properties of the stimulus-outcome association. Separately, our data demonstrate that CNO alone is sufficient to disrupt affective, but not sensory-specific processes, an effect that was not due to generalized motor disruption. This non-specific effect on general PIT may be related to CNO-induced shifts in internal state. Together, these data identify BLA CamKII neurons as critical for the expression of SS-PIT and reveal important considerations for using CNO to study general affective motivation.}, } @article {pmid31933521, year = {2019}, author = {Liu, DW and Ma, L and Zhang, XH and Wang, YY}, title = {Conditioned taste aversion memory extinction temporally induces insular cortical BDNF release and inhibits neuronal apoptosis.}, journal = {Neuropsychiatric disease and treatment}, volume = {15}, number = {}, pages = {2403-2414}, pmid = {31933521}, issn = {1176-6328}, abstract = {BACKGROUND: Memory extinction has been reported to be related to psychiatric disorders, such as post-traumatic stress disorder (PTSD). Secretion and synthesis of brain-derived neurotrophic factor (BDNF) have been shown to temporally regulate various memory processes via activation of tropomyosin-related kinase B (TrkB) receptors. However, whether memory extinction induces the synthesis and secretion of BDNF on the basis of its localization is not understood. In this study, we aim to investigate activity-dependent BDNF secretion and synthesis in the insular cortex (IC) in the setting of conditioned taste aversion (CTA) memory extinction.

MATERIALS AND METHODS: Rats were subjected to CTA memory extinction and BDNF antibody (or the equal volume of vehicle) was microinjected into the IC immediately after the extinction testing. Real-time polymerase chain reaction and in situ hybridization were used to detect the gene expression of BDNF, NGF and NT4. The protein levels of BDNF were determined through the enzyme-linked immunosorbent assay. In addition, the levels of phosphorylated TrkB normalized to total TrkB were evaluated using immunoprecipitation and immunoblotting. c-Fos, total extracellular signal-regulated kinase (Erk), phosphorylated Erk, and apoptosis-related protein (caspase-3), were detected by Western blotting.

RESULTS: We found that blocking BDNF signaling within the IC disrupts CTA extinction, suggesting that BDNF signaling in the IC is necessary for CTA extinction. Increased expression levels of c-Fos indicate the induced neuronal activity in the IC during CTA extinction. In addition, temporal changes in the gene expression and protein levels of BDNF in the IC were noted during extinction. Moreover, we found that phosphorylation of TrkB increased prior to the enhanced BDNF expression, suggesting that CTA extinction induces rapid activity-dependent BDNF secretion in the IC. Finally, we found decreased expression of caspase-3 in the IC after CTA extinction.

CONCLUSION: These results demonstrate that CTA memory extinction temporally induces the release and synthesis of BDNF in the IC and inhibits neuronal apoptosis.}, } @article {pmid31927082, year = {2020}, author = {Bouton, ME and Broomer, MC and Rey, CN and Thrailkill, EA}, title = {Unexpected food outcomes can return a habit to goal-directed action.}, journal = {Neurobiology of learning and memory}, volume = {169}, number = {}, pages = {107163}, pmid = {31927082}, issn = {1095-9564}, support = {R01 DA033123/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Behavior, Animal ; *Conditioning, Operant ; Extinction, Psychological ; Female ; *Goals ; *Habits ; Rats, Wistar ; *Reinforcement, Psychology ; }, abstract = {Three experiments examined the return of a habitual instrumental response to the status of goal-directed action. In all experiments, rats received extensive training in which lever pressing was reinforced with food pellets on a random-interval schedule of reinforcement. In Experiment 1, the extensively-trained response was not affected by conditioning a taste aversion to the reinforcer, and was therefore considered a habit. However, if the response had earned a new and unexpected food pellet during the final training session, the response was affected by taste aversion conditioning to the (first) reinforcer, and had thus been converted to a goal-directed action. In Experiment 3, 30 min of prefeeding with an irrelevant food pellet immediately before the test also converted a habit back to action, as judged by the taste-aversion devaluation method. That result was consistent with difficulty in finding evidence of habit with the sensory-specific satiety method after extensive instrumental training (Experiment 2). The results suggest that an instrumental behavior's status as a habit is not permanent, and that a habit can be returned to action status by associating it with a surprising reinforcer (Experiment 1) or by giving the animal an unexpected prefeeding immediately prior to the action/habit test (Experiment 3).}, } @article {pmid31927081, year = {2020}, author = {Trask, S and Shipman, ML and Green, JT and Bouton, ME}, title = {Some factors that restore goal-direction to a habitual behavior.}, journal = {Neurobiology of learning and memory}, volume = {169}, number = {}, pages = {107161}, pmid = {31927081}, issn = {1095-9564}, support = {R01 DA033123/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Behavior, Animal ; *Conditioning, Operant ; *Goals ; *Habits ; Male ; Rats, Wistar ; *Reinforcement, Psychology ; }, abstract = {Recent findings from our laboratory suggest that an extensively-practiced instrumental behavior can appear to be a goal-directed action (rather than a habit) when a second behavior is added and reinforced during intermixed final sessions (Shipman et al., 2018). The present experiments were designed to explore and understand this finding. All used the taste aversion method of devaluing the reinforcer to distinguish between goal-directed actions and habits. Experiment 1 confirmed that reinforcing a second response in a separate context (but not mere exposure to that context) can return an extensively-trained habit to the status of goal-directed action. Experiment 2 showed that training of the second response needs to be intermixed with training of the first response to produce this effect; training the second response after the first-response training was complete preserved the first response as a habit. Experiment 3 demonstrated that reinforcing the second response with a different reinforcer breaks the habit status of the first response. Experiment 4 found that free reinforcers (that were not response-contingent) were sufficient to restore goal-directed performance. Together, the results suggest that unexpected reinforcer delivery can render a habitual response goal-directed again.}, } @article {pmid31882185, year = {2020}, author = {Alapin, JM and Dines, M and Lamprecht, R}, title = {EphB2 receptor forward signaling is needed for normal long-term memory formation in aged mice.}, journal = {Neurobiology of aging}, volume = {86}, number = {}, pages = {11-15}, doi = {10.1016/j.neurobiolaging.2019.10.019}, pmid = {31882185}, issn = {1558-1497}, mesh = {Animals ; Healthy Aging/*psychology ; Male ; Memory, Long-Term/*physiology ; Mice, Inbred C57BL ; Receptor, EphB2/*metabolism/*physiology ; Signal Transduction/*physiology ; Taste Perception/physiology ; }, abstract = {The molecular mechanisms underpinning age-related changes in the ability to form long-term memory need to be clarified. EphB2 receptors and their ephrin ligands are involved in key cellular functions such as neuronal morphogenesis and synaptic transmission believed to be involved in long-term memory formation. We were therefore interested to explore whether EphB2 is involved in the alterations in memory formation abilities observed in old age. Toward that end, we examined the ability to form long-term memory in mice that lack EphB2 (EphB2[-/-]). A previous study has shown that the ability to form long-term conditioned taste aversion (CTA) memory in young EphB2[-/-] mice remains intact. In the present study, we report that long-term CTA memory formation is improved in old wild-type mice but not in age-matched old EphB2[-/-] mice. To further explore EphB2 mechanisms responsible for this difference in memory formation ability, we examined CTA memory in EphB2[lacZ/lacZ] mice devoid of EphB2 forward signaling. We found that the ability to create CTA long-term memory is unaffected in young EphB2[lacZ/lacZ] mice. However, the ability to form an increased long-term CTA memory shown in old wild-type mice is impaired in old EphB2[lacZ/lacZ] mice. The inability to form enhanced CTA long-term memory in EphB2[-/-] and EphB2[lacZ/lacZ] old mice was not caused by differences in taste perception or ability to consume fluids. Thus, our observations show that the absence of EphB2 forward signaling in old mice impairs the ability to form enhanced long-term CTA memory and indicate that EphB2 forward signaling is needed for normal memory formation in aged mice.}, } @article {pmid31829643, year = {2020}, author = {Keefer, SE and Petrovich, GD}, title = {The basolateral amygdala-medial prefrontal cortex circuitry regulates behavioral flexibility during appetitive reversal learning.}, journal = {Behavioral neuroscience}, volume = {134}, number = {1}, pages = {34-44}, pmid = {31829643}, issn = {1939-0084}, support = {R01 DK085721/DK/NIDDK NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Amygdala/physiology ; Animals ; Basolateral Nuclear Complex/metabolism/*physiology ; Behavior, Animal/physiology ; Brain/physiology ; Conditioning, Classical/physiology ; Cues ; Extinction, Psychological/physiology ; Male ; Memory/physiology ; Neural Pathways/physiology ; Prefrontal Cortex/metabolism/*physiology ; Rats ; Rats, Long-Evans ; Reinforcement, Psychology ; Reversal Learning/*physiology ; }, abstract = {Environmental cues can become predictors of food availability through Pavlovian conditioning. Two forebrain regions important in this associative learning are the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). Recent work showed the BLA-mPFC pathway is activated when a cue reliably signals food, suggesting the BLA informs the mPFC of the cue's value. The current study tested this hypothesis by altering the value of 2 food cues using reversal learning and illness-induced devaluation paradigms. Rats that received unilateral excitotoxic lesions of the BLA and mPFC contralaterally placed, along with ipsilateral and sham controls, underwent discriminative conditioning, followed by reversal learning and then devaluation. All groups successfully discriminated between 2 auditory stimuli that were followed by food delivery (conditional stimulus [CS] +) or not rewarded (CS-), demonstrating this learning does not require BLA-mPFC communication. When the outcomes of the stimuli were reversed, the rats with disconnected BLA-mPFC (contralateral condition) showed increased responding to the CSs, especially to the rCS + (original CS-) during the first session, suggesting impaired cue memory recall and behavioral inhibition compared to the other groups. For devaluation, all groups successfully learned conditioned taste aversion; however, there was no evidence of cue devaluation or differences between groups. Interestingly, at the end of testing, the nondevalued contralateral group was still responding more to the original CS + (rCS-) compared to the devalued contralateral group. These results suggest a potential role for BLA-mPFC communication in guiding appropriate responding during periods of behavioral flexibility when the outcomes, and thus the values, of learned cues are altered. (PsycINFO Database Record (c) 2020 APA, all rights reserved).}, } @article {pmid31744862, year = {2020}, author = {Torruella-Suárez, ML and Vandenberg, JR and Cogan, ES and Tipton, GJ and Teklezghi, A and Dange, K and Patel, GK and McHenry, JA and Hardaway, JA and Kantak, PA and Crowley, NA and DiBerto, JF and Faccidomo, SP and Hodge, CW and Stuber, GD and McElligott, ZA}, title = {Manipulations of Central Amygdala Neurotensin Neurons Alter the Consumption of Ethanol and Sweet Fluids in Mice.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {40}, number = {3}, pages = {632-647}, pmid = {31744862}, issn = {1529-2401}, support = {K01 AA023555/AA/NIAAA NIH HHS/United States ; U01 AA020911/AA/NIAAA NIH HHS/United States ; K01 DK115902/DK/NIDDK NIH HHS/United States ; P60 AA011605/AA/NIAAA NIH HHS/United States ; U24 AA025475/AA/NIAAA NIH HHS/United States ; F31 AA026183/AA/NIAAA NIH HHS/United States ; R00 MH115165/MH/NIMH NIH HHS/United States ; T32 NS007431/NS/NINDS NIH HHS/United States ; T32 MH093315/MH/NIMH NIH HHS/United States ; K99 MH115165/MH/NIMH NIH HHS/United States ; R37 AA014983/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking/*psychology ; Animals ; Anxiety/psychology ; Central Amygdaloid Nucleus/cytology/*physiology ; Food Preferences/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity/physiology ; Neural Pathways/cytology/physiology ; Neurons/*physiology ; Neurotensin/*physiology ; Optogenetics ; Parabrachial Nucleus/cytology/physiology ; Patch-Clamp Techniques ; Reward ; Sweetening Agents ; Taste/physiology ; }, abstract = {The central nucleus of the amygdala plays a significant role in alcohol use and other affective disorders; however, the genetically-defined neuronal subtypes and projections that govern these behaviors are not well known. Here we show that neurotensin neurons in the central nucleus of the amygdala of male mice are activated by in vivo ethanol consumption and that genetic ablation of these neurons decreases ethanol consumption and preference in non-ethanol-dependent animals. This ablation did not impact preference for sucrose, saccharin, or quinine. We found that the most robust projection of the central amygdala neurotensin neurons was to the parabrachial nucleus, a brain region known to be important in feeding behaviors, conditioned taste aversion, and alarm. Optogenetic stimulation of projections from these neurons to the parabrachial nucleus is reinforcing, and increases ethanol drinking as well as consumption of sucrose and saccharin solutions. These data suggest that this central amygdala to parabrachial nucleus projection influences the expression of reward-related phenotypes and is a novel circuit promoting consumption of ethanol and palatable fluids.SIGNIFICANCE STATEMENT Alcohol use disorder (AUD) is a major health burden worldwide. Although ethanol consumption is required for the development of AUD, much remains unknown regarding the underlying neural circuits that govern initial ethanol intake. Here we show that ablation of a population of neurotensin-expressing neurons in the central amygdala decreases intake of and preference for ethanol in non-dependent animals, whereas the projection of these neurons to the parabrachial nucleus promotes consumption of ethanol as well as other palatable fluids.}, } @article {pmid31733301, year = {2020}, author = {Basu, S and Alapin, JM and Dines, M and Lamprecht, R}, title = {Long-term memory is maintained by continuous activity of Arp2/3 in lateral amygdala.}, journal = {Neurobiology of learning and memory}, volume = {167}, number = {}, pages = {107115}, doi = {10.1016/j.nlm.2019.107115}, pmid = {31733301}, issn = {1095-9564}, mesh = {Actin-Related Protein 2-3 Complex/antagonists & inhibitors/*physiology ; Animals ; Basolateral Nuclear Complex/drug effects/*physiology ; Conditioning, Classical/drug effects/physiology ; Fear ; Indoles/administration & dosage ; Male ; Memory, Long-Term/drug effects/*physiology ; Rats, Sprague-Dawley ; }, abstract = {Evidence indicates that long-term memory formation involves alterations in synaptic efficacy produced by modifications in neural transmission and morphology. However, it is not clear how such changes induced by learning, that encode memory, are maintained over long period of time to preserve long-term memory. It has been shown that the actin nucleating protein Arp2/3 is essential for supporting neuronal morphology and synaptic transmission. We therefore hypothesized that continuous Arp2/3 activity is needed to maintain long-term memory over time. To test this hypothesis we microinjected into lateral amygdala (LA) of rats CK-666, a specific inhibitor of Arp2/3, two days after fear conditioning and tested the effect on long-term fear memory maintenance a day afterward. We found that injection of CK-666 two days after training abolished fear conditioning memory. Fear conditioning could be formed when a control compound CK-689 was applied two days after training. Microinjection of CK-666 a day before fear conditioning training had no effect on fear conditioning learning and long-term memory formation. We revealed that Arp2/3 is also needed to maintain long-term conditioned taste aversion (CTA) memory in LA. Microinjection of CK-666 two days after CTA training impaired long-term memory tested a day afterwards. We conclude that continuous activity of Arp2/3 in LA is essential for the maintenance of long-term memory.}, } @article {pmid31726218, year = {2020}, author = {Ali, J and Chiang, M and Lee, JB and Voronin, GO and Bennett, J and Cram, A and Kagan, L and Garnett, MC and Roberts, CJ and Gershkovich, P}, title = {Is rat a good model for assessment of particulate-based taste-masked formulations?.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {146}, number = {}, pages = {1-9}, doi = {10.1016/j.ejpb.2019.11.001}, pmid = {31726218}, issn = {1873-3441}, mesh = {Administration, Oral ; Animals ; Aversive Agents/administration & dosage ; Chemistry, Pharmaceutical ; Child ; Drug Compounding/*methods ; Drug Evaluation, Preclinical/*standards ; Drug Liberation ; Excipients/*chemistry ; Flavoring Agents/administration & dosage ; Humans ; Models, Animal ; Mouth Mucosa/metabolism/physiology ; Rats/*physiology ; Saliva/chemistry/physiology ; Species Specificity ; Taste/*drug effects/physiology ; }, abstract = {Recently there has been an increased interest to develop specialised dosage forms that are better suited to specific patient populations, such as paediatrics and geriatrics. In these patient populations the acceptability of the oral dosage form can be paramount to the products success. However, many Active Pharmaceutical Ingredients (APIs) are known to cause an aversive taste response. One way to increase the acceptability and to enhance the palatability of the formulation is to design coated taste-masked particulate-based dosage forms. The masking of poorly tasting drugs with physical barriers such as polymer coatings can be utilised to prevent the release of drug within the oral cavity, thus preventing a taste response. However, currently, there are few assessment tools and models available to test the efficiency of these particulate-based taste-masked formulations. The rat brief access taste aversion model has been shown to be useful in assessment of taste for liquid dosage forms. However, the applicability of the rat model for particulate-based taste masked formulations is yet to be assessed. It is not understood whether dissolution, solubility and thus exposure of the drug to taste receptors would be the same in rat and human. Therefore, rat saliva must be compared to human saliva to determine the likelihood that drug release would be similar within the oral cavity for both species. In this study rat saliva was characterised for parameters known to be important for drug dissolution, such as pH, buffer capacity, surface tension, and viscosity. Subsequently dissolution of model bitter tasting compounds, sildenafil citrate and efavirenz, in rat saliva was compared to dissolution in human saliva. For all parameters characterised and for the dissolution of both drugs in rat saliva, a substantial difference was observed when compared to human saliva. This discrepancy in saliva parameters and dissolution of model drugs suggests that preclinical taste evaluation of particulate-based taste-masked formulations suggests rat is not a good model for predicting taste of solid dosage forms or undissolved drug where dissolution is required. Alternative preclinical in vivo models in other species, or improved biorelevant in vitro models should be considered instead.}, } @article {pmid31655082, year = {2019}, author = {Song, L and Chen, K and Yan, J and Zhang, Y and Mao, X and Lu, B and Sun, B}, title = {Maternal high-fat diet during gestation and lactation increases conditioned aversion threshold for sucrose and alters sweet taste receptors expression in taste buds in rat offspring.}, journal = {Physiology & behavior}, volume = {212}, number = {}, pages = {112709}, doi = {10.1016/j.physbeh.2019.112709}, pmid = {31655082}, issn = {1873-507X}, mesh = {Animals ; Avoidance Learning/*physiology ; Choice Behavior/drug effects ; *Diet, High-Fat ; Female ; Lactation ; Male ; Maternal Nutritional Physiological Phenomena/*physiology ; Pregnancy ; Rats ; Receptors, G-Protein-Coupled/biosynthesis/*physiology ; Sex Factors ; Sucrose/pharmacology ; Taste/drug effects/*physiology ; Taste Buds/metabolism/physiology ; Taste Threshold/*physiology ; Transducin/biosynthesis ; }, abstract = {Maternal high-fat (HF) diet affects offspring's metabolic phenotype. Sweet taste is an important factor in promoting appetite. In order to determine the effects of maternal HF diet throughout gestation and lactation on taste sensitivity to sucrose in rat offspring, we measured conditioned aversion threshold for sucrose by conditioned taste aversion (CTA) associated with two-bottle choice tests, and measured mRNA expression of sweet taste receptors in taste buds. In male offspring, conditioned aversion threshold for sucrose lay between 0.007 M and 0.009 M in control group, while in those with HF dams, the threshold significantly increased to be between 0.011 M and 0.02 M. In female offspring, conditioned aversion threshold for sucrose lay between 0.003 M and 0.005 M in control group, whereas maternal HF diet increased it to be between 0.007 M and 0.009 M. Maternal HF diet increased T1R2 and T1R3 mRNA expression in taste buds of male offspring, while only increased T1R2 mRNA expression in female offspring. Both male and female offspring with HF dams had lower α-gustducin mRNA expression, whereas only male offspring with HF dams had lower OB-Rb mRNA expression in taste buds. Our data suggest that maternal HF diet decreased taste sensitivity to sucrose in both male and female offspring, which may be partly due to altered expression of sweet taste receptors and related downstream pathways in taste buds.}, } @article {pmid31597726, year = {2019}, author = {Kayyal, H and Yiannakas, A and Kolatt Chandran, S and Khamaisy, M and Sharma, V and Rosenblum, K}, title = {Activity of Insula to Basolateral Amygdala Projecting Neurons is Necessary and Sufficient for Taste Valence Representation.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {39}, number = {47}, pages = {9369-9382}, pmid = {31597726}, issn = {1529-2401}, support = {//CIHR/Canada ; }, mesh = {Amygdala/chemistry/*physiology ; Animals ; Avoidance Learning/*physiology ; Basolateral Nuclear Complex/chemistry/*physiology ; Male ; Mice ; Neural Pathways/chemistry/physiology ; Neurons/chemistry/*physiology ; Organ Culture Techniques ; Random Allocation ; Taste/*physiology ; }, abstract = {Conditioned taste aversion (CTA) is an associative learning paradigm, wherein consumption of an appetitive tastant (e.g., saccharin) is paired to the administration of a malaise-inducing agent, such as intraperitoneal injection of LiCl. Aversive taste learning and retrieval require neuronal activity within the anterior insula (aIC) and the basolateral amygdala (BLA). Here, we labeled neurons of the aIC projecting to the BLA in adult male mice using a retro-AAV construct and assessed their necessity in aversive and appetitive taste learning. By restricting the expression of chemogenetic receptors in aIC-to-BLA neurons, we demonstrate that activity within the aIC-to-BLA projection is necessary for both aversive taste memory acquisition and retrieval, but not for its maintenance, nor its extinction. Moreover, inhibition of the projection did not affect incidental taste learning per se, but effectively suppressed aversive taste memory retrieval when applied either during or before the encoding of the unconditioned stimulus for CTA (i.e., malaise). Remarkably, activation of the projection after novel taste consumption, without experiencing any internal discomfort, was sufficient to form an artificial aversive taste memory, resulting in strong aversive behavior upon retrieval. Our results indicate that aIC-to-BLA projecting neurons are an essential component in the ability of the brain to associate taste sensory stimuli with body states of negative valence and guide the expression of valence-specific behavior upon taste memory retrieval.SIGNIFICANCE STATEMENT In the present study we subjected mice to the conditioned taste aversion paradigm, where animals learn to associate novel taste with malaise (i.e., assign it negative valence). We show that activation of neurons in the anterior insular cortex (aIC) that project into the basolateral amygdala (BLA) in response to conditioned taste aversion is necessary to form a memory for a taste of negative valence. Moreover, artificial activation of this pathway (without any feeling of pain) after the sampling of a taste can also lead to such associative memory. Thus, activation of aIC-to-BLA projecting neurons is necessary and sufficient to form and retrieve aversive taste memory.}, } @article {pmid31561365, year = {2019}, author = {Har-Paz, I and Roisman, N and Michaelson, DM and Moran, A}, title = {Extra-Hippocampal Learning Deficits in Young Apolipoprotein E4 Mice and Their Synaptic Underpinning.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {72}, number = {1}, pages = {71-82}, doi = {10.3233/JAD-190564}, pmid = {31561365}, issn = {1875-8908}, mesh = {Animals ; Apolipoprotein E4/genetics/*metabolism ; Avoidance Learning/*physiology ; Extinction, Psychological/physiology ; Female ; Hippocampus/*metabolism ; Male ; Memory Disorders/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Synapses/genetics/*metabolism ; }, abstract = {The E4 allele of apolipoprotein (apoE4) is the primary genetic risk factor for late onset Alzheimer's disease (AD), yet the exact manner in which apoE4 leads to the development of AD is undetermined. Human and animal studies report that apoE4-related memory deficits appear earlier than the AD clinical manifestation, thus suggesting the existence of early, pre-pathological, apoE4 impairments that may later lead to AD onset. While current research regards the hippocampus as the initial and primary effected locus by apoE4, we presently investigate the possibility that apoE4 innately impairs any brain area that requires synaptic plasticity. To test this hypothesis, we trained young (3-4-month-old) target-replacement apoE3 and apoE4 mice in conditioned taste aversion (CTA) acquisition and extinction learnings- hippocampus-independent learnings that are easily performed at a young age. Synaptic vesicular markers analysis was conducted in the gustatory cortex (GC), basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and hippocampal CA3 to reveal underlying apoE4-related impairments. We have found that young apoE4 mice are severely impaired in CTA acquisition and extinction learning. CTA acquisition impairments were correlated with reduced vGat and vGlut levels in the BLA and GC, but not in the CA3. CTA extinction was correlated with lower synaptophysin and vGlut levels in the mPFC, a central region in CTA extinction. Our results support apoE4-related early-life plasticity impairments that precede the AD clinical manifestations and affect any brain area that depends on extensive plasticity; early impairments that may promote the development of AD pathologies later in life.}, } @article {pmid31521799, year = {2019}, author = {He, ABH and Huang, CL and Kozłowska, A and Chen, JC and Wu, CW and Huang, ACW and Liu, YQ}, title = {Involvement of neural substrates in reward and aversion to methamphetamine addiction: Testing the reward comparison hypothesis and the paradoxical effect hypothesis of abused drugs.}, journal = {Neurobiology of learning and memory}, volume = {166}, number = {}, pages = {107090}, doi = {10.1016/j.nlm.2019.107090}, pmid = {31521799}, issn = {1095-9564}, mesh = {Amphetamine-Related Disorders/*metabolism ; Animals ; Basolateral Nuclear Complex/*drug effects/metabolism ; Central Nervous System Stimulants/*administration & dosage ; Cerebral Cortex/drug effects ; Conditioning, Operant/drug effects ; Drug-Seeking Behavior/drug effects ; Extinction, Psychological/drug effects ; Immunohistochemistry ; MAP Kinase Signaling System/physiology ; Male ; Methamphetamine/administration & dosage ; Nucleus Accumbens/*drug effects/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Rats, Wistar ; Reward ; }, abstract = {Clinical studies of drug addiction focus on the reward impact of abused drugs that produces compulsive drug-seeking behavior and drug dependence. However, a small amount of research has examined the opposite effect of aversion to abused drugs to balance the reward effect for drug taking. An aversive behavioral model of abused drugs in terms of conditioned taste aversion (CTA) was challenged by the reward comparison hypothesis (Grigson, 1997). To test the reward comparison hypothesis, the present study examined the rewarding or aversive neural substrates involved in methamphetamine-induced conditioned suppression. The behavioral data showed that methamphetamine induced conditioned suppression on conditioning and reacquisition but extinguished it on extinction. A higher level of stressful aversive corticosterone occurred on conditioning and reacquisition but not extinction. The c-Fos or p-ERK immunohistochemical activity showed that the cingulated cortex area 1 (Cg1), infralimbic cortex (IL), prelimbic cortex (PrL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) of the hippocampus were overexpressed in aversive CTA induced by methamphetamine. These data may indicate that the Cg1, IL, PrL, BLA, NAc, and DG probably mediated the paradoxical effect-reward and aversion. Altogether, our data conflicted with the reward comparison hypothesis, and methamphetamine may simultaneously induce the paradoxical effect of reward and aversion in the brain to support the paradoxical effect hypothesis of abused drugs. The present data implicate some insights for drug addiction in clinical aspects.}, } @article {pmid31520676, year = {2019}, author = {Nakajima, S}, title = {Further demonstration of running-based food avoidance learning in laboratory mice (Mus musculus).}, journal = {Behavioural processes}, volume = {168}, number = {}, pages = {103962}, doi = {10.1016/j.beproc.2019.103962}, pmid = {31520676}, issn = {1872-8308}, mesh = {Animals ; Association Learning ; *Avoidance Learning ; Conditioning, Classical ; *Feeding Behavior ; Habituation, Psychophysiologic ; Male ; Mice ; *Running ; Taste ; }, abstract = {Voluntary wheel running has hedonically bivalent properties in laboratory rats and mice. While it works as a reward for instrumental performance such as bar pressing, it also functions as an aversive stimulus to establish Pavlovian conditioned avoidance of the paired stimulus. The present study focused on the latter case. Running in closed wheels hampered habituation of a reluctance to eat a target snack in rats (Experiment 1A) and mice (Experiment 1B) trained by pairing access to a target snack with confinement to a wheel attached to the cage. Experiment 2 successfully confirmed and extended this finding with mice running in both open and closed wheels. A differential conditioning procedure employed in Experiment 3 ensured that this phenomenon is specific to the snack paired with running, implying that it reflects Pavlovian conditioned flavor avoidance (CFA). Free exploration in cages without wheels, however, did not results in a CFA.}, } @article {pmid31473281, year = {2019}, author = {Osorio-Gómez, D and Bermúdez-Rattoni, F and Guzmán-Ramos, K}, title = {Artificial taste avoidance memory induced by coactivation of NMDA and β-adrenergic receptors in the amygdala.}, journal = {Behavioural brain research}, volume = {376}, number = {}, pages = {112193}, doi = {10.1016/j.bbr.2019.112193}, pmid = {31473281}, issn = {1872-7549}, mesh = {Amygdala/drug effects/physiology ; Animals ; Avoidance Learning/*physiology ; Cerebral Cortex/drug effects/physiology ; Conditioning, Classical/*physiology ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/pharmacology ; Male ; Memory/physiology ; N-Methylaspartate/pharmacology ; Norepinephrine/pharmacology ; Rats ; Rats, Wistar ; Receptors, Adrenergic, beta/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Saccharin/pharmacology ; Taste/drug effects/*physiology ; }, abstract = {The association between a taste and gastric malaise allows animals to avoid the ingestion of potentially toxic food. This association has been termed conditioned taste aversion (CTA) and relies on the activity of key brain structures such as the amygdala and the insular cortex. The establishment of this gustatory-avoidance memory is related to glutamatergic and noradrenergic activity within the amygdala during two crucial events: gastric malaise (unconditioned stimulus, US) and the post-acquisition spontaneous activity related to the association of both stimuli. To understand the functional implications of these neurochemical changes on avoidance memory formation, we assessed the effects of pharmacological stimulation of β-adrenergic and glutamatergic NMDA receptors through the administration of a mixture of L-homocysteic acid and isoproterenol into the amygdala after saccharin exposure on specific times to emulate the US and post-acquisition local signals that would be occurring naturally under CTA training. Our results show that activation of NMDA and β-adrenergic receptors generated a long-term avoidance response to saccharin, like a naturally induced rejection with LiCl. Moreover, the behavioral outcome was accompanied by changes in glutamate, norepinephrine and dopamine levels within the insular cortex, analogous to those displayed during memory retrieval of taste aversion memory. Therefore, we suggest that taste avoidance memory can be induced artificially through the emulation of specific amygdalar neurochemical signals, promoting changes in the amygdala-insular cortex circuit enabling memory establishment.}, } @article {pmid31434277, year = {2019}, author = {Cunningham, CL}, title = {Genetic Relationships Between Ethanol-Induced Conditioned Place Aversion and Other Ethanol Phenotypes in 15 Inbred Mouse Strains.}, journal = {Brain sciences}, volume = {9}, number = {8}, pages = {}, pmid = {31434277}, issn = {2076-3425}, support = {P60 AA010760/AA/NIAAA NIH HHS/United States ; R01AA007702/AA/NIAAA NIH HHS/United States ; }, abstract = {The genetic relationships between different behaviors used to index the aversive effects of ethanol are unknown. To address this issue, ethanol-induced conditioned place aversion (CPA) was tested in a genetically diverse panel of 15 inbred mouse strains. Mice were exposed to an unbiased place conditioning procedure using ethanol doses of 0, 2, or 4 g/kg; all injections were given immediately after 5-min exposure to distinctive tactile cues. There were dose-dependent effects of ethanol on CPA and on the change in pre-injection activity rates between the first and last conditioning trials. Most strains (80%) developed CPA, demonstrating the generalizability of this behavior. Moreover, genotype had significant effects on CPA magnitude and locomotor activity rates. Strain means from this study and previously published studies were then used to examine genetic correlations. These analyses showed significant genetic correlations between CPA and ethanol intake/preference, conditioned taste aversion, and drug withdrawal (but not blood ethanol concentration or conditioned place preference), supporting the idea of commonality in the genes underlying CPA and each of these behaviors. The overall pattern of findings is consistent with previous data suggesting that genetic differences in sensitivity to ethanol's aversive effects play a role in determining strain differences in ethanol drinking. The broader implication is that individuals who are more sensitive to the aversive effects of ethanol may be protected from developing the excessive drinking behaviors characteristic of alcohol use disorders.}, } @article {pmid31414153, year = {2020}, author = {Galistu, A and D'Aquila, PS}, title = {Daily memantine treatment blunts hedonic response to sucrose in rats.}, journal = {Psychopharmacology}, volume = {237}, number = {1}, pages = {103-114}, pmid = {31414153}, issn = {1432-2072}, mesh = {Analysis of Variance ; Animals ; Behavior, Animal/drug effects ; Binge-Eating Disorder/*drug therapy ; Conditioning, Classical/drug effects ; Dopamine Agents/*pharmacology ; Eating/drug effects ; Feeding Behavior/*drug effects ; Male ; Memantine/*pharmacology ; Motivation/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; Reward ; Sucrose/administration & dosage ; Taste/drug effects ; }, abstract = {RATIONALE: Preclinical and clinical studies suggest the potential use of memantine in the treatment of binge eating disorder. The aim of this study was to further investigate the mechanisms by which memantine influences the motivational aspects of ingestion through the analysis of licking microstructure. To interpret treatment effects in relation to drug action at specific functionally relevant times, we compared the effect of two different administration schedules.

METHODS: Memantine was administered daily for a week, either 1 h before or immediately after a 30-min daily session. The effects on the microstructure of licking for a 10% sucrose solution in rats were examined in the course of treatment and for 15 days after treatment discontinuation.

RESULTS: Treatment before testing reduced ingestion due to reduced burst size and increased latency in the first session. However, a progressive increase in burst number across sessions led to a full recovery of ingestion levels by the end of treatment. Daily post-session administration induced a dramatic decrease of activation of licking behaviour, indicated by reduced burst number, accompanied to reduced burst size. A slow recovery of ingestion took place after treatment discontinuation.

CONCLUSION: These results suggest a reduced hedonic/reward evaluation response, an effect likely due to NMDA receptor blockade occurring during the testing time and support the hypothesis that memantine interferes with the hedonic/non-homeostatic mechanisms regulating food intake and food-seeking. The effect of post-session administration might be explained by the development of conditioned taste aversion.}, } @article {pmid31410739, year = {2019}, author = {Wills, AJ and Edmunds, CER and Le Pelley, ME and Milton, F and Newell, BR and Dwyer, DM and Shanks, DR}, title = {Dissociable learning processes, associative theory, and testimonial reviews: A comment on Smith and Church (2018).}, journal = {Psychonomic bulletin & review}, volume = {26}, number = {6}, pages = {1988-1993}, pmid = {31410739}, issn = {1531-5320}, mesh = {Conditioning, Classical ; Feedback ; Humans ; Learning ; *Psychology, Comparative ; }, abstract = {Smith and Church (Psychonomic Bulletin & Review, 25, 1565-1584 2018) present a "testimonial" review of dissociable learning processes in comparative and cognitive psychology, by which we mean they include only the portion of the available evidence that is consistent with their conclusions. For example, they conclude that learning the information-integration category-learning task with immediate feedback is implicit, but do not consider the evidence that people readily report explicit strategies in this task, nor that this task can be accommodated by accounts that make no distinction between implicit and explicit processes. They also consider some of the neuroscience relating to information-integration category learning, but do not report those aspects that are more consistent with an explicit than an implicit account. They further conclude that delay conditioning in humans is implicit, but do not report evidence that delay conditioning requires awareness; nor do they present the evidence that conditioned taste aversion, which should be explicit under their account, can be implicit. We agree with Smith and Church that it is helpful to have a clear definition of associative theory, but suggest that their definition may be unnecessarily restrictive. We propose an alternative definition of associative theory and briefly describe an experimental procedure that we think may better distinguish between associative and non-associative processes.}, } @article {pmid31404849, year = {2019}, author = {Harris, AC and Muelken, P and Swain, Y and Palumbo, M and Jain, V and Goniewicz, ML and Stepanov, I and LeSage, MG}, title = {Non-nicotine constituents in e-cigarette aerosol extract attenuate nicotine's aversive effects in adolescent rats.}, journal = {Drug and alcohol dependence}, volume = {203}, number = {}, pages = {51-60}, pmid = {31404849}, issn = {1879-0046}, support = {R03 DA042009/DA/NIDA NIH HHS/United States ; T32 DA007097/DA/NIDA NIH HHS/United States ; }, mesh = {Aerosols ; Age Factors ; Alkaloids/administration & dosage ; Animals ; Aversive Agents/*administration & dosage ; Avoidance Learning/drug effects/physiology ; E-Cigarette Vapor/*administration & dosage ; *Electronic Nicotine Delivery Systems ; Female ; Male ; Menthol/*administration & dosage ; Nicotine/*administration & dosage ; Rats ; Rats, Sprague-Dawley ; Self Stimulation/drug effects ; }, abstract = {BACKGROUND: Development of preclinical methodology for evaluating the abuse liability of electronic cigarettes (ECs) in adolescents is urgently needed to inform FDA regulation of these products. We previously reported reduced aversive effects of EC liquids containing nicotine and a range of non-nicotine constituents (e.g., propylene glycol, minor tobacco alkaloids) compared to nicotine alone in adult rats as measured using intracranial self-stimulation. The goal of this study was to compare the aversive effects of nicotine alone and EC aerosol extracts in adolescent rats as measured using conditioned taste aversion (CTA), which can be conducted during the brief adolescent period.

METHODS AND RESULTS: In Experiment 1, nicotine alone (1.0 or 1.5 mg/kg, s.c.) produced significant CTA in adolescent rats in a two-bottle procedure, thereby establishing a model to study the effects of EC extracts. At a nicotine dose of 1.0 mg/kg, CTA to Vuse Menthol EC extract, but not Aroma E-Juice EC extract, was attenuated compared to nicotine alone during repeated two-bottle CTA tests (Experiment 2a). At a nicotine dose of 0.5 mg/kg, CTA to Vuse Menthol EC extract did not differ from nicotine alone during the first two-bottle CTA test but extinguished more rapidly across repeated two-bottle tests (Experiment 2b).

CONCLUSIONS: Non-nicotine constituents in Vuse Menthol EC extracts attenuated CTA in a two-bottle procedure in adolescents. This model may be useful for anticipating the abuse liability of ECs in adolescents and for modeling FDA-mandated changes in product standards for nicotine or other constituents in ECs.}, } @article {pmid31401881, year = {2019}, author = {Cui, Y and Wu, H and Li, Q and Liao, J and Gao, P and Sun, F and Zhang, H and Lu, Z and Wei, X and He, C and Ma, T and Wei, X and Chen, X and Zheng, H and Yang, G and Liu, D and Zhu, Z}, title = {Impairment of Bitter Taste Sensor Transient Receptor Potential Channel M5-Mediated Aversion Aggravates High-Salt Intake and Hypertension.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {74}, number = {4}, pages = {1021-1032}, doi = {10.1161/HYPERTENSIONAHA.119.13358}, pmid = {31401881}, issn = {1524-4563}, mesh = {Animals ; Feeding Behavior/*physiology ; Humans ; Hypertension/genetics/*metabolism/physiopathology ; Mice ; Mice, Knockout ; Sodium Chloride, Dietary ; TRPM Cation Channels/genetics/*metabolism ; Taste/genetics/*physiology ; Taste Perception/genetics/*physiology ; Tongue/metabolism ; }, abstract = {Excessive salt consumption leads to cardiovascular diseases. Despite various measures designed to reduce salt intake, daily salt intake remains at a high level. Appropriate salt intake is balanced by salt taste preference triggered by epithelium sodium channel and salt taste aversion evoked by bitter taste sensor, transient receptor potential channel M5 (TRPM5). However, the behavioral mechanism of excessive salt intake remains largely elusive. In this study, wild type and TRPM5[-/-] mice were applied to study the influence of high-salt administration on epithelium sodium channel/TRPM5 and the associated behavior to salt consumption. We found that long-term high-salt intake impaired the aversive behavior to high-salt stimulation but did not alter the preference to low salt in mice. The mechanistic evidence demonstrated that high-salt intake blunted the TRPM5-mediated aversive behavior to noxious salt stimulation through inhibiting PKC (protein kinase C) activity and PKC-dependent threonine phosphorylation in the tongue epithelium but did not affect the epithelium sodium channel-dependent salt taste preference. Inhibition of TRPM5 also resulted in an impaired aversive response to high salt, with reduced taste perception in bitter cortical field of mice. TRPM5[-/-] mice showed a lowered aversion to high-salt diet and developed salt-induced hypertension. The impaired perception to bitter taste evoked by high-salt intake also existed in hypertensive patients with high-salt consumption. We demonstrate that long-term high-salt consumption impairs aversive response to concentrated salt by downregulating bitter taste sensor TRPM5. It suggests that enhancing TRPM5 function might antagonize excessive salt intake and high salt-induced hypertension.}, } @article {pmid31374869, year = {2019}, author = {Ruiz, F and Keeley, A and Léglise, P and Tuleu, C and Lachuer, C and Rwabihama, JP and Bachalat, N and Boulaich, I and Abdallah, F and Rabus, M and Ribemont, AC and Michelon, H and Wojcicki, AD and Orlu, M and Vallet, T and Boudy, V}, title = {Sex Differences in Medicine Acceptability: A New Factor to Be Considered in Medicine Formulation.}, journal = {Pharmaceutics}, volume = {11}, number = {8}, pages = {}, pmid = {31374869}, issn = {1999-4923}, abstract = {Palatability is a recognized driver of medicine acceptability in pediatrics but deemed less relevant in older populations due to sensory decline. Preliminary findings from an observational study implicated palatability problems with one Alzheimer's medicine. Among 1517 observer reports combining multiple measures on medicines uses in patients aged over 64, we focused on two original formulations of memantine (Ebixa[®], tablets (n = 25) and oral solution (n = 60)). Evaluations were scored with an acceptability reference framework (CAST), the rodent Brief Access Taste Aversion (BATA) model tested aversiveness. Focusing on women treated with Ebixa[®] (n = 54), the oral formulation sub-group was classified as "negatively accepted", while the coated tablet was associated with the "positively accepted" cluster. In men, both formulations belonged to the "positively accepted" profile. Using BATA, the original oral solution was categorized as highly aversive/untolerated while solutions of excipients only were well tolerated. Furthermore, the number of licks was significantly lower in female than in male rats. These results revealed that medicine palatability remains important for acceptability in older populations. Moreover, converging results from humans and animal models highlighted that palatability profiles can significantly vary between the sexes. These drivers should be closely considered during drug development to enhance acceptability in this population.}, } @article {pmid31325496, year = {2019}, author = {Olvera, MJ and Miranda, MI}, title = {Specific inter-stimulus interval effect of NMDA receptor activation in the insular cortex during conditioned taste aversion.}, journal = {Neurobiology of learning and memory}, volume = {164}, number = {}, pages = {107043}, doi = {10.1016/j.nlm.2019.107043}, pmid = {31325496}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Cerebral Cortex/drug effects/*physiology ; Conditioning, Classical/drug effects/*physiology ; Excitatory Amino Acid Agonists/administration & dosage ; Extinction, Psychological/drug effects/physiology ; Male ; N-Methylaspartate/administration & dosage ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/agonists/*physiology ; Taste Perception/*physiology ; Time Factors ; }, abstract = {Taste memory recognition is crucial for species survival; thus, the acquisition of conditioned taste aversion (CTA) protects animals against consuming poisons or toxins. In nature, food and poison are confined in the same edible item; however, in the laboratory these food constituents are usually presented separately for experimental analysis. The taste, or conditioned stimulus (CS), can be hours apart from the gastric malaise, or unconditioned stimulus (US); this extended inter-stimulus interval (ISI) allows the analysis of a particular learning phase. Evidence indicates a relevant function of glutamatergic activity in the insular cortex (IC) throughout the ISI. N-methyl-D-aspartate receptors (NMDAR) are crucial during CTA acquisition and retrieval. However, the exact participation of NMDAR in the IC during the ISI has not been demonstrated. Thus, the aim of this work was to evaluate the effects of temporal NMDAR activation during four time frames throughout the ISI of conditioned sugar aversion with bilateral injections of NMDA at a physiological dose (1 µg/µl) in the IC, given (1) immediately before or (2) immediately after sugar presentation, or (3) immediately before or (4) immediately after LiCl i.p. injection. The results showed that NMDAR activation in the IC had a specific ISI effect during CTA acquisition, increasing aversive memory formation and delaying extinction only after CS presentation. Overall, these results demonstrate that NMDAR in the IC have a particular enhancing associative effect after CS and suggest that there is a precise coincidence in neurochemical events in the IC that correlates with the stimulus to be associated and the glutamate NMDAR activity that must be finely tuned in the ISI during CTA acquisition.}, } @article {pmid31310793, year = {2019}, author = {Tobajas, J and Gómez-Ramírez, P and María-Mojica, P and Navas, I and García-Fernández, AJ and Ferreras, P and Mateo, R}, title = {Selection of new chemicals to be used in conditioned aversion for non-lethal predation control.}, journal = {Behavioural processes}, volume = {166}, number = {}, pages = {103905}, doi = {10.1016/j.beproc.2019.103905}, pmid = {31310793}, issn = {1872-8308}, mesh = {Animals ; Animals, Wild ; Avoidance Learning/*drug effects ; Conditioning, Classical/drug effects ; Dogs ; Fluconazole/pharmacology ; Isoxazoles/pharmacology ; Levamisole/pharmacology ; Male ; Predatory Behavior/*drug effects ; *Taste ; Thiabendazole/pharmacology ; Thiram/pharmacology ; }, abstract = {Globally, native predators and scavengers are threatened through the incidence of illegal poisoning due to increasing human-wildlife conflicts. The use of conditioned taste aversion (CTA) may mitigate such conflicts. CTA is a robust learning paradigm that occurs when animals associate a food with a discomfort induced by a chemical, thereby avoiding that food in subsequent encounters. We reviewed the potential of 167 chemical compounds to be used in CTA, considering effects, margin of safety, accessibility, and detectability. After the review, 15 compounds fulfilled the required characteristics, but only five (thiabendazole, thiram, levamisole, fluconazole and fluralaner) were finally selected to be tested in CTA assays with dogs. Of the tested compounds, thiabendazole, thiram and levamisole caused target food rejection by dogs and reduced the time spent eating during post-conditioning. However, despite being microencapsulated, levamisole appeared to be detectable by dogs, whereas thiram and thiabendazole were not. Fluconazole and fluralaner did not produce any CTA effect. Thiabendazole, thiram and levamisole can therefore induce CTA, and thus are potential candidates as aversive compounds for wildlife management. Thiram is an undetectable, relatively safe and accessible compound that can induce CTA in canids, and opens new possibilities to develop methods of non-lethal predation control.}, } @article {pmid31287232, year = {2020}, author = {Tobajas, J and Gómez-Ramírez, P and Ferreras, P and García-Fernández, AJ and Mateo, R}, title = {Conditioned food aversion in domestic dogs induced by thiram.}, journal = {Pest management science}, volume = {76}, number = {2}, pages = {568-574}, doi = {10.1002/ps.5548}, pmid = {31287232}, issn = {1526-4998}, mesh = {Animals ; Animals, Wild ; Dogs ; Odorants ; Predatory Behavior ; *Thiram ; }, abstract = {BACKGROUND: The conflict between predators and humans for resources such as game species or livestock is an ancient issue, and it is especially sharp in the case of medium-large wild canids. In order to manage this conflict, lethal control methods are often used, which can sometimes be illegal, such as poisoning. As an alternative, conditioned food aversion (CFA) is a non-lethal method to reduce predation in which animals learn to avoid a given food due to the adverse effects caused by the ingestion of an undetectable chemical compound added to this food. The present study aimed to test thiram as a CFA agent in penned dogs as a first approach to use this substance for reducing the predation conflict associated with wild canids.

RESULTS: Thiram, with or without an additional odor cue, produced CFA in penned dogs for more than 2 months. Moreover, thiram seemed to be undetectable and safe after the third ingestion of a 40-60 mg kg[-1] dose. Desirable adverse effects, such as vomits, appeared around 1 h after exposure. These characteristics make thiram optimal for its use in predation reduction through CFA. However, individual variability could prevent CFA acquisition by some animals.

CONCLUSIONS: Thiram has the potential to be used as a CFA agent in wildlife management and conservation to reduce predation by wild canids. Since thiram produced CFA without the problems of detectability and toxicity caused by other substances, it may be an alternative to lethal control methods used to reduce predation on game, livestock and endangered species. © 2019 Society of Chemical Industry.}, } @article {pmid31257806, year = {2019}, author = {Li, LM and Liao, YY and Jiang, ES}, title = {[The electrophysiological response of chorda tympani nerve to taste stimuli in rats with conditioned taste aversion to saltiness].}, journal = {Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology}, volume = {35}, number = {3}, pages = {239-244}, doi = {10.12047/j.cjap.5768.2019.051}, pmid = {31257806}, issn = {1000-6834}, mesh = {Amiloride/pharmacology ; Animals ; Chorda Tympani Nerve/*physiology ; *Conditioning, Classical ; *Electrophysiological Phenomena ; Male ; Rats ; Rats, Sprague-Dawley ; Sodium Chloride ; Taste/*physiology ; }, abstract = {OBJECTIVE: To explore the characteristic changes of the peripheral chorda tympanic nerve (CT) electrophysiological responses to salty stimulus and other taste stimuli in rats with the conditioned taste aversion to saltiness.

METHODS: Fourteen adult SD male rats were divided into a conditioned taste aversion to salty group (CTA) and a control group (Ctrl) (n=7/group). On the first day of the experiment, rats were given a 0.1 mol/L NaCl intake for 30 min, then, the rats in CTA and Ctrl groups were injected intraperitoneally with 2 ml of 0.15 mol/L LiCl and the same amount of saline respectively. On day 2, 3 and 4, the 30 min consumption of NaCl and distilled water was measured for both groups of rats. On the 4th day after the behavioral test of that day, CT electrophysiological recording experiments were performed on CTA rats and control rats.

RESULTS: Compared with the rats in Ctrl group, the electrophysiological characteristics of CT in CTA group rats did not change significantly the responses to the series of NaCl and other four basic taste stimuli (P＞0.05). The amiloride, the epithelial sodium channel blocker, strongly inhibited the response of CT to NaCl in CTA and Ctrl group rats (P＜0.01).

CONCLUSION: The electrophysiological responses of CT to various gustatory stimuli do not significantly change in rats after the establishment of conditional taste aversion to the saltiness.}, } @article {pmid31235467, year = {2019}, author = {Inui, T and Sugishita, T and Inui-Yamamoto, C and Yasoshima, Y and Shimura, T}, title = {The Basolateral Nucleus of the Amygdala Executes the Parallel Processes of Avoidance and Palatability in the Retrieval of Conditioned Taste Aversion in Male Rats.}, journal = {eNeuro}, volume = {6}, number = {4}, pages = {}, pmid = {31235467}, issn = {2373-2822}, mesh = {Animals ; Avoidance Learning/*physiology ; Basolateral Nuclear Complex/*physiology ; Behavior, Animal ; Conditioning, Classical ; Male ; Mental Recall/*physiology ; Rats, Wistar ; Taste/*physiology ; }, abstract = {Conditioned taste aversion (CTA) is an essential behavior for animal survival. Conditioned animals show avoidance and decreased palatability to a conditioned stimulus (CS) on CTA retrieval. In this study, we aimed to determine whether the basolateral nucleus of the amygdala (BLA) is involved in CTA retrieval and whether avoidance and palatability in CTA retrieval are processed in the BLA. We developed an experimental chamber for time-course analysis of the behavior to approach a spout and lick a CS. In this experimental chamber, we analyzed the behavior of male rats following microinjections of GABAA receptor agonist muscimol or saline into the BLA. The rats showed two types of approach behavior: they either (1) approached and licked the spout or (2) approached but did not lick the spout. Muscimol injection into the BLA decreased the frequency of the latter type of approach behavior, indicating that BLA inactivation reduced avoidance to the CS. The muscimol injection into the BLA also significantly increased the consumption of the CS. Lick microstructure analysis demonstrated that intra-BLA muscimol significantly increased licking burst number and size, indicating that BLA inactivation attenuated aversion to the CS as large burst licking is an indicator of high palatability. These results suggest that the increase in CS consumption with intra-BLA muscimol injection was due to alterations in approach and aversive responses to the CS. Therefore, we conclude that the BLA plays an essential role in CTA retrieval by parallel processing of avoidance and palatability.}, } @article {pmid31229633, year = {2019}, author = {Tanaka, DH and Li, S and Mukae, S and Tanabe, T}, title = {Genetic Access to Gustatory Disgust-Associated Neurons in the Interstitial Nucleus of the Posterior Limb of the Anterior Commissure in Male Mice.}, journal = {Neuroscience}, volume = {413}, number = {}, pages = {45-63}, doi = {10.1016/j.neuroscience.2019.06.021}, pmid = {31229633}, issn = {1873-7544}, mesh = {Animals ; Anterior Commissure, Brain/*metabolism ; Avoidance Learning/physiology ; Conditioning, Classical/physiology ; Cytoskeletal Proteins/genetics/metabolism ; *Disgust ; Lithium Chloride ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Tissue Proteins/genetics/metabolism ; Neurons/*metabolism ; Proto-Oncogene Proteins c-fos/genetics/metabolism ; Quinine ; Saccharin ; Taste/physiology ; Taste Perception/*physiology ; }, abstract = {Orofacial and somatic disgust reactions are observed in rats following intraoral infusion of not only bitter quinine (innate disgust) but also sweet saccharin previously paired with illness (learned disgust). It remains unclear, however, whether these innate and learned disgust reactions share a common neural basis and which brain regions, if any, host it. In addition, there is no established method to genetically access neurons whose firing is associated with disgust (disgust-associated neurons). Here, we examined the expression of cFos and Arc, two markers of neuronal activity, in the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) of male mice that showed innate disgust and mice that showed learned disgust. Furthermore, we used a targeted recombination in active populations (TRAP) method to genetically label the disgust-associated neurons in the IPAC with YFP. We found a significant increase of both cFos-positive neurons and Arc-positive neurons in the IPAC of mice that showed innate disgust and mice that showed learned disgust. In addition, TRAP following quinine infusion (Quinine-TRAP) resulted in significantly more YFP-positive neurons in the IPAC, compared to TRAP following water infusion. A significant number of the YFP-positive neurons following Quinine-TRAP were co-labeled with Arc following the second quinine infusion, confirming that Quinine-TRAP preferentially labeled quinine-activated neurons in the IPAC. Our results suggest that the IPAC activity is associated with both innate and learned disgust and that disgust-associated neurons in the IPAC are genetically accessible by TRAP.}, } @article {pmid31216290, year = {2019}, author = {Schier, LA and Hyde, KM and Spector, AC}, title = {Conditioned taste aversion versus avoidance: A re-examination of the separate processes hypothesis.}, journal = {PloS one}, volume = {14}, number = {6}, pages = {e0217458}, pmid = {31216290}, issn = {1932-6203}, support = {R01 DK106112/DK/NIDDK NIH HHS/United States ; T32 DC000044/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Aversive Agents/pharmacology ; Avoidance Learning/drug effects/*physiology ; Lithium Chloride/pharmacology ; Male ; *Models, Biological ; Rats ; Rats, Sprague-Dawley ; Saccharin/pharmacology ; Taste/*physiology ; Taste Perception/drug effects/*physiology ; }, abstract = {Rats not only avoid ingesting a substance associated with LiCl toxicosis, but they display rejection reflexes (e.g., gapes) to its taste; this latter response is thought to reflect disgust or taste aversion. Prior work has shown that rats also avoid consuming foods/fluids associated with other adverse gastrointestinal (GI) effects like lactose indigestion but without the concomitant change in oromotor responses (taste reactivity; TR) indicative of aversion. Because of interpretive limitations of the methods used in those studies, we revisited the taste aversion-avoidance distinction with a design that minimized non-treatment differences among groups. Effects on intake and preference (Experiments 1a, 1b, and 2), as well as consummatory (TR, Experiment 1a and 1b) and appetitive (Progressive Ratio, Experiment 2) behaviors to the taste stimulus were assessed after training. In both experiments, rats were trained to associate 0.2% saccharin (CS) with intraduodenal infusions of LiCl, Lactose, or NaCl control. Rats trained with 18% lactose, 0.3 and 1.5 mEq/kg dose of LiCl subsequently avoided the taste CS in post-training single-bottle intake tests and two-bottle choice tests. However, only those trained with 1.5 mEq/kg LiCl displayed post-conditioning increases in taste CS-elicited aversive TR (Experiment 1a and 1b). This dose of LiCl also led to reductions in breakpoint for saccharin. The fact that conditioned avoidance is not always accompanied by changes in other common appetitive and/or consummatory indices of ingestive motivation further supports a functional dissociation between these processes, and highlights the intricacies of visceral influences on taste-guided ingestive motivation.}, } @article {pmid31205005, year = {2019}, author = {Devineni, AV and Sun, B and Zhukovskaya, A and Axel, R}, title = {Acetic acid activates distinct taste pathways in Drosophila to elicit opposing, state-dependent feeding responses.}, journal = {eLife}, volume = {8}, number = {}, pages = {}, pmid = {31205005}, issn = {2050-084X}, support = {54951//Simons Foundation/International ; }, mesh = {Acetic Acid/*pharmacology ; Animals ; Appetite/drug effects/physiology ; Drosophila melanogaster/*drug effects/physiology ; Feeding Behavior/*drug effects/physiology ; Hunger/physiology ; Neural Pathways/drug effects/physiology ; Sensory Receptor Cells/*drug effects/physiology ; Taste/*drug effects/physiology ; }, abstract = {Taste circuits are genetically determined to elicit an innate appetitive or aversive response, ensuring that animals consume nutritious foods and avoid the ingestion of toxins. We have examined the response of Drosophila melanogaster to acetic acid, a tastant that can be a metabolic resource but can also be toxic to the fly. Our data reveal that flies accommodate these conflicting attributes of acetic acid by virtue of a hunger-dependent switch in their behavioral response to this stimulus. Fed flies show taste aversion to acetic acid, whereas starved flies show a robust appetitive response. These opposing responses are mediated by two different classes of taste neurons, the sugar- and bitter-sensing neurons. Hunger shifts the behavioral response from aversion to attraction by enhancing the appetitive sugar pathway as well as suppressing the aversive bitter pathway. Thus a single tastant can drive opposing behaviors by activating distinct taste pathways modulated by internal state.}, } @article {pmid31200091, year = {2019}, author = {González-Sánchez, H and Tovar-Díaz, J and Morin, JP and Roldán-Roldán, G}, title = {NMDA receptor and nitric oxide synthase activity in the central amygdala is involved in the acquisition and consolidation of conditioned odor aversion.}, journal = {Neuroscience letters}, volume = {707}, number = {}, pages = {134327}, doi = {10.1016/j.neulet.2019.134327}, pmid = {31200091}, issn = {1872-7972}, mesh = {Animals ; *Avoidance Learning ; *Behavior, Animal ; Central Amygdaloid Nucleus/*metabolism ; Conditioning, Psychological ; Male ; Nitric Oxide Synthase Type I/*metabolism ; Odorants ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/*metabolism ; *Smell ; }, abstract = {Rats readily learn to avoid a tasteless odorized solution if they experience visceral malaise after consuming it. This phenomenon is referred to as conditioned odor aversion (COA). Several studies have shown that COA depends on the functional integrity of the amygdala, with most studies focusing on the basolateral nucleus. On the other hand, the role of the central amygdala (CeA) which is known to be involved in the consolidation of conditioned taste aversion (CTA) remains to be established. To address this issue, we evaluated the effect of inhibiting NMDA receptor activity in this structure on COA memory formation. Intra-CeA infusions of non-competitive NMDA receptor inhibitor MK-801 prevented memory formation both when administered before and up to 15 min after COA conditioning, while no effect of this drug was observed when given before long-term memory test. We next evaluated the role of one of the main downstream effectors of brain NMDA receptor signaling, nitric oxide synthase (NOS), known to play a key role in a wide variety learning tasks including some types of olfactory conditioning. Similar results were obtained with inhibition of either NOS or neuron-specific NOS; which proved to be required both during and after COA training, though for a shorter time span than NMDA receptors. Also, neither isoform showed to be required to memory retrieval. These results suggest that the US signaling during acquisition and the initial consolidation step of COA depends on glutamate-NO system activation in the CeA.}, } @article {pmid31087376, year = {2019}, author = {Dannenhoffer, CA and Spear, LP}, title = {Excitatory/inhibitory balance across ontogeny contributes to age-specific behavioral outcomes of ethanol-like challenge in conditioned taste aversion.}, journal = {Developmental psychobiology}, volume = {61}, number = {8}, pages = {1157-1167}, pmid = {31087376}, issn = {1098-2302}, support = {T32 AA025606/AA/NIAAA NIH HHS/United States ; U01 AA019972/AA/NIAAA NIH HHS/United States ; }, mesh = {Age Factors ; Animals ; Avoidance Learning/*drug effects ; Behavior, Animal/*drug effects ; Central Nervous System Depressants/administration & dosage/*pharmacology ; Conditioning, Classical/*drug effects ; Ethanol/administration & dosage/*pharmacology ; Excitatory Amino Acid Antagonists/administration & dosage/*pharmacology ; Female ; GABA-A Receptor Agonists/administration & dosage/*pharmacology ; Isoxazoles/pharmacology ; Male ; Piperidines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/*antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors ; Taste Perception/*drug effects ; }, abstract = {Adolescent-typical sensitivities to ethanol (EtOH) are characterized in part by reduced sensitivity to EtOH's aversive effects. Rodent studies have shown that adolescents are less sensitive than adults to aversive properties of EtOH in a conditioned taste aversion (CTA) paradigm. To the extent that EtOH exerts antagonist-like actions upon glutamate receptors and/or agonist-like actions upon γ-aminobutyric acid (GABA) receptors, age differences in excitatory/inhibitory balance may regulate age-specific EtOH sensitivities, such as attenuated sensitivity of adolescents to EtOH aversion. In our experiments, adolescent and adult Sprague-Dawley rats were tested for CTA following challenge with one of the following pharmacological agents: glutamatergic AMPA1 receptor antagonist NBQX, glutamatergic N-methyl-d-aspartate NR2B receptor antagonist ifenprodil, and extrasynaptic GABAA receptor agonist THIP to determine whether these induced age-specific aversive sensitivities like those seen with EtOH. NBQX administration did not induce CTA. The highest dose of extrasynaptic GABAA agonist THIP induced CTA in adolescents but not adults, an opposite ontogenetic profile as seen following EtOH. Ifenprodil exerted an age-specific pattern of CTA similar to that seen with EtOH in males, with adolescents being insensitive to ifenprodil's aversive effects relative to adults. Thus, only antagonism of NR2B receptors in male rats mimicked age-specific sensitivities to the aversive effects of EtOH.}, } @article {pmid31082409, year = {2019}, author = {Grau-Perales, AB and Gómez-Chacón, B and Gallo, M}, title = {Differential activity pattern of c-Fos in the nucleus accumbens between adult and aged rats during flavor recognition memory.}, journal = {Behavioural brain research}, volume = {371}, number = {}, pages = {111935}, doi = {10.1016/j.bbr.2019.111935}, pmid = {31082409}, issn = {1872-7549}, mesh = {*Age Factors ; Animals ; Avoidance Learning/physiology ; Conditioning, Classical/physiology ; Female ; Male ; Memory/physiology ; Nucleus Accumbens/*metabolism ; Proto-Oncogene Proteins c-fos/*metabolism ; Rats ; Rats, Wistar ; Recognition, Psychology/physiology ; Taste/*physiology ; }, abstract = {Previous studies have addressed the role of the nucleus accumbens core (NAcbC) and shell (NAcbSh) in taste aversion learning and in the processing of taste palatability which is affected by aging. However, little is known about its implication in safe taste memory and the aging impact. To explore the role of the NAcb in flavor neophobia and its attenuation during aging, we applied c-Fos immunohistochemistry as an index of neural activity of the NAcbC and NAcbSh. Twenty one adult (5-month-old) and 24 aged (24-month-old) male Wistar rats were exposed to a 3% cider vinegar solution for 1, 2 or 6 consecutive days (n = 7 adult and n = 8 aged rats per group). Aged rats exhibited slower attenuation of flavor neophobia than adult rats. Adult rats showed increased NAcbSh c-Fos activity on day 2 compared to days 1 and 6, while this increase was delayed to day 6 in aged rats. There were no differences in the number of NAcbC c-Fos positive cells. This suggests that changes in the activity of neural circuits of palatability processing during normal aging could contribute to the slower attenuation of flavor neophobia in aged rats.}, } @article {pmid31001093, year = {2019}, author = {Totani, Y and Aonuma, H and Oike, A and Watanabe, T and Hatakeyama, D and Sakakibara, M and Lukowiak, K and Ito, E}, title = {Monoamines, Insulin and the Roles They Play in Associative Learning in Pond Snails.}, journal = {Frontiers in behavioral neuroscience}, volume = {13}, number = {}, pages = {65}, pmid = {31001093}, issn = {1662-5153}, abstract = {Molluscan gastropods have long been used for studying the cellular and molecular mechanisms underlying learning and memory. One such gastropod, the pond snail Lymnaea stagnalis, exhibits long-term memory (LTM) following both classical and operant conditioning. Using Lymnaea, we have successfully elucidated cellular mechanisms of learning and memory utilizing an aversive classical conditioning procedure, conditioned taste aversion (CTA). Here, we present the behavioral changes following CTA training and show that the memory score depends on the duration of food deprivation. Then, we describe the relationship between the memory scores and the monoamine contents of the central nervous system (CNS). A comparison of learning capability in two different strains of Lymnaea, as well as the filial 1 (F1) cross from the two strains, presents how the memory scores are correlated in these populations with monoamine contents. Overall, when the memory scores are better, the monoamine contents of the CNS are lower. We also found that as the insulin content of the CNS decreases so does the monoamine contents which are correlated with higher memory scores. The present review deepens the relationship between monoamine and insulin contents with the memory score.}, } @article {pmid30964149, year = {2019}, author = {Williams, RSB and Andrews, PLR}, title = {Advice on avoiding the Valley of Death: insights from a 3Rs model of aversive and emetic compound identification.}, journal = {ALTEX}, volume = {36}, number = {3}, pages = {466-469}, doi = {10.14573/altex.1810182}, pmid = {30964149}, issn = {1868-8551}, support = {NC/M001504/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; NC/S01201/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, mesh = {*Animal Testing Alternatives ; Animals ; Dictyostelium/drug effects ; Emetics/*adverse effects ; Humans ; Pharmaceutical Preparations/*chemistry ; Taste/*drug effects ; }, } @article {pmid30936142, year = {2019}, author = {Ratner, C and He, Z and Grunddal, KV and Skov, LJ and Hartmann, B and Zhang, F and Feuchtinger, A and Bjerregaard, A and Christoffersen, C and Tschöp, MH and Finan, B and DiMarchi, RD and Leinninger, GM and Williams, KW and Clemmensen, C and Holst, B}, title = {Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway.}, journal = {Diabetes}, volume = {68}, number = {6}, pages = {1329-1340}, pmid = {30936142}, issn = {1939-327X}, support = {P30 DK020572/DK/NIDDK NIH HHS/United States ; R01 DK100699/DK/NIDDK NIH HHS/United States ; R01 DK119169/DK/NIDDK NIH HHS/United States ; }, mesh = {Adiposity/*drug effects ; Animals ; Blood Glucose/*drug effects/metabolism ; Body Weight/*drug effects ; Delayed-Action Preparations ; Drug Synergism ; Eating/*drug effects ; Fatty Liver/metabolism/pathology ; Hypoglycemic Agents/*pharmacology ; Liraglutide/*pharmacology ; Liver/drug effects/metabolism/pathology ; Melanocortins/metabolism ; Mice ; Mice, Knockout ; Neurotensin/*pharmacology ; Obesity/*metabolism ; Polyethylene Glycols ; }, abstract = {Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT-induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy.}, } @article {pmid30900905, year = {2019}, author = {Keeley, A and Teo, M and Ali, Z and Frost, J and Ghimire, M and Rajabi-Siahboomi, A and Orlu, M and Tuleu, C}, title = {In Vitro Dissolution Model Can Predict the in Vivo Taste Masking Performance of Coated Multiparticulates.}, journal = {Molecular pharmaceutics}, volume = {16}, number = {5}, pages = {2095-2105}, doi = {10.1021/acs.molpharmaceut.9b00060}, pmid = {30900905}, issn = {1543-8392}, mesh = {Administration, Oral ; Adolescent ; Adult ; Animals ; Cellulose/analogs & derivatives/chemistry ; Chlorpheniramine/administration & dosage/pharmacology ; Drug Compounding/*methods ; Drug Development/*methods ; *Drug Liberation ; Female ; Healthy Volunteers ; Humans ; Hydrogen-Ion Concentration ; Inhibitory Concentration 50 ; Male ; Middle Aged ; Rats ; Single-Blind Method ; Solubility ; Sugars/chemistry ; Taste/*physiology ; Young Adult ; }, abstract = {The majority of active pharmaceutical ingredients (APIs) are bitter. Therefore, compliance can be a problem where adequate taste masking has not been achieved; this is most problematic in pediatrics. Taste masking is thus a key stage during pharmaceutical development with an array of strategies available to the formulation scientist. Solid oral dosage forms can be taste-masked quite simply by polymer coating, which prevents drug release in the mouth, without unwantedly impairing drug release further down the gastrointestinal tract. At the early stages of pharmaceutical development, an in vitro method for the assessment of taste masking is necessary given the lack of toxicological data preventing the use of human taste panels. Currently, there is no such tool allowing prediction of taste masking efficiency. In this study, drug dissolution in the context of aversive taste thresholds was proposed as a means to bridge this knowledge gap. Thus, a biorelevant buccal dissolution test was developed in which previously determined taste thresholds in vivo were used to evaluate taste masking efficiency: if drug release exceeded said thresholds, the formulation was deemed to be poorly taste-masked, and vice versa. This novel dissolution test was compared to the USP I (basket) dissolution test, and the biopharmaceutical implications of taste masking were also assessed by performing USP I (basket) dissolution testing in simulated gastric fluid (SGF). Chlorphenamine maleate, a model bitter BCS class 1 API, was layered onto sugar spheres and taste-masked using polymer coatings. An array of coating technologies were employed and assessed single blinded: two pH-independent water-insoluble coatings (Surelease:Opadry at 8, 12, and 16% weight gain and Opadry EC at 4, 6, and 8% weight gain) and a pH-dependent water-insoluble reverse-enteric coating (developmental fully formulated system based on Kollicoat Smartseal 100P at 10% weight gain). Both the biorelevant buccal and the USP I dissolution tests were capable of discriminating between both type and level of coating used. However, only the buccal dissolution test was able to provide absolute quantification of the level of taste masking achieved in the context of previously determined taste thresholds, while the USP I test merely provided a relative comparison between the different technologies assessed. When the release data from the buccal test were assessed in parallel to that in SGF, it was possible to predict in vitro optimized taste masking without compromising bioavailability. The fully formulated system based on Smartseal 100P was identified as the most effective coating and Surelease:Opadry the least effective. The developed methodology provides true insight for the formulator, enabling more informed patient-centric formulation decisions, better taste masking, and ultimately more effective medicines.}, } @article {pmid30797833, year = {2019}, author = {Saalfield, J and Spear, L}, title = {Fos activation patterns related to acute ethanol and conditioned taste aversion in adolescent and adult rats.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {78}, number = {}, pages = {57-68}, pmid = {30797833}, issn = {1873-6823}, support = {P50 AA017823/AA/NIAAA NIH HHS/United States ; }, mesh = {Age Factors ; Animals ; Avoidance Learning/*drug effects ; Brain/*metabolism ; Conditioning, Psychological/*drug effects ; Edinger-Westphal Nucleus ; Ethanol/*pharmacology ; Immunohistochemistry ; Male ; Nucleus Accumbens/metabolism ; Proto-Oncogene Proteins c-fos/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reward ; *Taste Perception ; }, abstract = {Studies in rats have revealed marked age differences in sensitivity to the aversive properties of ethanol, with a developmental insensitivity to ethanol aversion that is most pronounced during pre- and early adolescence, declining thereafter to reach the enhanced aversive sensitivity of adults. The adolescent brain undergoes significant transitions throughout adolescence, including in regions linked with drug reward and aversion; however, it is unknown how ontogenetic changes within this reward/aversion circuitry contribute to developmental differences in aversive sensitivity. The current study examined early adolescent (postnatal day [P]28-30) and adult (P72-74) Sprague-Dawley male rats for conditioned taste aversion (CTA) after doses of 0, 1.0, or 2.5 g/kg ethanol, and patterns of neuronal activation in response to ethanol using Fos-like immunohistochemistry (Fos+) to uncover regions where age differences in activation are associated with ethanol aversion. An adolescent-specific ethanol-induced increase in Fos+ staining was seen within the nucleus accumbens shell and core. An age difference was also noted within the Edinger-Westphal nucleus (EW) following administration of the lower dose of ethanol, with 1 g/kg ethanol producing CTA in adults but not in adolescents and inducing a greater EW Fos response in adults than adolescents. Regression analysis revealed that greater numbers of Fos+ neurons within the EW and insula (Ins) were related to lower consumption of the conditioned stimulus (CS) on test day (reflecting greater CTA). Some regionally specific age differences in Fos+ were noted under baseline conditions, with adolescents displaying fewer Fos+ neurons than adults within the prelimbic (PrL) cortex, but more than adults in the bed nucleus of the stria terminalis (BNST). In the BNST (but not PrL), ethanol-induced increases in Fos-immunoreactivity (IR) were evident at both ages. Increased ethanol-induced activity within critical appetitive brain regions (NAc core and shell) supports a role for greater reward-related activation during adolescence, possibly along with attenuated responsiveness to ethanol in EW and Ins in the age-typical resistance of adolescents to the aversive properties of ethanol.}, } @article {pmid30769105, year = {2019}, author = {Pohjanvirta, R and Mahiout, S}, title = {Aryl hydrocarbon receptor is indispensable for β-naphthoflavone-induced novel food avoidance and may be involved in LiCl-triggered conditioned taste aversion in rats.}, journal = {Physiology & behavior}, volume = {204}, number = {}, pages = {58-64}, doi = {10.1016/j.physbeh.2019.02.014}, pmid = {30769105}, issn = {1873-507X}, mesh = {Animals ; Avoidance Learning/*drug effects ; Basic Helix-Loop-Helix Transcription Factors/drug effects/genetics/*physiology ; Cytochrome P-450 CYP1A1/biosynthesis/genetics ; Enzyme Induction/drug effects ; Feeding Behavior/*drug effects ; Gene Knockout Techniques ; Lithium Chloride/*pharmacology ; Neurons, Afferent/physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Aryl Hydrocarbon/drug effects/genetics/*physiology ; Taste/*drug effects ; Vagotomy ; beta-Naphthoflavone/*pharmacology ; }, abstract = {Previous studies have shown that several aryl hydrocarbon receptor (AHR) agonists, including β-naphthoflavone (BNF), elicit avoidance of novel food items in rodents, with this behavioral response displaying a similar dose-response to hepatic induction of CYP1A1. The avoidance has been found to bear substantial similarity to conditioned taste avoidance/aversion (CTA). The present study set out to confirm the indispensability of AHR in the avoidance response, to verify whether vagal afferent fibers are involved in it, and to see if AHR signaling might interfere with the effect of the classic trigger of CTA, LiCl. To this end, globally AHR deficient (AHRKO) or vagotomized wildtype rats were treated by gavage with 60 mg/kg BNF or ip with 0.15 M LiCl (4 ml/kg), and presented with chocolate which was either novel or familiar to them. Both the avoidance response and Cyp1a1 induction were missing in AHRKO rats. In contrast, Ahr[+/-] rats exhibited them in full, save for a single outlier. Total subdiaphragmatic vagotomy failed to interfere with the avoidance of novel or familiar chocolate or induction of Cyp1a1. After LiCl administration, male AHRKO rats showed a significantly mitigated suppression of chocolate consumption compared with wildtype animals (~60% vs. ~10% of control chocolate intake, respectively). A similar tendency was seen in females, but they were less responsive to LiCl. These findings corroborate AHR as a prerequisite of the BNF-induced novel food avoidance, prove vagal afferents unlikely mediators of this response, and imply an unforeseen involvement of AHR signaling in the thoroughly-characterized CTA instigated by LiCl.}, } @article {pmid30676659, year = {2019}, author = {Katzman, DK and Norris, ML and Zucker, N}, title = {Avoidant restrictive food intake disorder: First do no harm.}, journal = {The International journal of eating disorders}, volume = {52}, number = {4}, pages = {459-461}, doi = {10.1002/eat.23021}, pmid = {30676659}, issn = {1098-108X}, support = {R33-MH-097959/MH/NIMH NIH HHS/United States ; }, mesh = {Anorexia Nervosa/*psychology/therapy ; Feeding and Eating Disorders/*psychology/therapy ; Humans ; Retrospective Studies ; }, abstract = {OBJECTIVE: This opinion piece offers some considerations, both medical and psychological, for the use of nasogastric tube (NGT) feedings in the treatment of avoidant restrictive food intake disorder (ARFID) in children and adolescents.

METHOD: Although there is empirical support for the use of NGT feedings in the treatment of anorexia nervosa, this evidence base does not exist for the treatment of ARFID. As such, there is need to delineate pragmatic considerations in the use of this procedure.

RESULTS: Issues of medical necessity notwithstanding, we advise that the use of this procedure be considered more cautiously due to the oral sensitivities inherent in many individuals with ARFID and the potential psychological consequences. These sensitivities may make the experience of NGT feedings particularly aversive, with the potential of creating iatrogenic conditioned food aversions.

DISCUSSION: This article encourages clinicians to give careful thought and attention when considering NGT feedings in children and adolescents with ARFID.}, } @article {pmid30639358, year = {2019}, author = {Patel, S and Alvarez-Guaita, A and Melvin, A and Rimmington, D and Dattilo, A and Miedzybrodzka, EL and Cimino, I and Maurin, AC and Roberts, GP and Meek, CL and Virtue, S and Sparks, LM and Parsons, SA and Redman, LM and Bray, GA and Liou, AP and Woods, RM and Parry, SA and Jeppesen, PB and Kolnes, AJ and Harding, HP and Ron, D and Vidal-Puig, A and Reimann, F and Gribble, FM and Hulston, CJ and Farooqi, IS and Fafournoux, P and Smith, SR and Jensen, J and Breen, D and Wu, Z and Zhang, BB and Coll, AP and Savage, DB and O'Rahilly, S}, title = {GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.}, journal = {Cell metabolism}, volume = {29}, number = {3}, pages = {707-718.e8}, pmid = {30639358}, issn = {1932-7420}, support = {200848/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; /DH_/Department of Health/United Kingdom ; U54 GM104940/GM/NIGMS NIH HHS/United States ; 106263/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; 095515/Z/11/Z/WT_/Wellcome Trust/United Kingdom ; MC_UU_00014/5/MRC_/Medical Research Council/United Kingdom ; MC_UU_12012/1/MRC_/Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; G0600717/MRC_/Medical Research Council/United Kingdom ; MC_UU_00014/2/MRC_/Medical Research Council/United Kingdom ; MC_UU_12012/3/MRC_/Medical Research Council/United Kingdom ; MC_UU_00014/3/MRC_/Medical Research Council/United Kingdom ; 107064//Wellcome Trust/United Kingdom ; MC_UU_12012/2/MRC_/Medical Research Council/United Kingdom ; 106262/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; 098497/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; G0802051/MRC_/Medical Research Council/United Kingdom ; G9824984/MRC_/Medical Research Council/United Kingdom ; 100574/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; G0900554/MRC_/Medical Research Council/United Kingdom ; G0400192/MRC_/Medical Research Council/United Kingdom ; WT 107064/WT_/Wellcome Trust/United Kingdom ; MC_UU_00014/1/MRC_/Medical Research Council/United Kingdom ; 100140//Wellcome Trust/United Kingdom ; MC_UU_12012/5/MRC_/Medical Research Council/United Kingdom ; RG/12/13/29853/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Adult ; Animals ; Cell Line ; Diet, High-Fat/methods ; Energy Intake/*physiology ; Growth Differentiation Factor 15/*metabolism/pharmacology ; Humans ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Young Adult ; }, abstract = {GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.}, } @article {pmid30609665, year = {2019}, author = {Crabbe, JC and Metten, P and Savarese, AM and Ozburn, AR and Schlumbohm, JP and Spence, SE and Hack, WR}, title = {Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice.}, journal = {Brain sciences}, volume = {9}, number = {1}, pages = {}, pmid = {30609665}, issn = {2076-3425}, support = {IK2 BX002488/BX/BLRD VA/United States ; AA013519/AA/NIAAA NIH HHS/United States ; T32 AA007468/AA/NIAAA NIH HHS/United States ; U01 AA013519/AA/NIAAA NIH HHS/United States ; P60 AA010760/AA/NIAAA NIH HHS/United States ; I01 BX000313/BX/BLRD VA/United States ; AA010760/AA/NIAAA NIH HHS/United States ; AA07468/AA/NIAAA NIH HHS/United States ; R24 AA020245/AA/NIAAA NIH HHS/United States ; AA020245/AA/NIAAA NIH HHS/United States ; }, abstract = {Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol.}, } @article {pmid30597200, year = {2019}, author = {Gore-Langton, JK and Spear, LP}, title = {Prenatal ethanol exposure attenuates sensitivity to the aversive effects of ethanol in adolescence and increases adult preference for a 5% ethanol solution in males, but not females.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {79}, number = {}, pages = {59-69}, pmid = {30597200}, issn = {1873-6823}, support = {P50 AA017823/AA/NIAAA NIH HHS/United States ; }, mesh = {Age Factors ; *Alcohol Drinking ; Animals ; Avoidance Learning/*drug effects ; Central Nervous System Depressants/*pharmacology ; Conditioning, Classical/*drug effects ; Ethanol/*pharmacology ; Female ; Male ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced ; Rats ; Rats, Sprague-Dawley ; Saccharin/administration & dosage ; Sex Factors ; Sodium Chloride/administration & dosage ; Taste/*drug effects ; }, abstract = {The present set of experiments investigated the effects of a moderate dose of ethanol (2 g/kg; 20% v/v intragastrically) during late gestation (G17-20 [gestational day]) on ethanol-induced conditioned taste aversion (CTA) in adolescence, and on ethanol consumption during adolescence and early adulthood. In experiment 1, male and female Sprague-Dawley rats were given 30-min access to a sweetened "supersaccharin" (SS) solution or sodium chloride (NaCl), followed by an intraperitoneal injection of 20% ethanol (0, 1, 1.25, or 1.5 g/kg) for three conditioning/test sessions. Among animals conditioned with SS, prenatally ethanol-exposed males exhibited attenuated ethanol-induced CTA relative to males prenatally gavaged with water or non-manipulated, whereas prenatal treatment had no effect on CTA in females. Among animals conditioned with NaCl, there were no exposure group differences in males, with modest evidence for attenuated CTA in prenatally ethanol-exposed females. In experiment 2, the effects of prenatal ethanol exposure on ethanol consumption in adolescents (P35 ± 1 day [postnatal day]) and adults (P56-60) were explored. At the beginning of the dark cycle, pair-housed rats were given three bottles containing 0, 5, and 10% ethanol for 18 h every other day (i.e., Monday, Wednesday, Friday) for 3 weeks. Relative to water controls, adult males prenatally exposed to ethanol showed greater preference and more intake (g/kg) of 5% ethanol, while showing lower intake of 10% ethanol. These intake and preference differences were not evident in adolescent males. Among females at both ages, ethanol-exposed animals showed lower preference and intake (g/kg) of 5% ethanol than their water-exposed controls. Thus, moderate ethanol exposure during late gestation produced a largely male-specific attenuation in the aversive effects of ethanol during adolescence that could contribute to later increases in preference and intake of a 5% ethanol solution, although this emergent effect was not evident in adolescence (or in females), but only manifested in adulthood.}, } @article {pmid30596779, year = {2018}, author = {Mura, E and Taruno, A and Yagi, M and Yokota, K and Hayashi, Y}, title = {Innate and acquired tolerance to bitter stimuli in mice.}, journal = {PloS one}, volume = {13}, number = {12}, pages = {e0210032}, pmid = {30596779}, issn = {1932-6203}, mesh = {Adaptation, Physiological/*drug effects ; Animals ; Behavior, Animal/*drug effects ; Female ; Isoleucine/*pharmacology ; Mice ; Taste Perception/*drug effects ; Tryptophan/*pharmacology ; }, abstract = {Tolerance to bitter foods and its potentiation by repetitive exposure are commonly experienced and potentially underlie the consumption of bitter foods, but it remains unknown whether permissive and adaptive responses are general phenomena for bitter-tasting substances or specific to certain substances, and they have not been rigorously studied in mice. Here, we investigated the effects of prolonged exposure to a bitter compound on both recognition and rejection behaviors to the same compound in mice. Paired measurements of rejection (RjT) and apparent recognition (aRcT) thresholds were conducted using brief-access two-bottle choice tests before and after taste aversion conditioning, respectively. First, RjT was much higher than aRcT for the bitter amino acids L-tryptophan and L-isoleucine, which mice taste daily in their food, indicating strong acceptance of those familiar stimuli within the concentration range between RjT and aRcT. Next, we tested five other structurally dissimilar bitter compounds, to which mice were naive at the beginning of experiments: denatonium benzoate, quinine-HCl, caffeine, salicin, and epigallocatechin gallate. RjT was moderately higher than aRcT for all the compounds tested, indicating the presence of innate acceptance to these various, unfamiliar bitter stimuli in mice. Lastly, a 3-week forced exposure increased RjT for all the bitter compounds except salicin, demonstrating that mice acquire tolerance to a broad array of bitter compounds after long-term exposure to them. Although the underlying mechanisms remain to be determined, our studies provide behavioral evidence of innate and acquired tolerance to various bitter stimuli in mice, suggesting its generality among bitterants.}, } @article {pmid30564271, year = {2018}, author = {Zhou, D and Zhao, Y and Hook, M and Zhao, W and Starlard-Davenport, A and Cook, MN and Jones, BC and Hamre, KM and Lu, L}, title = {Ethanol's Effect on Coq7 Expression in the Hippocampus of Mice.}, journal = {Frontiers in genetics}, volume = {9}, number = {}, pages = {602}, pmid = {30564271}, issn = {1664-8021}, support = {R01 AA021951/AA/NIAAA NIH HHS/United States ; U01 AA014425/AA/NIAAA NIH HHS/United States ; }, abstract = {Coenzyme Q (CoQ) is a well-studied molecule, present in every cell membrane in the body, best known for its roles as a mitochondrial electron transporter and a potent membrane anti-oxidant. Much of the previous work was done in vitro in yeast and more recent work has suggested that CoQ may have additional roles prompting calls for a re-assessment of its role using in vivo systems in mammals. Here we investigated the putative role of Coenzyme Q in ethanol-induced effects in vivo using BXD RI mice. We examined hippocampal expression of Coq7 in saline controls and after an acute ethanol treatment, noting enriched biologic processes and pathways following ethanol administration. We also identified 45 ethanol-related phenotypes that were significantly correlated with Coq7 expression, including six phenotypes related to conditioned taste aversion and ethanol preference. This analysis highlights the need for further investigation of Coq7 and related genes in vivo as well as previously unrecognized roles that it may play in the hippocampus.}, } @article {pmid30557602, year = {2019}, author = {Nakajima, S}, title = {Food avoidance learning based on voluntary wheel running in laboratory mice (Mus musculus).}, journal = {Behavioural processes}, volume = {159}, number = {}, pages = {31-36}, doi = {10.1016/j.beproc.2018.12.010}, pmid = {30557602}, issn = {1872-8308}, mesh = {Animals ; *Avoidance Learning ; *Conditioning, Classical ; *Food ; Food Deprivation ; Male ; Mice/*psychology ; *Motor Activity ; Taste ; }, abstract = {Mice show a reluctance to eat unfamiliar food, when they first encounter it. This neophobic reaction is conventionally habituated by repeated trials: the mice gradually increase their consumption of the novel food. The new finding reported here is that the consumption remains low in mice that voluntarily run in activity wheels after the novel food access. This effect implies that running yields Pavlovian conditioned flavor aversion, which suppresses, otherwise increasing, consumption of the novel food. In the present research, the effect was demonstrated with a between-group design by pitting experimental mice receiving cheese-running paired treatment against cheese/running unpaired control mice (Experiment 1). The running-based food avoidance in mice was also shown in a differential conditioning paradigm, where one of two novel snacks (chocolate and marshmallow) was paired with running while the other was not, in non-deprived animals (Experiment 2 A) and food-deprived animals (Experiment 2B). These results concord with those previously reported in rats, indicating the generality of the phenomenon.}, } @article {pmid30500564, year = {2019}, author = {Serita, T and Miyahara, M and Tanimizu, T and Takahashi, S and Oishi, S and Nagayoshi, T and Tsuji, R and Inoue, H and Uehara, M and Kida, S}, title = {Dietary magnesium deficiency impairs hippocampus-dependent memories without changes in the spine density and morphology of hippocampal neurons in mice.}, journal = {Brain research bulletin}, volume = {144}, number = {}, pages = {149-157}, doi = {10.1016/j.brainresbull.2018.11.019}, pmid = {30500564}, issn = {1873-2747}, mesh = {Animals ; Anxiety/physiopathology ; Conditioning, Classical/physiology ; Dendritic Spines ; Dietary Supplements ; Fear/physiology ; Glutamic Acid/pharmacology ; Hippocampus/drug effects ; Learning/physiology ; Magnesium/metabolism ; Magnesium Deficiency/*metabolism/physiopathology ; Male ; Memory/*drug effects/*physiology ; Mice ; Mice, Inbred C57BL ; Neuronal Plasticity/physiology ; Neurons/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Recognition, Psychology ; Synaptic Transmission/physiology ; }, abstract = {Magnesium (Mg[2+]) is an essential mineral for maintaining biological functions. One major action of Mg[2+] in the brain is modulating the voltage-dependent blockade of N-methyl-d-aspartate type glutamate receptors, thereby controlling their opening, which is crucial for synaptic plasticity. Therefore, Mg[2+] has been shown to play critical roles in learning and memory, and synaptic plasticity. However, the effects of dietary Mg[2+] deficiency (MgD) on learning and memory and the morphology of neurons contributing to memory performance have not been examined in depth. Here, we show that MgD impairs hippocampus-dependent memories in mice. Mice fed an MgD diet showed deficits in hippocampus-dependent contextual fear, spatial and social recognition memories, although they showed normal amygdala- and insular cortex-dependent conditioned taste aversion memory, locomotor activity, and emotional behaviors such as anxiety-related and social behaviors. However, MgD mice showed normal spine density and morphology of hippocampal neurons. These findings suggest that MgD impairs hippocampus-dependent memory without affecting the morphology of hippocampal neurons.}, } @article {pmid30472309, year = {2019}, author = {Barney, TM and Vore, AS and Gano, A and Mondello, JE and Deak, T}, title = {The influence of central interleukin-6 on behavioral changes associated with acute alcohol intoxication in adult male rats.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {79}, number = {}, pages = {37-45}, pmid = {30472309}, issn = {1873-6823}, support = {P50 AA017823/AA/NIAAA NIH HHS/United States ; T32 AA025606/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcoholic Intoxication/*metabolism ; Animals ; Conditioning, Classical/*drug effects ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/*pharmacology ; Ethanol/administration & dosage ; Interleukin-6/*pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Reflex, Righting/*drug effects ; Signal Transduction/drug effects ; Sucrose/administration & dosage ; Taste/drug effects ; Tyrphostins/*pharmacology ; }, abstract = {Recent studies have demonstrated brain cytokine fluctuations associated with acute ethanol intoxication (increased IL-6) and withdrawal (increased IL-1β and TNFα). The purpose of the present studies was to examine the potential functional role of increased central interleukin-6 (IL-6). We utilized two tests of ethanol sensitivity to establish a potential role for IL-6 after high (3.5-4.0 g/kg, intraperitoneally [i.p.]) or moderate (2.0 g/kg, i.p.) doses of ethanol: loss of righting reflex (LORR) and conditioned taste aversion (CTA), respectively. Briefly, guide cannulae were implanted into the third ventricle of adult male Sprague-Dawley rats. In the first experiments, rats were infused with 25, 50, 100, or 200 ng of IL-6; or 0.3, 3.0, or 9.0 μg of the JAK/STAT inhibitor AG490 30 min prior to a high-dose ethanol challenge. Although sleep time was not affected by exogenous IL-6, infusion of AG490 increased latency to lose the righting reflex relative to vehicle-infused rats. Next, we assessed whether IL-6 was sufficient to produce a CTA. Moderately water-deprived rats received intracerebroventricular (i.c.v.) infusions of 25, 50, or 100 ng IL-6 immediately after 60-min access to 5% sucrose solution. Forty-eight hours later, rats were returned to the context and given 60-min access to sucrose solution. IL-6 infusion had no significant effect on sucrose intake when all rats were considered together. However, a median split revealed that low sucrose-consuming rats significantly increased their drinking on test day, an effect that was not seen in rats that received 50 or 100 ng of IL-6. In the last study, AG490 had no effect on ethanol-induced CTA (2 g/kg). Overall, these studies suggest that IL-6 had only a minor influence on ethanol-induced behavioral changes, yet phenotypic differences in sensitivity to IL-6 were apparent. These studies are among the first to examine a potential functional role for IL-6 in ethanol-related behaviors, and may have important implications for understanding the relationship between acute ethanol intoxication and its associated behavioral alterations.}, } @article {pmid30465759, year = {2018}, author = {Barik, A and Krashes, MJ}, title = {Remembering a Bad Taste.}, journal = {Neuron}, volume = {100}, number = {4}, pages = {765-767}, doi = {10.1016/j.neuron.2018.11.012}, pmid = {30465759}, issn = {1097-4199}, mesh = {*Avoidance Learning ; Conditioning, Classical ; Memory ; Neurons ; *Taste ; }, abstract = {The phenomenon of conditioned taste aversion (CTA) is generated after ingestion of a specific food is associated with an adverse outcome, i.e., sickness. In this issue of Neuron, Chen et al. (2018) interrogate the pivotal role of PBN[CGRP] neurons in both the acquisition and the expression of CTA.}, } @article {pmid30447220, year = {2019}, author = {Delay, ER and Weaver, B and Lane, DR and Kondoh, T}, title = {Dried bonito dashi: Contributions of mineral salts and organic acids to the taste of dashi.}, journal = {Physiology & behavior}, volume = {199}, number = {}, pages = {127-136}, doi = {10.1016/j.physbeh.2018.11.016}, pmid = {30447220}, issn = {1873-507X}, mesh = {Animals ; Avoidance Learning/*drug effects ; Flavoring Agents/*pharmacology ; Generalization, Psychological/*drug effects ; Male ; Mice ; Salts/*pharmacology ; Smell/*drug effects ; }, abstract = {Dried bonito dashi is often used in Japanese cuisine with a number of documented positive health effects. Its major taste is thought to be umami, elicited by inosine 5'-monophosphate (IMP) and L-amino acids. Previously we found that lactic acid, a major component of dried bonito dashi, enhanced the contribution of many of these amino acids to the taste of dried bonito dashi, and reduced the contribution of other amino acids. In addition to amino acids, dried bonito dashi also has a significant mineral salt component. The present study used conditioned taste aversion methods with mice (all had compromised olfactory systems) to compare the taste qualities of dried bonito dashi with four salts (NaCl, KCl, CaCl2 and MgCl2), with and without lactic acid or citric acid. A conditioned taste aversion to 25% dried bonitio dashi generalized significantly to NaCl and KCl, with or without 0.9% lactic acid added but not when citric acid was added. Generalization of the CTA to dried bonito dashi was much stronger to the divalent salts, but when either lactic acid or citric acid was added, this aversion was eliminated. These results suggest that these salts contribute to the complex taste of dried bonito dashi and that both organic acids appear able to modify the tastes of divalent salts.}, } @article {pmid30407064, year = {2018}, author = {Bernal-Gamboa, R and Rosas, JM and Nieto, J}, title = {Extinction makes acquisition context-specific in conditioned taste aversion regardless of the context where acquisition and testing take place.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {44}, number = {4}, pages = {385-395}, doi = {10.1037/xan0000183}, pmid = {30407064}, issn = {2329-8464}, mesh = {Analysis of Variance ; Animals ; *Association ; Attention/*physiology ; Avoidance Learning/*physiology ; Conditioning, Classical/*physiology ; Cues ; Extinction, Psychological/*physiology ; Feeding Behavior ; Female ; Mental Recall ; Rats ; Rats, Wistar ; Taste/*physiology ; Time Factors ; }, abstract = {Retrieval of a flavor-illness association has been found to show contextual dependence when the association is learned after a nontarget flavor-illness association has been extinguished in what has been named as the extinction makes acquisition context-specific (EMACS) effect. Four experiments were designed to further explore the EMACS effect in conditioned taste aversion. Experiments 1 and 2 replicated the EMACS effect using rats that did not experience extinction, and rats that underwent extinction of a different flavor as controls. Experiments 3 and 4 found that the experience of extinction with the nontarget Flavor X in a given context (A) led to context-specificity of performance to the target Flavor Y both, when Y was trained in a highly familiar context (B) and tested in the context where X had been trained (Context A, Experiment 3), and when the test was conducted in a less familiar context (C) where no cues or outcomes were presented before (Experiment 4). These results are consistent with the idea that the experience of extinction encourages organism's attention to the contexts, making retrieval of new learning context-specific. (PsycINFO Database Record (c) 2018 APA, all rights reserved).}, } @article {pmid30407063, year = {2018}, author = {Thrailkill, EA and Trask, S and Vidal, P and Alcalá, JA and Bouton, ME}, title = {Stimulus control of actions and habits: A role for reinforcer predictability and attention in the development of habitual behavior.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {44}, number = {4}, pages = {370-384}, pmid = {30407063}, issn = {2329-8464}, support = {R01 DA033123/DA/NIDA NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Attention/*physiology ; Avoidance Learning/physiology ; Conditioning, Operant/*physiology ; Discrimination, Psychological/*physiology ; Fasting ; Female ; *Habits ; Rats ; Rats, Wistar ; Reaction Time/physiology ; *Reinforcement, Psychology ; Time Factors ; }, abstract = {Goal-directed actions are instrumental behaviors whose performance depends on the organism's knowledge of the reinforcing outcome's value. In contrast, habits are instrumental behaviors that are insensitive to the outcome's current value. Although habits in everyday life are typically controlled by stimuli that occasion them, most research has studied habits using free-operant procedures in which no discrete stimuli are present to occasion the response. We therefore studied habit learning when rats were reinforced for lever pressing on a random-interval 30-s schedule in the presence of a discriminative stimulus (S) but not in its absence. In Experiment 1, devaluing the reinforcer with taste aversion conditioning weakened instrumental responding in a 30-s S after 4, 22, and 66 sessions of instrumental training. Even extensive practice thus produced goal-directed action, not habit. Experiments 2 and 3 contrastingly found habit when the duration of S was increased from 30 s to 8 min. Experiment 4 then found habit with the 30-s S when it always contained a reinforcer; goal-directed action was maintained when reinforcers were earned at the same rate but occurred in only 50% of Ss (as in the previous experiments). The results challenge the view that habits are an inevitable consequence of repeated reinforcement (as in the law of effect) and instead suggest that discriminated habits develop when the reinforcer becomes predictable. Under those conditions, organisms may pay less attention to their behavior, much as they pay less attention to signals associated with predicted reinforcers in Pavlovian conditioning. (PsycINFO Database Record (c) 2018 APA, all rights reserved).}, } @article {pmid30375738, year = {2019}, author = {Yasumatsu, K and Iwata, S and Inoue, M and Ninomiya, Y}, title = {Fatty acid taste quality information via GPR120 in the anterior tongue of mice.}, journal = {Acta physiologica (Oxford, England)}, volume = {226}, number = {1}, pages = {e13215}, doi = {10.1111/apha.13215}, pmid = {30375738}, issn = {1748-1716}, support = {JP 26670810//JSPS KAKENHI/International ; JP 15H02571//JSPS KAKENHI/International ; JP 18H02968//JSPS KAKENHI/International ; JP 18K19653//JSPS KAKENHI/International ; //Japan Society for the Promotion of Science/International ; }, mesh = {Animals ; Behavior, Animal ; Benzoates/pharmacology ; Chorda Tympani Nerve/drug effects/physiology ; Fatty Acids/*pharmacology ; Gene Expression Regulation/drug effects ; Mice ; Pyrimidines/pharmacology ; Receptors, G-Protein-Coupled/antagonists & inhibitors/genetics/*metabolism ; Sulfonamides/pharmacology ; Taste/*physiology ; Tongue/*physiology ; Xanthenes/pharmacology ; }, abstract = {AIM: To elucidate whether fatty acid taste has a quality that does not overlap with other primary qualities, we investigated potential neuron types coding fatty acid information and how GPR120 is involved.

METHODS: Single fibre recordings in the chorda tympani (CT) nerve and behavioural response measurements using a conditioned taste aversion paradigm were performed in GPR120-knockout (KO) and wild-type (WT) mice.

RESULTS: Single fibres can be classified into fatty acid (F)-, S-, M-, electrolyte (E)-, Q-, and N-type groups according to the maximal response among oleic acid, sucrose, monopotassium glutamate (MPG), HCl, quinine hydrochloride, and NaCl respectively. Among fibres, 4.0% in GPR120-KO and 17.9% in WT mice showed a maximal response to oleic acid (F-type). Furthermore, half or more of S- and M-type fibres showed responses to fatty acids in both mouse strains, although the thresholds in KO mice were significantly higher and impulse frequencies lower than those in WT mice. GPR120-KO mice conditioned to avoid linoleic acid showed generalized stimulus avoidances for MPG, indicating qualitative similarity between linoleic acid and MPG. The KO mice showed a higher generalization threshold for linoleic acid than that of WT mice.

CONCLUSION: Fatty acid taste is suggested to have a unique quality owing to the discovery of F-type fibres, with GPR120 involved in neural information pathways for a unique quality and palatable taste qualities in the mouse CT nerve. GPR120 plays roles in distinguishing fatty acid taste from other primary tastes and the detection of low linoleic acid concentrations.}, } @article {pmid30359063, year = {2019}, author = {Schoenberg, HL and Sola, EX and Seyller, E and Kelberman, M and Toufexis, DJ}, title = {Female rats express habitual behavior earlier in operant training than males.}, journal = {Behavioral neuroscience}, volume = {133}, number = {1}, pages = {110-120}, doi = {10.1037/bne0000282}, pmid = {30359063}, issn = {1939-0084}, mesh = {Animals ; *Conditioning, Operant ; Extinction, Psychological ; Female ; *Habits ; Male ; Rats, Long-Evans ; *Reinforcement, Psychology ; }, abstract = {Habitual behavior can be advantageous by increasing the availability of cognitive resources for use in other tasks. However, habitual behaviors are problematic when they are coopted to prolong the maladaptive responding present in several psychopathologies such as substance abuse, dysregulated fear responding in posttraumatic stress disorder, and obsessive-compulsive disorder. Although sex differences exist in the occurrence or progression of these psychopathologies, there are no studies that compare the development of habitual behavior systematically in male and female animals. In the present study, male and female rats were identically trained on a variable interval 30-s (VI 30-s) schedule of reinforcement to nose-poke for sucrose pellet reinforcers. Subsequently, the sucrose was devalued in one half of the animals by pairing its presentation with injections of lithium chloride (LiCl) to induce nausea, thus conditioning a taste aversion. Habitual behavior was operationalized as continued operant responding in an extinction test following devaluation of the sucrose reinforcer. Successful devaluation was confirmed with both a consumption and reacquisition test. Given identical training to 240 sucrose pellets, female rats demonstrate habitual behavior whereas male rats remain goal-directed. Additionally, females are habitual after 200 or 160 reinforcers earned on a VI 30-s schedule, but remain goal-directed at 120 and 80 reinforcers on this schedule. These data suggest that behavioral flexibility may be compromised in female rats compared to males due to accelerated habit formation in females. These results are important because sex differences are present in several psychopathologies, which may be related to differences in the development of habitual behavior. (PsycINFO Database Record (c) 2019 APA, all rights reserved).}, } @article {pmid30344042, year = {2018}, author = {Chen, JY and Campos, CA and Jarvie, BC and Palmiter, RD}, title = {Parabrachial CGRP Neurons Establish and Sustain Aversive Taste Memories.}, journal = {Neuron}, volume = {100}, number = {4}, pages = {891-899.e5}, pmid = {30344042}, issn = {1097-4199}, support = {/HHMI_/Howard Hughes Medical Institute/United States ; R01 DA024908/DA/NIDA NIH HHS/United States ; T32 DA007278/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*physiology ; Calcitonin Gene-Related Peptide/genetics/*metabolism ; Female ; Male ; Memory/*physiology ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Neurons/chemistry/*metabolism ; Parabrachial Nucleus/chemistry/*metabolism ; Photic Stimulation/methods ; Taste/*physiology ; }, abstract = {Food aversions develop when the taste of a novel food is associated with sickness, which often occurs after food poisoning or chemotherapy treatment. We identified calcitonin-gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) as sufficient and necessary for establishing a conditioned taste aversion (CTA). Photoactivating projections from CGRP[PBN] neurons to either the central nucleus of the amygdala or the bed nucleus of the stria terminalis can also induce robust CTA. CGRP[PBN] neurons undergo plasticity following CTA, and inactivation of either Arc or Grin1 (genes involved in memory consolidation) prevents establishment of a strong CTA. Calcium imaging reveals that the novel food re-activates CGRP[PBN] neurons after conditioning. Inhibition of these neurons or inactivation of the Grin1 gene after conditioning attenuates CTA expression. Our results indicate that CGRP[PBN] neurons not only play a key role for learning food aversions but also contribute to the maintenance and expression of those memories.}, } @article {pmid30336209, year = {2018}, author = {Arthurs, J and Lin, JY and Reilly, S}, title = {Inhibiting gustatory thalamus or medial amygdala has opposing effects on taste neophobia.}, journal = {Neurobiology of learning and memory}, volume = {156}, number = {}, pages = {24-32}, pmid = {30336209}, issn = {1095-9564}, support = {R01 DC006456/DC/NIDCD NIH HHS/United States ; R56 DC006456/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*drug effects ; Behavior, Animal/drug effects ; Conditioning, Classical/*drug effects ; Corticomedial Nuclear Complex/*drug effects ; GABA Agonists/*pharmacology ; Genetic Techniques ; Male ; Rats ; Rats, Sprague-Dawley ; Taste Perception/*drug effects ; Ventral Thalamic Nuclei/*drug effects ; }, abstract = {Taste neophobia is a feeding system defense mechanism that limits consumption of an unknown, and therefore potentially dangerous, edible until the post-ingestive consequences are experienced. We found that transient pharmacological inhibition (induced with the GABA agonists baclofen and muscimol) of the gustatory thalamus (GT; Experiment 1), but not medial amygdala (MeA; Experiment 2), during exposure to a novel saccharin solution attenuated taste neophobia. In Experiment 3 we found that inhibition of MeA neurons (induced with the chemogenetic receptor hM4DGi) enhanced the expression of taste neophobia whereas excitation of MeA neurons (with hM3DGq) had no influence of taste neophobia. Overall, these results refine the temporal involvement of the GT in the occurrence of taste neophobia and support the hypothesis that neuronal excitation in the GT is necessary for taste neophobia. Conversely, we show that chemogenetically, but not pharmacologically, inhibiting MeA neurons is sufficient to exaggerate the expression of taste neophobia.}, } @article {pmid30322892, year = {2018}, author = {Flores, VL and Parmet, T and Mukherjee, N and Nelson, S and Katz, DB and Levitan, D}, title = {The role of the gustatory cortex in incidental experience-evoked enhancement of later taste learning.}, journal = {Learning & memory (Cold Spring Harbor, N.Y.)}, volume = {25}, number = {11}, pages = {587-600}, pmid = {30322892}, issn = {1549-5485}, support = {F31 DC015931/DC/NIDCD NIH HHS/United States ; R01 DC006666/DC/NIDCD NIH HHS/United States ; R01 DC007703/DC/NIDCD NIH HHS/United States ; T32 GM084907/GM/NIGMS NIH HHS/United States ; R90 DA033463/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Cerebral Cortex/cytology/*physiology ; Citric Acid ; Dietary Sucrose ; Female ; Gene Expression ; Immunohistochemistry ; Learning/*physiology ; Optogenetics ; Proto-Oncogene Proteins c-fos/metabolism ; Random Allocation ; Rats, Long-Evans ; Sodium Chloride ; Taste Perception/*physiology ; }, abstract = {The strength of learned associations between pairs of stimuli is affected by multiple factors, the most extensively studied of which is prior experience with the stimuli themselves. In contrast, little data is available regarding how experience with "incidental" stimuli (independent of any conditioning situation) impacts later learning. This lack of research is striking given the importance of incidental experience to survival. We have recently begun to fill this void using conditioned taste aversion (CTA), wherein an animal learns to avoid a taste that has been associated with malaise. We previously demonstrated that incidental exposure to salty and sour tastes (taste preexposure-TPE) enhances aversions learned later to sucrose. Here, we investigate the neurobiology underlying this phenomenon. First, we use immediate early gene (c-Fos) expression to identify gustatory cortex (GC) as a site at which TPE specifically increases the neural activation caused by taste-malaise pairing (i.e., TPE did not change c-Fos induced by either stimulus in isolation). Next, we use site-specific infection with the optical silencer Archaerhodopsin-T to show that GC inactivation during TPE inhibits the expected enhancements of both learning and CTA-related c-Fos expression, a full day later. Thus, we conclude that GC is almost certainly a vital part of the circuit that integrates incidental experience into later associative learning.}, } @article {pmid30314288, year = {2018}, author = {Kivell, BM and Paton, KF and Kumar, N and Morani, AS and Culverhouse, A and Shepherd, A and Welsh, SA and Biggerstaff, A and Crowley, RS and Prisinzano, TE}, title = {Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.}, journal = {Molecules (Basel, Switzerland)}, volume = {23}, number = {10}, pages = {}, pmid = {30314288}, issn = {1420-3049}, support = {P20 GM113117/GM/NIGMS NIH HHS/United States ; T32 GM008545/GM/NIGMS NIH HHS/United States ; R01 DA018151/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Anxiety/drug therapy/metabolism ; Behavior, Animal/*drug effects ; Cocaine/*adverse effects ; Cocaine-Related Disorders/drug therapy/*metabolism/*psychology ; Diterpenes/adverse effects/chemistry/*pharmacology ; Diterpenes, Clerodane/adverse effects/chemistry/*pharmacology ; Learning/drug effects ; Male ; Mesylates/adverse effects/chemistry/*pharmacology ; Mice ; Motor Activity/drug effects ; Nociception/drug effects ; Pain/drug therapy/etiology/metabolism ; Rats ; Receptors, Opioid, kappa/*agonists ; Recognition, Psychology/drug effects ; }, abstract = {The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.}, } @article {pmid30300803, year = {2018}, author = {Tai, S and Vasiljevik, T and Sherwood, AM and Eddington, S and Wilson, CD and Prisinzano, TE and Fantegrossi, WE}, title = {Assessment of rimonabant-like adverse effects of purported CB1R neutral antagonist / CB2R agonist aminoalkylindole derivatives in mice.}, journal = {Drug and alcohol dependence}, volume = {192}, number = {}, pages = {285-293}, pmid = {30300803}, issn = {1879-0046}, support = {P20 GM113117/GM/NIGMS NIH HHS/United States ; R01 DA018151/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Cannabinoid Receptor Agonists/adverse effects/*pharmacology ; Cannabinoid Receptor Antagonists/adverse effects/*pharmacology ; Cannabinoids/pharmacology ; Dose-Response Relationship, Drug ; Male ; Mice ; Reaction Time ; Receptor, Cannabinoid, CB1/*antagonists & inhibitors/physiology ; Receptor, Cannabinoid, CB2/*agonists/physiology ; Rimonabant/adverse effects/*pharmacology ; Taste/drug effects/physiology ; }, abstract = {BACKGROUND: Cannabinoids may be useful in the treatment of CNS disorders including drug abuse and addiction, where both CB1R antagonists / inverse agonists and CB2R agonists have shown preclinical efficacy. TV-5-249 and TV-6-41, two novel aminoalkylindoles with dual action as neutral CB1R antagonists and CB2R agonists, previously attenuated abuse-related effects of ethanol in mice.

PURPOSE: To further characterize these drugs, TV-5-249 and TV-6-41 were compared with the CB1R antagonist / inverse agonist rimonabant in assays relevant to adverse effects and cannabinoid withdrawal.

PROCEDURES AND FINDINGS: The cannabinoid tetrad confirmed that TV-5-249 and TV-6-41 were devoid of CB1R agonist effects at behaviorally-relevant doses, and neither of the novel drugs induced rimonabant-like scratching. Generalized aversive effects were assessed, and rimonabant and TV-5-249 induced taste aversion, but TV-6-41 did not. Schedule-controlled responding and observation of somatic signs were used to assess withdrawal-like effects precipitated by rimonabant or TV-6-41 in mice previously treated with the high-efficacy CB1R agonist JWH-018 or vehicle. Rimonabant and TV-6-41 dose-dependently suppressed response rates in all subjects, but TV-6-41 did so more potently in JWH-018-treated mice than in vehicle-treated mice, while rimonabant equally suppressed responding in both groups. Importantly, rimonabant elicited dramatic withdrawal signs, but TV-6-41 did not.

CONCLUSIONS: These findings suggest differences in both direct adverse effects and withdrawal-related effects elicited by rimonabant, TV-5-249, and TV-6-41, which could relate to neutral CB1R antagonism, CB2R agonism, or a combination of both. Both mechanisms should be explored and exploited in future drug design efforts to develop pharmacotherapies for drug dependence.}, } @article {pmid30295681, year = {2018}, author = {Molero-Chamizo, A}, title = {Effects of extensive amygdaloid lesions on conditioned taste aversion in rats.}, journal = {Acta neurobiologiae experimentalis}, volume = {78}, number = {3}, pages = {242-250}, pmid = {30295681}, issn = {1689-0035}, mesh = {Amygdala/*drug effects ; Animals ; Avoidance Learning/drug effects ; Brain Mapping/methods ; Conditioning, Classical/*physiology ; Lithium Chloride/*pharmacology ; Male ; Rats, Wistar ; Taste/*physiology ; }, abstract = {The role of the amygdala in the acquisition of conditioned taste aversion (CTA) is unclear. The lesion studies that have explored specific nuclei of the amygdala point to a probable involvement of the basolateral amygdala, but it remains unclear whether the function of the amygdala in CTA is limited to the activity of the basolateral amygdala. In the current study, extensive bilateral lesions of the amygdala were performed in Wistar rats to explore if the destruction of the amygdala affects the acquisition of CTA, as has been reported with selective lesions of the basolateral amygdala. The magnitude of the taste aversion of animals with extensive lesions of the amygdala was compared with those of animals with similar lesions of the striatum (a structure apparently unrelated to CTA) and animals without lesions. Taste aversion was analyzed by the one‑bottle test and two‑bottle choice test. The results of the one‑bottle test indicated that amygdaloid lesions significantly reduced the magnitude of taste aversion compared with that of animals without lesions. Animals with lesions of the amygdala also showed a greater preference for the conditioned taste stimulus, but this preference did not reach statistical significance. Besides the effect on CTA, animals with amygdaloid lesions showed no evidence of taste neophobia on the day of conditioning. These findings suggest that amygdaloid lesions may affect CTA by disrupting the perception of novelty during conditioning in a manner similar to the effect reported with basolateral lesions.}, } @article {pmid30282846, year = {2019}, author = {Nakajima, S}, title = {Food aversion learning based on voluntary running in non-deprived rats: a technique for establishing aversive conditioning with minimized discomfort.}, journal = {Experimental animals}, volume = {68}, number = {1}, pages = {71-79}, pmid = {30282846}, issn = {1881-7122}, mesh = {Animals ; Avoidance Learning/*physiology ; Conditioning, Operant/*physiology ; Eating/*psychology ; *Food ; Kaolin/administration & dosage ; Male ; Memory/physiology ; Nausea/physiopathology/psychology ; Rats, Wistar ; Running/*psychology ; }, abstract = {This article presents an experimental preparation for establishing conditioned food aversion (CFA) by voluntary wheel running in rats with laboratory chow and water freely available. In Experiment 1, unfamiliar food (raisins) was avoided by rats when they first encountered it. This neophobic food avoidance was habituated by repeated tests; the rats gradually increased their raisin consumption. However, the consumption remained suppressed in rats that accessed the raisins after wheel running. This finding implies that running yielded CFA, which suppressed consumption of the unfamiliar food rather than increasing it. Because running generated kaolin clay ingestion, which is a behavioral marker of nausea, it is suggested that the running-based CFA was mediated by weak gastrointestinal discomfort. Experiment 2 supported the claim that the suppressed consumption is due to running-based CFA by showing the specificity of food suppression. Demonstration of CFA based on voluntary activity in non-deprived rats will contribute to basic research on learning and memory as an alternative technique for studying aversive conditioning with minimized discomfort in animals.}, } @article {pmid30267837, year = {2018}, author = {Soto, J and Keeley, A and Keating, AV and Mohamed-Ahmed, AHA and Sheng, Y and Winzenburg, G and Turner, R and Desset-Brèthes, S and Orlu, M and Tuleu, C}, title = {Rats can predict aversiveness of Active Pharmaceutical Ingredients.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {133}, number = {}, pages = {77-84}, doi = {10.1016/j.ejpb.2018.09.027}, pmid = {30267837}, issn = {1873-3441}, mesh = {Adult ; Animals ; Chemistry, Pharmaceutical/methods ; Female ; Humans ; Male ; Pharmaceutical Preparations/*chemistry ; Rats ; Rats, Sprague-Dawley ; Taste/*drug effects ; Young Adult ; }, abstract = {Taste is crucial for patient acceptability and compliance with prescribed medicines, in particular with pediatric patients. Evaluating the taste of new active pharmaceutical ingredients (APIs) is therefore essential to put in place adequate taste-masking techniques, if needed, which will lead to acceptable palatable formulations. Thus, there is an urgent need to develop and optimize taste assessment methods that could be used at different stages of the drug development process. The aim of this study was to investigate the suitability of the rat brief-access taste aversion (BATA) model as a screening tool for assessment of APIs aversiveness that could predict human taste responses. Presently, the taste intensity of nine marketed APIs known to have different levels of bitter intensity (quinine hydrochloride dihydrate, 6-n-propylthiouracil, sildenafil citrate, diclofenac sodium, ranitidine hydrochloride, caffeine citrate, isoniazid, telbivudine and paracetamol) was investigated at different overlapping concentrations with two in vivo taste assessment methods: the rat BATA model and human taste panels with the intention of determining the drugs' concentrations to produce half of the maximal rating. Overall there was a strong correlation (R[2] = 0.896) between rats IC50 and humans EC50 values. This correlation verifies the BATA model as a rapid and reliable tool for quantitative assessment of API aversiveness. A comparable ranking order was obtained mainly for high and medium aversive compounds, whereas it was less aligned for weakly aversive compounds. It was nonetheless possible to propose a classification of poor taste intensity determined in rats that would predict human taste tolerability.}, } @article {pmid30219263, year = {2019}, author = {Rodríguez-Blanco, LA and Rivera-Olvera, A and Escobar, ML}, title = {Consolidation of an aversive taste memory requires two rounds of transcriptional and epigenetic regulation in the insular cortex.}, journal = {Behavioural brain research}, volume = {356}, number = {}, pages = {371-374}, doi = {10.1016/j.bbr.2018.09.009}, pmid = {30219263}, issn = {1872-7549}, mesh = {Animals ; Avoidance Learning/drug effects ; Cerebral Cortex/*drug effects/physiology ; Conditioning, Classical/drug effects/physiology ; Epigenesis, Genetic/*drug effects ; Male ; Memory/*drug effects/physiology ; Memory, Long-Term/drug effects ; Rats, Wistar ; Taste/*drug effects ; }, abstract = {The current view of the neurobiology of learning and memory suggests that long-term memory (LTM) depends not only on the de novo protein synthesis but also on the synthesis of mRNA even hours after the acquisition of memory, as well as that the regulation of transcription through the histone acetylation is essential for the memory establishment. Our previous studies showed that protein synthesis inhibition around the time of training and 5-7 hours after acquisition in the insular cortex (IC) prevents the consolidation of conditioned taste aversion (CTA), a well-established learning and memory paradigm in which an animal learns to associate a novel taste with nausea. However, the participation of mRNA synthesis and the epigenetic regulation through histone acetylation in this process remains unexplored. In the present study we evaluated the effect of the inhibition of transcription as well as deacetylation of histones at two temporal windows on the consolidation of CTA. Thus, immediately or seven hours after CTA acquisition animals received a microinfusion of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) or MS-275 in the IC, respectively. The present results show that transcription inhibition immediately and 7 h after acquisition impairs the CTA memory consolidation, whereas the inhibition of histone deacetylation strengths this memory at those temporal windows. These findings reveal that CTA memory requires recurrent rounds of transcriptional modulation events in the IC in order to consolidate this memory trace, demonstrating that transcriptional and epigenetic modulation substantially contribute to memory-consolidation-related functions performed by a neocortical area even several hours after memory acquisition.}, } @article {pmid30172953, year = {2018}, author = {Lin, JY and Arthurs, J and Reilly, S}, title = {The effects of amygdala and cortical inactivation on taste neophobia.}, journal = {Neurobiology of learning and memory}, volume = {155}, number = {}, pages = {322-329}, pmid = {30172953}, issn = {1095-9564}, support = {R01 DC006456/DC/NIDCD NIH HHS/United States ; R56 DC006456/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Baclofen/administration & dosage ; Basolateral Nuclear Complex/drug effects/*physiology ; Cerebral Cortex/drug effects/*physiology ; Eating ; GABA-A Receptor Agonists/administration & dosage ; Male ; Muscimol/administration & dosage ; Rats, Sprague-Dawley ; Taste Perception/drug effects/*physiology ; }, abstract = {The current study examined the effects of transient inactivation of the basolateral amygdala (BLA; Experiment 1) and gustatory cortex (GC; Experiment 2) on the expression of taste neophobia and its recovery. We found that inactivation (induced by infusions of baclofen/muscimol) of each structure before exposure to a novel saccharin (0.5%) solution elevated intake on Trial 1 (i.e., taste neophobia was attenuated) and, surprisingly, decreased intake on Trial 2. It seems unlikely that this intake reduction on Trial 2 can be attributed to taste aversion learning caused by drug infusions because in the subsequent experiments with the same set of the implanted animals, the rats did not decrease intake when baclofen/muscimol was infused after taste presentation on Trial 1. The latter result suggests that BLA or GC inactivation that attenuates taste neophobia may also impair memory consolidation of a safe taste experience.}, } @article {pmid30129253, year = {2019}, author = {Weera, MM and Agim, ZS and Cannon, JR and Chester, JA}, title = {Genetic correlations between nicotine reinforcement-related behaviors and propensity toward high or low alcohol preference in two replicate mouse lines.}, journal = {Genes, brain, and behavior}, volume = {18}, number = {3}, pages = {e12515}, pmid = {30129253}, issn = {1601-183X}, support = {R01ES025750/ES/NIEHS NIH HHS/United States ; P60 AA007611/AA/NIAAA NIH HHS/United States ; P50 AA007611/AA/NIAAA NIH HHS/United States ; AA013522, AA07611/AA/NIAAA NIH HHS/United States ; U24 AA015512/AA/NIAAA NIH HHS/United States ; R01 ES025750/ES/NIEHS NIH HHS/United States ; U01 AA013522/AA/NIAAA NIH HHS/United States ; U24 AA013522/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcoholism/*genetics ; Animals ; Biogenic Monoamines/metabolism ; Female ; *Genotype ; Male ; Mecamylamine/pharmacology ; Mice ; Nicotine/*pharmacology ; Nicotinic Agonists/pharmacology ; Nicotinic Antagonists/pharmacology ; Nucleus Accumbens/drug effects/metabolism ; *Reinforcement, Psychology ; Tobacco Smoking/*genetics ; }, abstract = {Common genetic factors may contribute to the high comorbidity between tobacco smoking and alcohol use disorder. Here, we assessed behavioral and biological effects of nicotine in replicate mouse lines selectively bred for high (HAP2/3) or low alcohol preference (LAP2/3). In Experiment 1, free-choice (FC) oral nicotine and quinine intake were assessed in HAP2/3 and LAP2/3 mice. Effects of nicotinic acetylcholine receptor blockade by mecamylamine on nicotine intake in HAP2 mice were also examined. In Experiment 2, HAP2/3 and LAP2/3 mice were tested for differences in sensitivity to nicotine-induced taste conditioning. In Experiment 3, the effects of a single nicotine injection on nucleus accumbens (NAc) and dorsal striatum monoamine levels in HAP2/3 and LAP2/3 mice were tested. In Experiment 1, HAP2/3 mice showed greater nicotine intake and intake ratio than LAP2/3 mice. There were no line differences in quinine intake. Mecamylamine reduced nicotine intake and intake ratio in HAP2 mice. In Experiment 2, HAP2/3 mice showed weaker nicotine-induced conditioned taste aversion (CTA) compared with LAP2/3 mice. In Experiment 3, nicotine treatment increased NAc dopamine turnover across both HAP2/3 and LAP2/3 mouse lines. These results show that there is a positive genetic correlation between oral alcohol intake (high alcohol intake/preference selection phenotype) and oral nicotine intake and a negative genetic correlation between oral alcohol intake and sensitivity to nicotine-induced CTA.}, } @article {pmid30126972, year = {2018}, author = {Moschak, TM and Wang, X and Carelli, RM}, title = {A Neuronal Ensemble in the Rostral Agranular Insula Tracks Cocaine-Induced Devaluation of Natural Reward and Predicts Cocaine Seeking.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {38}, number = {39}, pages = {8463-8472}, pmid = {30126972}, issn = {1529-2401}, support = {R01 DA014339/DA/NIDA NIH HHS/United States ; }, mesh = {Affect/drug effects/*physiology ; Animals ; Cerebral Cortex/drug effects/*physiology ; Cocaine/*administration & dosage ; Conditioning, Operant ; Drug-Seeking Behavior/drug effects/*physiology ; Lithium Chloride/administration & dosage ; Male ; Neurons/drug effects/*physiology ; Quinine/administration & dosage ; Rats, Sprague-Dawley ; *Reward ; Saccharin/administration & dosage ; Taste/drug effects/physiology ; Taste Perception/drug effects/physiology ; }, abstract = {In substance use disorders, negative affect associated with drug withdrawal can elicit strong drug craving and promote relapse. One brain region implicated in those processes is the rostral agranular insular cortex (RAIC), although precisely how this region encodes negative affect associated with drug seeking is unknown. Here, a preclinical model was used where RAIC activity was examined in male Sprague Dawley rats during intraoral infusions of a sweet (saccharin) paired with impending but delayed access to cocaine self-administration, and for comparative purposes, during the sweet predicting saline self-administration or injection of lithium chloride (LiCl), or during intraoral infusions of a bitter taste (quinine). Consistent with previous work, cocaine-paired saccharin, LiCl-paired saccharin, and quinine all elicited aversive taste reactivity. However, the aversive taste reactivity elicited by the cocaine-paired tastant was qualitatively different from that evoked by the other two agents. Furthermore, differences in taste reactivity were reflected in RAIC cell firing, where distinct shifts in neural signaling were observed specifically after cocaine but not LiCl conditioning. Notably, low motivation for cocaine (indicated by low loading and slower latencies to lever press) was correlated with this shift in RAIC signaling, but aversive (gaping) responses were not. Collectively, these findings indicate that cocaine-paired tastants elicit unique aspects of aversive behaviors that differ from traditional conditioned taste aversion (LiCl) or quinine and that the RAIC plays a role in modulating drug-seeking behaviors driven by drug-induced dysphoria (craving), but not negative affect per se.SIGNIFICANCE STATEMENT In substance use disorders, negative affect associated with drug cues can elicit craving and promote relapse; however, the underlying neurocircuitry of this phenomenon is unknown. Here, we investigated the role of the rostral agranular insula cortex (RAIC) in these processes using a preclinical model wherein intraoral delivery of a sweet is paired with delayed access to cocaine self-administration. The taste comes to elicit negative affect that predicts heightened drug seeking. Here, we found that a population of RAIC neurons became inhibited during presentation of the cocaine-paired tastant (when negative affect is high) and that this inhibitory neural profile predicted lower drug seeking. These findings suggest that the RAIC may function to oppose cue-induced cocaine craving and help reduce motivation for the drug.}, } @article {pmid30115766, year = {2018}, author = {Kubilius, RA and Kaplick, PM and Wotjak, CT}, title = {Highway to hell or magic smoke? The dose-dependence of Δ[9]-THC in place conditioning paradigms.}, journal = {Learning & memory (Cold Spring Harbor, N.Y.)}, volume = {25}, number = {9}, pages = {446-454}, pmid = {30115766}, issn = {1549-5485}, mesh = {Animals ; Behavior, Animal/*drug effects ; Cannabinoid Receptor Agonists/*pharmacology ; Conditioning, Classical/*drug effects ; Dronabinol/*pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; }, abstract = {The prerequisites for responsible cannabis use are at the heart of current inquiries into cannabis decriminalization by policy makers as well as academic and nonacademic stakeholders at a global scale. Δ[9]-tetrahydrocannabinol (Δ[9]-THC), the prime psychoactive compound of the cannabis sativa, as well as cannabimimetics that resemble the pharmacological properties and psychological effects of Δ[9]-THC, lend themselves handsomely to the preclinical scrutiny of reward-related behavior because they carry marked translational value. Although a functional dichotomy of the psychological effects of Δ[9]-THC (rewarding versus aversive) has been abundantly reported in place conditioning (PC) paradigms, and might be best attributed to a dose-dependence of Δ[9]-THC, most PC studies with Δ[9]-THC feature no significant effects at all. Therefore, after decades of rigorous research, it still remains undetermined whether Δ[9]-THC generally exerts rewarding or aversive effects in rodents. Here, we set out to extrapolate the commonly alleged dose-dependence of the rewarding and aversive effects of Δ[9]-THC from the existing literature, at the behavioral pharmacological level of analysis. Specifically, our meta-analysis investigated: (i) the alleged bidirectional effects and dose-dependence of Δ[9]-THC in the PC test; (ii) methodological inconsistencies between PC studies; and (iii) other pharmacological studies on cannabinoids (i.e., dopamine release, anxiety, stress, conditioned taste aversion, catalepsy) to substantiate the validity of PC findings. Our findings suggest that: (i) Δ[9]-THC dose-dependently generates rewarding (1 mg/kg) and aversive (5 mg/kg) effects in PC; (ii) an inconsistent use of priming injections hampers a clear establishment of the rewarding effects of Δ[9]-THC in PC tests and might explain the seemingly contradictory plethora of nonsignificant THC studies in the PC test; and (iii) other pharmacological studies on Δ[9]-THC substantiate the dose-dependent biphasic effects of Δ[9]-THC in PC. A standardized experimental design would advance evidence-based practice in future PC studies with Δ[9]-THC and facilitate the pointed establishment of rewarding and aversive effects of the substance.}, } @article {pmid30110433, year = {2018}, author = {Agee, LA and Monfils, MH}, title = {Effect of demonstrator reliability and recency of last demonstration on acquisition of a socially transmitted food preference.}, journal = {Royal Society open science}, volume = {5}, number = {6}, pages = {172391}, pmid = {30110433}, issn = {2054-5703}, abstract = {In the social transmission of food preference paradigm, naive observer rats acquire safety information about novel food sources in the environment through social interaction with a demonstrator rat that has recently eaten said food. Research into the behavioural mechanisms governing this form of learning has found that observers show increased reliance on socially acquired information when the state of the environment makes personal examination of their surroundings risky. We aimed to (1) determine whether reliance on social information would decrease if previous reliance on social learning was unsuccessful, and (2) whether reliance on the specific demonstrator that had transmitted poor information would similarly decrease. By inducing illness in observers following consumption of a socially demonstrated food, we created an environmental situation in which reliance on socially acquired information was maladaptive. We found that under these conditions, observers showed no change in their reliance on a specific demonstrator or socially learned information in general. Our experiment also unexpectedly produced results showing that recent demonstrators were more influential in later transmissions than demonstrators that had been learned from less recently. Notably, this effect only emerged when the observer simultaneously interacted with both demonstrators, indicating that demonstrators must be in direct competition for this effect to manifest.}, } @article {pmid30085976, year = {2018}, author = {Gartner, SN and Klockars, A and Prosser, C and Carpenter, EA and Levine, AS and Olszewski, PK}, title = {Identification of central mechanisms underlying anorexigenic effects of intraperitoneal L-tryptophan.}, journal = {Neuroreport}, volume = {29}, number = {15}, pages = {1293-1300}, doi = {10.1097/WNR.0000000000001110}, pmid = {30085976}, issn = {1473-558X}, mesh = {Animals ; Anti-Obesity Agents/*administration & dosage ; Brain/*drug effects/metabolism ; Camphanes/pharmacology ; Central Nervous System Agents/pharmacology ; Eating/*drug effects/physiology ; Food Deprivation ; Injections, Intraperitoneal ; Male ; Motivation/drug effects/physiology ; Neurons/drug effects/metabolism ; Piperazines/pharmacology ; Rats, Sprague-Dawley ; Receptors, Oxytocin/antagonists & inhibitors/metabolism ; Taste Perception ; Tryptophan/*administration & dosage ; }, abstract = {A free essential amino acid, L-tryptophan (TRP), administered through a diet or directly into the gut, decreases food intake by engaging neural mechanisms. The ability of intragastric TRP to cross into the general circulation and through the blood-brain barrier, at least partly underlies hypophagia. It is unclear although, whether TRP's anorexigenic effects and accompanying neural processes occur in the absence of the initial action of TRP on the gut mucosa. Here, we addressed this issue by using a fundamental approach of examining effects of intraperitoneally administered TRP on feeding and neuronal activation in rats. We found that 30 mg/kg, intraperitoneal, TRP decreases deprivation-induced intake of standard chow and thirst-driven water intake. A 100 mg/kg dose was necessary to suppress consumption of palatable chow and of sucrose and saccharin solutions in nondeprived animals. Intraperitoneally TRP did not induce a conditioned taste aversion; thus, its anorexigenic effects were unrelated to sickness/malaise. c-Fos mapping in feeding-related brain sites revealed TRP-induced changes in the dorsal vagal complex, hypothalamic paraventricular and supraoptic nuclei and in the basolateral amygdala. TRP enhanced activation of hypothalamic neurons synthesizing an anorexigen, oxytocin (OT). Pharmacological blockade of the OT receptor with a blood-brain barrier -penetrant antagonist, L-368,899, attenuated TRP-induced decrease in deprivation-induced chow intake, but not in thirst-driven water consumption. We conclude that TRP triggers anorexigenic action and underlying neural responses even when it does not directly contact the gut mucosa. TRP requires OT to decrease energy intake, whereas OT is nonobligatory in TRP's effects on drinking behavior.}, } @article {pmid30035267, year = {2018}, author = {Chambers, KC}, title = {Conditioned taste aversions.}, journal = {World journal of otorhinolaryngology - head and neck surgery}, volume = {4}, number = {1}, pages = {92-100}, pmid = {30035267}, issn = {2589-1081}, abstract = {When one becomes ill after consuming a meal, there is a propensity to target a particular taste as the cause of the illness. The qualities of the taste most likely targeted include more novel, less preferred, and higher protein content. This association between a particular taste and illness is a form of learning that is termed conditioned taste aversion (CTA). A consequence of the learned association is that the taste will become aversive. When experiencing the taste again, individuals will show aversive reactions such as expressions of loathing, will experience mimicked illness sensations such as nausea, and subsequently, will avoid further exposure to the taste. The ability to acquire CTA occurs across species and across ages within a species. In the rat animal model, however, age differences exist in the capability of acquiring CTAs when increasingly longer intervals are imposed between consumption of a novel sweet solution and onset of illness. Pups have a decreased ability compared to young adults while aged rats have an increased ability. Evidence suggests that the failure of pups to acquire CTA at longer intervals is due to an immature retrieval mechanism and the facilitated ability of aged rats is due to a compromised clock mechanism that tracks the passage of time. Learned taste-illness association serves the critical function of informing individuals of the toxic nature of certain foods, thus preventing further illness and potentially death. Additionally, it contributes to the hypophagia observed during cancer chemotherapy and may contribute to the hypophagia found while suffering from bacterial infection, chronic medical conditions such as cancer, and restrictive food intake disorders such as anorexia nervosa.}, } @article {pmid30029019, year = {2018}, author = {Loney, GC and Pautassi, RM and Kapadia, D and Meyer, PJ}, title = {Nicotine affects ethanol-conditioned taste, but not place, aversion in a simultaneous conditioning procedure.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {71}, number = {}, pages = {47-55}, pmid = {30029019}, issn = {1873-6823}, support = {R01 AA024112/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Conditioning, Classical/*drug effects ; Cues ; Drug Interactions ; Ethanol/*pharmacology ; Male ; Motor Activity/drug effects ; Nicotine/*pharmacology ; Rats ; Taste Perception/*drug effects ; }, abstract = {The conditioned taste aversion (CTA) induced by ethanol is a key factor limiting ethanol intake. Nicotine, a drug co-consumed with ethanol, may decrease this aversion by modulating the unconditioned effects of ethanol or by disrupting the association between ethanol and its associated cues. This study analyzed ethanol-induced CTA and conditioned place aversion (CPA) in Long-Evans rats with subchronic exposure to nicotine. The rats were treated with nicotine (0.0 or 0.4 mg/kg) three times before conditioning (on lickometer training sessions 3, 4, and 5) and across conditioning days. During the conditioning the rats were given ethanol (1.3 g/kg) preceded and followed by presentation of a taste (NaCl) and tactile (rod or hole floors) conditioned stimulus (CS+), respectively. On CS- conditioning days, the rats were given vehicle and exposed to alternative stimuli. Three CTA and CPA testing sessions were then conducted. It was found that nicotine reduced ethanol-induced CTA and enhanced locomotor activity, but did not significantly modify the magnitude of ethanol-induced CPA. The effects of nicotine on CTA were observed during both conditioning and testing sessions, and were specific to the NaCl CS+, having no effect on reactivity to water. The dissociation between the effect of nicotine on ethanol-induced CTA and CPA suggests that nicotine does not alter ethanol's motivational properties by generally increasing its positive rewarding effects, nor does it blunt all aversive-like responses to this drug. Instead, nicotine may impede ethanol-induced CTA induced by ethanol by disrupting the neural underpinnings of this specific form of associative learning.}, } @article {pmid29996089, year = {2018}, author = {Lavi, K and Jacobson, GA and Rosenblum, K and Lüthi, A}, title = {Encoding of Conditioned Taste Aversion in Cortico-Amygdala Circuits.}, journal = {Cell reports}, volume = {24}, number = {2}, pages = {278-283}, doi = {10.1016/j.celrep.2018.06.053}, pmid = {29996089}, issn = {2211-1247}, mesh = {Amygdala/*physiology ; Animals ; Avoidance Learning/*physiology ; *Conditioning, Classical ; Imaging, Three-Dimensional ; Male ; Mice, Inbred C57BL ; Nerve Net/*physiology ; Taste/*physiology ; }, abstract = {Avoidance of potentially toxic food by means of conditioned taste aversion is critical for survival of many animals. However, the underlying neuronal mechanisms are poorly understood. Here, using two-photon calcium imaging of defined gustatory cortex neurons in vivo, we show that conditioned taste aversion dynamically shifts neuronal population coding by stimulus-specific recruitment of neurons that project to the basolateral amygdala.}, } @article {pmid29955564, year = {2018}, author = {Aonuma, H and Totani, Y and Sakakibara, M and Lukowiak, K and Ito, E}, title = {Comparison of brain monoamine content in three populations of Lymnaea that correlates with taste-aversive learning ability.}, journal = {Biophysics and physicobiology}, volume = {15}, number = {}, pages = {129-135}, pmid = {29955564}, issn = {2189-4779}, abstract = {To find a causal mechanism of learning and memory is a heuristically important topic in neuroscience. In the pond snail Lymnaea stagnalis, the following experimental facts have accrued regarding a classical conditioning procedure known as conditioned taste aversion (CTA): (1) one-day food-deprived Dutch snails have superior CTA memory formation; (2) the one-day food-deprived snails have a low monoamine content (e.g., serotonin, dopamine, octopamine) in their central nervous system (CNS); (3) fed or five-day food-deprived snails have poorer CTA memory and a higher monoamine content; (4) the Dutch snails form better CTA memory than the Canadian TC1 strain; and, (5) the F1 cross snails between the Dutch and Canadian TC1 strains also form poor CTA memory. Here, in one-day food-deprived snails, we measured the monoamine content in the CNSs of the 3 populations. In most instances, the monoamine content of the Dutch strain was lower than in the other two populations. The F1 cross snails had the highest monoamine content. A lower monoamine content is correlated with the better CTA memory formation.}, } @article {pmid29922201, year = {2018}, author = {Angulo, R}, title = {Pre-exposure Schedule Effects on Generalization of Taste Aversion and Palatability for Thirsty and Not Thirsty Rats.}, journal = {Frontiers in psychology}, volume = {9}, number = {}, pages = {878}, pmid = {29922201}, issn = {1664-1078}, abstract = {The study reported four experiments aiming to test the effects of the pre-exposure schedule and water deprivation on the generalization of a conditioned taste aversion in rats, with a particular focus on testing whether or not the concurrent schedule might enhance generalization. In two experiments, non-water-deprived rats received concurrent, intermixed, or blocked exposure to a sweet-acid solution and a salty-acid solution before conditioning of one of these compounds and testing of both flavors. During pre-exposure, the rats consumed a greater amount of the sweet-acid solution than the salty-acid solution (Experiments 1 and 2), consumption of the former increasing during pre-exposure while consumption of the latter decreased (Experiment 1). Furthermore, consumption of the salty-acid solution was lower during concurrent than intermixed or blocked pre-exposure (Experiment 1 and 2) while consumption of the sweet-acid solution was greater during intermixed than concurrent or blocked pre-exposure (Experiment 1). It is discussed whether the pre-exposure schedule might modify stimulus perception beyond the mere enhancement of stimulus differentiation, by, for instance, affecting the palatability of gustatory stimuli. Evidence for enhanced generalization after concurrent pre-exposure was not found for either deprived (Experiments 1, 2, and 3) or non-deprived rats (Experiments 3 and 4), with deprivation leading to a general increase in consumption of both the conditioned and test flavors. This then raised the question of whether or not concurrent pre-exposure to flavors always increases generalization between them. The present study highlights the importance of this issue for various accounts of perceptual learning.}, } @article {pmid29920309, year = {2019}, author = {Caynas-Rojas, S and Rodríguez-García, G and Delint-Ramírez, I and Miranda, MI}, title = {Differential function of medial prefrontal cortex catecholaminergic receptors after long-term sugar consumption.}, journal = {Behavioural brain research}, volume = {356}, number = {}, pages = {495-503}, doi = {10.1016/j.bbr.2018.06.009}, pmid = {29920309}, issn = {1872-7549}, mesh = {Animals ; Avoidance Learning/*drug effects ; Cerebral Cortex/physiology ; Conditioning, Classical/physiology ; Extinction, Psychological/drug effects ; Male ; Memory/*drug effects/physiology ; Prefrontal Cortex/*drug effects/physiology ; Propranolol/pharmacology ; Rats, Wistar ; Sugars/*adverse effects ; Taste/drug effects ; Time ; }, abstract = {The medial prefrontal cortex (mPFC) has reciprocal projections with many cerebral structures that are crucial in the control of food ingestion behavior and reward processing; Thus the mPFC has an important function in taste memory recognition. Previous results indicate that long-term consumption of sugar produces changes in appetitive re-learning and suggest that this could trigger an escalating consumption due to the inability to learn new negative consequences related to the same taste. Further evidence suggests that general identity reward value could be encoded in the mPFC. Therefore, the purpose of this study was to evaluate in rats whether after 21 days of sugar consumption the increase in sweet taste preference and latent inhibition of conditioned taste aversion (CTA) were affected differentially by pharmacological activation or blockage of dopaminergic and β-adrenergic receptors, in the mPFC, during CTA acquisition. Results showed that after long-term sugar exposure, mPFC activation of β-adrenergic receptors with clenbuterol delayed aversive memory extinction, but the blockade with propranolol or activation of dopaminergic receptors with apomorphine increased CTA latent inhibition and accelerated aversive memory extinction only after acute sugar exposure. Only dopaminergic blockade with haloperidol prevented sweet taste preference expression after long-term sugar consumption, increased CTA latent inhibition and accelerated extinction after acute sugar exposure. Taken together, the present data provide evidence that catecholaminergic receptors in the mPFC after prolonged sugar consumption underwent functional changes related to re-learning and new aversive taste learning.}, } @article {pmid29862893, year = {2020}, author = {Vera-Rivera, G and Miranda, MI and Rangel-Hernández, JA and Badillo-Juárez, D and Fregoso-Urrutia, D and Caynas-Rojas, S}, title = {Effects of caloric or non-caloric sweetener long-term consumption on taste preferences and new aversive learning.}, journal = {Nutritional neuroscience}, volume = {23}, number = {2}, pages = {128-138}, doi = {10.1080/1028415X.2018.1478654}, pmid = {29862893}, issn = {1476-8305}, mesh = {Animals ; Avoidance Learning/drug effects ; Conditioning, Classical/drug effects/physiology ; Dietary Sugars/*administration & dosage ; *Energy Intake ; Extinction, Psychological/drug effects ; Food Preferences/drug effects/*physiology ; Male ; Rats ; Rats, Wistar ; Saccharin/*administration & dosage ; Taste/drug effects/*physiology ; }, abstract = {Food palatability and caloric content are crucial factors in guiding diet choice and amount consumed; as a result, sweet caloric tastes are associated with a positive hedonic value. Recent evidence in rodents indicates that consumption of artificial (non-caloric) sweeteners, in which sweet taste is dissociated from normal caloric consequences, could induce changes in energy and body weight regulation, suggesting that sweeteners not only modify intake and appetitive behavior, but could also change taste-learning processes. Particularly, there are different properties in some artificial sweeteners, like saccharin, that might differ from sugar in the reward responses that, after long-term consumption, could also be associated with the inability to learn new negative consequences related to the same taste. Thus, the main goal of this study was to determine, in adult rats, the effects of long-term consumption (14 days) of sugar or saccharin, on taste preference, on new aversive learning, i.e. latent inhibition (LI) of conditioned taste aversion (CTA), and appetitive taste re-learning after aversive taste associations. The results showed that 14 days' exposure to sugar, but not to saccharin, induced a significant increment in the LI of CTA and that taste preference is rapidly recovered during the next 3 days (e.g. CTA extinctions), indicating that long-term sugar consumption significantly accelerates aversive memory extinction during appetitive re-learning of a specific sweet taste; furthermore, high familiarization to sugar, but not to saccharin, promotes appetitive learning for the same taste. Overall, the results indicate that long-term consumption of sugar, but not saccharin, produces changes in appetitive re-learning and suggests that long-term sugar consumption could trigger escalating consumption due to the inability to learn new negative consequences associated with the same taste.}, } @article {pmid29687910, year = {2018}, author = {Varnon, CA and Dinges, CW and Black, TE and Wells, H and Abramson, CI}, title = {Failure to Find Ethanol-Induced Conditioned Taste Aversion in Honey Bees (Apis mellifera L.).}, journal = {Alcoholism, clinical and experimental research}, volume = {42}, number = {7}, pages = {1260-1270}, pmid = {29687910}, issn = {1530-0277}, support = {P20 GM103499/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Bees ; Conditioning, Classical/*drug effects/physiology ; Ethanol/*administration & dosage ; Odorants ; Smell/drug effects/physiology ; Sucrose/administration & dosage ; Taste/*drug effects/physiology ; }, abstract = {BACKGROUND: Conditioned taste aversion (CTA) learning is a highly specialized form of conditioning found across taxa that leads to avoidance of an initially neutral stimulus, such as taste or odor, that is associated with, but is not the cause of, a detrimental health condition. This study examines if honey bees (Apis mellifera L.) develop ethanol (EtOH)-induced CTA.

METHODS: Restrained bees were first administered a sucrose solution that was cinnamon scented, lavender scented, or unscented, and contained either 0, 2.5, 5, 10, or 20% EtOH. Then, 30 minutes later, we used a proboscis extension response (PER) conditioning procedure where the bees were taught to associate either cinnamon odor, lavender odor, or an air-puff with repeated sucrose feedings. For some bees, the odor of the previously consumed EtOH solution was the same as the odor associated with sucrose in the conditioning procedure. If bees are able to learn EtOH-induced CTA, they should show an immediate low level of response to odors previously associated with EtOH.

RESULTS: We found that bees did not develop CTA despite the substantial inhibitory and aversive effects EtOH has on behavior. Instead, bees receiving a conditioning odor that was previously associated with EtOH showed an immediate high level of response. While this demonstrates bees are capable of one-trial learning common to CTA experiments, this high level of response is the opposite of what would occur if the bees developed a CTA. Responding on subsequent trials also showed a general inhibitory effect of EtOH. Finally, we found that consumption of cinnamon extract reduced the effects of EtOH.

CONCLUSIONS: The honey bees' lack of learned avoidance to EtOH mirrors that seen in human alcoholism. These findings demonstrate the usefulness of honey bees as an insect model for EtOH consumption.}, } @article {pmid29684475, year = {2018}, author = {Risco, S and Mediavilla, C}, title = {Orexin A in the ventral tegmental area enhances saccharin-induced conditioned flavor preference: The role of D1 receptors in central nucleus of amygdala.}, journal = {Behavioural brain research}, volume = {348}, number = {}, pages = {192-200}, doi = {10.1016/j.bbr.2018.04.010}, pmid = {29684475}, issn = {1872-7549}, mesh = {Animals ; Avoidance Learning/drug effects ; Central Amygdaloid Nucleus/metabolism ; Cerebellar Nuclei/metabolism ; Conditioning, Psychological/drug effects ; Dopamine Antagonists/pharmacology ; Dopamine D2 Receptor Antagonists/pharmacology ; Male ; Orexins/*metabolism/*physiology ; Rats ; Rats, Wistar ; Receptors, Dopamine D1 ; Receptors, Dopamine D2/metabolism ; Saccharin/pharmacology ; Taste/drug effects ; Ventral Tegmental Area/*drug effects ; }, abstract = {In industrialized societies, food intake is largely determined by its hedonic characteristics, which can be modified by our experience via taste learning. In this learning, the hedonic value of a neutral flavor changes after its association with a motivationally significant stimulus. Experiment 1 analyzes the effect of orexin administration (53 and 107 ng) in the ventral tegmental area (VTA) on hedonic intake through acquisition of a flavor-taste preference and a flavor-taste aversion. Accordingly, animals underwent four one-bottle acquisition sessions with unilateral application of orexin-A or saline in the VTA at 10 min before a 15-min flavor intake period. Preference and aversion were tested by a two-bottle test containing the flavors used for CS+ and CS-. Results indicate that intra-VTA orexin strengthens flavor-taste conditioned flavor preference (CFP) by saccharin but does not facilitate flavor-taste aversion induced by association of a neutral flavor with the unpalatable taste of quinine. Experiment 2 examines the acquisition of a flavor-taste preference after co-administration of an effective dose of orexin-A in the VTA and of D1-like dopamine receptor antagonist SCH23390 (6 and 12 nmol) in the central nucleus of the amygdala (CeA). SCH23390 impedes the CFP strengthening observed after intra-VTA orexin administration, indicating that this effect may be mediated by dopaminergic receptors in the CeA. These data suggest that the simultaneous presentation of a flavor and a hedonically positive taste may be detected by orexinergic neurons that activate dopamine-releasing neurons of the VTA, thereby reinforcing the positive signals required to develop a taste preference.}, } @article {pmid29672108, year = {2018}, author = {Koh, MT and Ahrens, PS and Gallagher, M}, title = {A greater tendency for representation mediated learning in a ketamine mouse model of schizophrenia.}, journal = {Behavioral neuroscience}, volume = {132}, number = {2}, pages = {106-113}, pmid = {29672108}, issn = {1939-0084}, support = {P50 MH094268/MH/NIMH NIH HHS/United States ; }, mesh = {Amphetamine/pharmacology ; Animals ; Antipsychotic Agents/pharmacology ; Central Nervous System Stimulants/pharmacology ; Delusions/drug therapy ; Disease Models, Animal ; Feeding Behavior/drug effects ; Hallucinations/drug therapy ; Ketamine ; *Learning ; Male ; Mice, Inbred C57BL ; Motor Activity/drug effects ; Olfactory Perception/drug effects ; Risperidone/pharmacology ; Schizophrenia/drug therapy ; *Schizophrenic Psychology ; }, abstract = {Representation mediated learning is a behavioral paradigm that could be used to potentially capture psychotic symptoms including hallucinations and delusions in schizophrenia. In studies of mediated learning, representations of prior experience can enter into current associations. Using a ketamine model of schizophrenia, we investigated whether mice exposed to ketamine during late adolescence subsequently showed an increased tendency to use a representation of a prior gustatory experience to form associations in learning. Mice were given prior experience of an odor and a taste presented together. The odor was subsequently presented alone with gastrointestinal illness induced by a lithium chloride injection. A consumption test was then given to assess whether the taste, despite its absence during conditioning, entered into an association with the induced illness. Such learning would be mediated via a representation of the taste activated by the odor. Our results showed that control mice displayed no aversion to the taste following the procedures just described, but mice that had been treated developmentally with ketamine exhibited a significant taste aversion, suggesting a greater propensity for mediated learning. Complementary to that finding, ketamine-exposed mice also showed a greater susceptibility to mediated extinction. Chronic treatment with the antipsychotic drug, risperidone, in ketamine-exposed mice attenuated mediated learning, a finding that may be related to its known efficacy in reducing the positive symptoms of schizophrenia. These data provide a setting with potential relevance to preclinical research on schizophrenia, to study the neural mechanisms underlying a propensity for aberrant associations and assessment of therapeutics. (PsycINFO Database Record}, } @article {pmid29631000, year = {2018}, author = {Rivera-Olvera, A and Nelson-Mora, J and Gonsebatt, ME and Escobar, ML}, title = {Extinction of aversive taste memory homeostatically prevents the maintenance of in vivo insular cortex LTP: Calcineurin participation.}, journal = {Neurobiology of learning and memory}, volume = {154}, number = {}, pages = {54-61}, doi = {10.1016/j.nlm.2018.04.005}, pmid = {29631000}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*physiology ; Basolateral Nuclear Complex/physiology ; Calcineurin/*physiology ; Cerebral Cortex/*physiology ; Extinction, Psychological/*physiology ; *Long-Term Potentiation ; Male ; Memory/*physiology ; Neural Pathways/physiology ; Rats, Wistar ; Taste ; Taste Perception ; }, abstract = {Accumulating evidence indicates that homeostatic plasticity mechanisms dynamically adjust synaptic strength to promote stability that is crucial for memory storage. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of long-term potentiation (LTP) in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. We have also reported that induction of LTP in the Bla-IC pathway modifies the CTA extinction. Memoryextinction involves the formation of a new associativememorythat inhibits a previously conditioned association. The aim of the present study was to analyze the effect of CTA extinction on the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, 48 h after CTA extinction animals received high frequency stimulation in order to induce IC-LTP. Our results show that extinction training allows the induction but not the maintenance of IC-LTP. In addition, with the purpose of exploring part of the mechanisms involved in this process and since a body of evidence suggests that protein phosphatase calcineurin (CaN) is involved in the extinction of some behavioral tasks, we analyzed the participation of this phosphatase. The present results show that extinction training increases the CaN expression in the IC, as well as that the inhibition of this phosphatase reverts the effects of the CTA-extinction on the IC-LTP. These findings reveal that CTA extinction promotes a homeostatic regulation of subsequent IC synaptic plasticity maintenance through increases in CaN levels.}, } @article {pmid29593595, year = {2018}, author = {Garcia-Burgos, D and Maglieri, S and Vögele, C and Munsch, S}, title = {How Does Food Taste in Anorexia and Bulimia Nervosa? A Protocol for a Quasi-Experimental, Cross-Sectional Design to Investigate Taste Aversion or Increased Hedonic Valence of Food in Eating Disorders.}, journal = {Frontiers in psychology}, volume = {9}, number = {}, pages = {264}, pmid = {29593595}, issn = {1664-1078}, abstract = {Background: Despite on-going efforts to better understand dysregulated eating, the olfactory-gustatory deficits and food preferences in eating disorders (ED), and the mechanisms underlying the perception of and responses to food properties in anorexia nervosa (AN) and bulimia nervosa (BN) remain largely unknown; both during the course of the illness and compared to healthy populations. It is, therefore, necessary to systematically investigate the gustatory perception and hedonics of taste in patients with AN and BN. To this end, we will examine whether aversions to the taste of high-calorie food is related to the suppression of energy intake in restricting-type AN, and whether an increased hedonic valence of sweet, caloric-dense foods may be part of the mechanisms triggering binge-eating episodes in BN. In addition, the role of cognitions influencing these mechanisms will be examined. Method: In study 1, four mixtures of sweet-fat stimuli will be presented in a sensory two-alternative forced-choice test involving signal detection analysis. In study 2, a full-scale taste reactivity test will be carried out, including psychophysiological and behavioral measures to assess subtle and covert hedonic changes. We will compare the responses of currently-ill AN and BN patients to those who have recovered from AN and BN, and also to those of healthy normal-weight and underweight individuals without any eating disorder pathology. Discussion: If taste response profiles are differentially linked to ED types, then future studies should investigate whether taste responsiveness represents a useful diagnostic measure in the prevention, assessment and treatment of EDs. The expected results on cognitive mechanisms in the top-down processes of food hedonics will complement current models and contribute to the refinement of interventions to change cognitive aspects of taste aversions, to establish functional food preferences and to better manage food cravings associated with binge-eating episodes. No trial registration was required for this protocol, which was approved by the Swiss ethics committee (CER-VD, n° 2016-02150) and the Ethics Review Panel of the University of Luxembourg.}, } @article {pmid29588172, year = {2018}, author = {Yoshida, Y and Kawabata, F and Kawabata, Y and Nishimura, S and Tabata, S}, title = {Short-term perception of and conditioned taste aversion to umami taste, and oral expression patterns of umami taste receptors in chickens.}, journal = {Physiology & behavior}, volume = {191}, number = {}, pages = {29-36}, doi = {10.1016/j.physbeh.2018.03.020}, pmid = {29588172}, issn = {1873-507X}, mesh = {Analysis of Variance ; Animals ; Animals, Newborn ; Avoidance Learning/drug effects/*physiology ; Chickens ; Dose-Response Relationship, Drug ; Gene Expression Regulation/*drug effects ; Glutamic Acid/pharmacology ; Inosine Monophosphate/*pharmacology ; Piperidines/pharmacology ; RNA, Messenger/metabolism ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Taste/drug effects/*physiology ; Taste Perception/drug effects/*physiology ; Time Factors ; }, abstract = {Umami taste is one of the five basic tastes (sweet, umami, bitter, sour, and salty), and is elicited by l-glutamate salts and 5'-ribonucleotides. In chickens, the elucidation of the umami taste sense is an important step in the production of new feedstuff for the animal industry. Although previous studies found that chickens show a preference for umami compounds in long-term behavioral tests, there are limitations to our understanding of the role of the umami taste sense in chicken oral tissues because the long-term tests partly reflected post-ingestive effects. Here, we performed a short-term test and observed agonists of chicken umami taste receptor, l-alanine and l-serine, affected the solution intakes of chickens. Using this method, we found that chickens could respond to umami solutions containing monosodium l-glutamate (MSG) + inosine 5'-monophosphate (IMP) within 5 min. We also demonstrated that chickens were successfully conditioned to avoid umami solution by the conditioned taste aversion test. It is noted that conditioning to umami solution was generalized to salty and sweet solutions. Thus, chickens may perceive umami taste as a salty- and sweet-like taste. In addition, we found that umami taste receptor candidates were differentially expressed in different regions of the chicken oral tissues. Taken together, the present results strongly suggest that chickens have a sense of umami taste and have umami taste receptors in their oral tissue.}, } @article {pmid29562120, year = {2017}, author = {Tingley, R and Ward-Fear, G and Schwarzkopf, L and Greenlees, MJ and Phillips, BL and Brown, G and Clulow, S and Webb, J and Capon, R and Sheppard, A and Strive, T and Tizard, M and Shine, R}, title = {New Weapons in the Toad Toolkit: A Review of Methods to Control and Mitigate the Biodiversity Impacts of Invasive Cane Toads (Rhinella Marina).}, journal = {The Quarterly review of biology}, volume = {92}, number = {2}, pages = {123-149}, doi = {10.1086/692167}, pmid = {29562120}, issn = {0033-5770}, mesh = {*Adaptation, Physiological ; Animals ; Australia ; *Biodiversity ; Bufo marinus/*physiology ; *Ecosystem ; *Introduced Species ; Pest Control/*methods ; Population Dynamics ; }, abstract = {Our best hope of developing innovative methods to combat invasive species is likely to come from the study of high-profile invaders that have attracted intensive research not only into control, but also basic biology. Here we illustrate that point by reviewing current thinking about novel ways to control one of the world’s most well-studied invasions: that of the cane toad in Australia. Recently developed methods for population suppression include more effective traps based on the toad’s acoustic and pheromonal biology. New tools for containing spread include surveillance technologies (e.g., eDNA sampling and automated call detectors), as well as landscape-level barriers that exploit the toad’s vulnerability to desiccation—a strategy that could be significantly enhanced through the introduction of sedentary, range-core genotypes ahead of the invasion front. New methods to reduce the ecological impacts of toads include conditioned taste aversion in free-ranging predators, gene banking, and targeted gene flow. Lastly, recent advances in gene editing and gene drive technology hold the promise of modifying toad phenotypes in ways that may facilitate control or buffer impact. Synergies between these approaches hold great promise for novel and more effective means to combat the toad invasion and its consequent impacts on biodiversity.}, } @article {pmid29560525, year = {2018}, author = {Brox, BW and Ellenbroek, BA}, title = {A genetic reduction in the serotonin transporter differentially influences MDMA and heroin induced behaviours.}, journal = {Psychopharmacology}, volume = {235}, number = {7}, pages = {1907-1914}, pmid = {29560525}, issn = {1432-2072}, mesh = {Analgesics, Opioid/administration & dosage ; Animals ; Avoidance Learning/*drug effects/physiology ; Behavior, Addictive/chemically induced/*genetics/metabolism ; Central Nervous System Stimulants/administration & dosage ; Dose-Response Relationship, Drug ; Heroin/*administration & dosage ; Locomotion/*drug effects/physiology ; Male ; N-Methyl-3,4-methylenedioxyamphetamine/*administration & dosage ; RNA-Binding Proteins/*genetics/metabolism ; Rats ; Rats, Transgenic ; Rats, Wistar ; Reinforcement, Psychology ; Self Administration ; Serotonin Agents/administration & dosage ; Taste/drug effects/physiology ; }, abstract = {BACKGROUND: Despite ongoing study and research to better understand drug addiction, it continues to be a heavy burden. Only a small percentage of individuals who take drugs of abuse go on to develop addiction. However, there is growing evidence to suggest that a reduction in the serotonin transporter may play an important role for those that transition to compulsive drug taking. Studies have demonstrated that reduced serotonin transporter function potentiates self-administration of psychostimulant drugs ("ecstasy," MDMA; cocaine); however, additional research revealed no differences between genotypes when the opioid heroin was self-administered. These results suggest that a reduction in the serotonin transporter may confer susceptibility to the development of addiction to some classes of drugs but not others. Importantly, the mechanism underlying facilitated psychostimulant self-administration is currently unknown.

METHODS: Therefore, to continue investigating the relationship between compromised serotonergic function and different classes of drugs, a series of experiments was conducted investigating locomotor activity (LMA) and conditioned taste aversion (CTA) in the serotonin transporter knockout (SERT KO) rat model.

RESULTS: MDMA-induced hyperactivity was reduced, while MDMA-induced CTA was enhanced, in SERT KO rats. However, there were no genotype differences in heroin-induced behaviours.

CONCLUSIONS: These results reinforce the idea that a reduction in the serotonin transporter drives differential effects between disparate classes of drugs of abuse.}, } @article {pmid29538098, year = {2018}, author = {Klockars, OA and Klockars, A and Levine, AS and Olszewski, PK}, title = {Oxytocin administration in the basolateral and central nuclei of amygdala moderately suppresses food intake.}, journal = {Neuroreport}, volume = {29}, number = {6}, pages = {504-510}, doi = {10.1097/WNR.0000000000001005}, pmid = {29538098}, issn = {1473-558X}, mesh = {Animals ; Avoidance Learning/drug effects ; Basolateral Nuclear Complex/*drug effects/metabolism ; Camphanes/pharmacology ; Central Amygdaloid Nucleus/*drug effects/metabolism ; Drinking/drug effects ; Eating/*drug effects ; Food Deprivation ; Male ; Oxytocics/*administration & dosage ; Oxytocin/*administration & dosage/antagonists & inhibitors ; Piperazines/pharmacology ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Oxytocin/genetics/metabolism ; Taste/drug effects ; }, abstract = {Oxytocin (OT) at acting central nuclei decreases meal size and reduces intake of palatable sweet solutions. It remains largely unclear as to which brain sites mediate OT's effect on palatability versus energy or the combination of those aspects of consumption. Here, we expanded the search for sites that mediate anorexigenic properties of OT by focusing on two subdivisions of the amygdala, its central (CNA) and basolateral (BLA) nuclei. We injected OT directly into the BLA or CNA in rats and assessed intake of standard chow induced by energy deprivation and intake of sweet solutions in nondeprived animals. We examined whether these effects are reversible by OT receptor (OTr) antagonism and whether OT presence in BLA or CNA induces taste aversion. We also determined the effect of energy deprivation and exposure to sweet saccharin on BLA and CNA expression of OTr mRNA. OT administration in BLA at 0.3 μg and in CNA at 1 μg reduced standard chow intake after deprivation by ~25%. Only administration of OT in BLA was effective in suppressing consumption of sucrose and saccharin solutions. The anorexigenic effects of OT in BLA and CNA were attenuated by OTr antagonist, L-368,899, pretreatment. OT at anorexigenic doses did not promote acquisition of taste aversion. BLA OTr mRNA expression was affected by exposure to palatable saccharin, whereas that of CNA OTr, by energy deprivation. OT in the amygdala moderately decreases food intake. The functional relationship between amygdalar OT and energy intake versus palatability-driven intake depends on the discrete localization of the OTr within this complex structure.}, } @article {pmid29499345, year = {2018}, author = {Richardson, RA and Michener, PN and Schachtman, TR}, title = {Effects of extinction of a nontarget CS on performance to a target CS.}, journal = {Behavioural processes}, volume = {154}, number = {}, pages = {13-20}, doi = {10.1016/j.beproc.2018.02.017}, pmid = {29499345}, issn = {1872-8308}, mesh = {Animals ; *Conditioning, Classical ; *Extinction, Psychological ; Male ; Rats ; Retrospective Studies ; }, abstract = {When a target conditioned stimulus (CS A) is paired with an unconditioned stimulus in the presence of a second, conditioned stimulus (CS B) during compound conditioning trials, the associative strength of CS B can influence the magnitude of the conditioned response (CR) to CS A. For example, extinction of the competing, nontarget CS B can influence the CR to CS A. An enhancement of the CR to the target CS A due to extinction of the nontarget CS B after compound conditioning is sometimes referred to as "recovery from overshadowing" - a type of retrospective revaluation. The present experiments examined retrospective revaluation effects using a conditioned taste aversion procedure. The experiments obtained an effect on the CR to CS A following extinction of CS B. The results are discussed with respect to the comparator hypothesis, within-compound associations, and retrieval as well as other relationships between the target CS and nontarget CS.}, } @article {pmid29486102, year = {2018}, author = {Dadam, F and Zádor, F and Caeiro, X and Szűcs, E and Erdei, AI and Samavati, R and Gáspár, R and Borsodi, A and Vivas, L}, title = {The effect of increased NaCl intake on rat brain endogenous μ-opioid receptor signalling.}, journal = {Journal of neuroendocrinology}, volume = {30}, number = {4}, pages = {e12585}, doi = {10.1111/jne.12585}, pmid = {29486102}, issn = {1365-2826}, mesh = {Animals ; Brain/*drug effects/metabolism ; Preoptic Area/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu/*metabolism ; Signal Transduction/*drug effects ; Sodium Chloride/*administration & dosage ; }, abstract = {Numerous studies demonstrate the significant role of central β-endorphin and its receptor, the μ-opioid receptor (MOR), in sodium intake regulation. The present study aimed to investigate the possible relationship between chronic high-NaCl intake and brain endogenous MOR functioning. We examined whether short-term (4 days) obligatory salt intake (2% NaCl solution) in rats induces changes in MOR mRNA expression, G-protein activity and MOR binding capacity in brain regions involved in salt intake regulation. Plasma osmolality and electrolyte concentrations after sodium overload and the initial and final body weight of the animals were also examined. After 4 days of obligatory hypertonic sodium chloride intake, there was clearly no difference in MOR mRNA expression and G-protein activity in the median preoptic nucleus (MnPO). In the brainstem, MOR binding capacity also remained unaltered, although the maximal efficacy of MOR G-protein significantly increased. Finally, no significant alterations were observed in plasma osmolality and electrolyte concentrations. Interestingly, animals that received sodium gained significantly less weight than control animals. In conclusion, we found no significant alterations in the MnPO and brainstem in the number of available cell surface MORs or de novo syntheses of MOR after hypertonic sodium intake. The increased MOR G-protein activity following acute sodium overconsumption may participate in the maintenance of normal blood pressure levels and/or in enhancing sodium taste aversion and sodium overload-induced anorexia.}, } @article {pmid29471071, year = {2018}, author = {Gartner, SN and Aidney, F and Klockars, A and Prosser, C and Carpenter, EA and Isgrove, K and Levine, AS and Olszewski, PK}, title = {Intragastric preloads of l-tryptophan reduce ingestive behavior via oxytocinergic neural mechanisms in male mice.}, journal = {Appetite}, volume = {125}, number = {}, pages = {278-286}, doi = {10.1016/j.appet.2018.02.015}, pmid = {29471071}, issn = {1095-8304}, mesh = {Animals ; Appetite/*drug effects ; Brain/cytology/*drug effects ; Dietary Fats/administration & dosage ; Dietary Sucrose/administration & dosage ; Dietary Supplements ; Drinking/drug effects ; Eating/*drug effects ; Energy Intake/*drug effects ; Feeding Behavior/*drug effects ; Food Deprivation ; Lipids/administration & dosage ; Male ; Mice, Inbred C57BL ; Oxytocin/*agonists ; Receptors, Oxytocin/metabolism ; Saccharin/administration & dosage ; Satiety Response/drug effects ; Sweetening Agents/administration & dosage ; Taste ; Thirst ; Tryptophan/*pharmacology ; Water ; }, abstract = {Human and laboratory animal studies suggest that dietary supplementation of a free essential amino acid, l-tryptophan (TRP), reduces food intake. It is unclear whether an acute gastric preload of TRP decreases consumption and whether central mechanisms underlie TRP-driven hypophagia. We examined the effect of TRP administered via intragastric gavage on energy- and palatability-induced feeding in mice. We sought to identify central mechanisms through which TRP suppresses appetite. Effects of TRP on consumption of energy-dense and energy-dilute tastants were established in mice stimulated to eat by energy deprivation or palatability. A conditioned taste aversion (CTA) paradigm was used to assess whether hypophagia is unrelated to sickness. c-Fos immunohistochemistry was employed to detect TRP-induced activation of feeding-related brain sites and of oxytocin (OT) neurons, a crucial component of satiety circuits. Also, expression of OT mRNA was assessed with real-time PCR. The functional importance of OT in mediating TRP-driven hypophagia was substantiated by showing the ability of OT receptor blockade to abolish TRP-induced decrease in feeding. TRP reduced intake of energy-dense standard chow in deprived animals and energy-dense palatable chow in sated mice. Anorexigenic doses of TRP did not cause a CTA. TRP failed to affect intake of palatable yet calorie-dilute or noncaloric solutions (10% sucrose, 4.1% Intralipid or 0.1% saccharin) even for TRP doses that decreased water intake in thirsty mice. Fos analysis revealed that TRP increases activation of several key feeding-related brain areas, especially in the brain stem and hypothalamus. TRP activated hypothalamic OT neurons and increased OT mRNA levels, whereas pretreatment with an OT antagonist abolished TRP-driven hypophagia. We conclude that intragastric TRP decreases food and water intake, and TRP-induced hypophagia is partially mediated via central circuits that encompass OT.}, } @article {pmid29469954, year = {2018}, author = {Blednov, YA and Da Costa, AJ and Harris, RA and Messing, RO}, title = {Apremilast Alters Behavioral Responses to Ethanol in Mice: II. Increased Sedation, Intoxication, and Reduced Acute Functional Tolerance.}, journal = {Alcoholism, clinical and experimental research}, volume = {42}, number = {5}, pages = {939-951}, pmid = {29469954}, issn = {1530-0277}, support = {R01 AA006399/AA/NIAAA NIH HHS/United States ; R37 AA006399/AA/NIAAA NIH HHS/United States ; U01 AA013520/AA/NIAAA NIH HHS/United States ; }, mesh = {*Alcoholic Intoxication ; Animals ; Behavior, Animal/*drug effects ; Drug Interactions ; Drug Tolerance ; Ethanol/antagonists & inhibitors/pharmacology ; Female ; Hypnotics and Sedatives/pharmacology ; Male ; Mice ; Thalidomide/*analogs & derivatives/pharmacology ; }, abstract = {BACKGROUND: In our companion paper, we reported that the phosphodiesterase type 4 inhibitor apremilast reduced ethanol (EtOH) intake and preference in different drinking models in male and female C57BL/6J mice. In this study, we measured the effects of apremilast on other behaviors that are correlated with EtOH consumption.

METHODS: The effects of apremilast (20 mg/kg) on the following behaviors were studied in male and female C57BL/6J mice: locomotor response to a novel situation; EtOH- and lithium chloride (LiCl)-induced conditioned taste aversion (CTA) to saccharin; conditioned place preference (CPP) and conditioned place avoidance (CPA) to EtOH; severity of handling-induced convulsions after EtOH administration; EtOH-induced anxiolytic-like behavior in the elevated plus maze; duration of EtOH-induced loss of righting reflex (LORR); recovery from EtOH-induced motor impairment on the rotarod; and acute functional tolerance (AFT) to EtOH's ataxic effects.

RESULTS: Apremilast did not change the acquisition of EtOH-induced CPP, severity of acute withdrawal from EtOH, or EtOH's anxiolytic-like effect. Apremilast did not alter the extinction of EtOH- or LiCl-induced CTA, but may interfere with acquisition of CTA to EtOH. Apremilast increased the acquisition of CPA to EtOH, reduced locomotor responses to a novel situation, and prolonged the duration of LORR and the recovery from acute motor incoordination induced by EtOH. The longer recovery from the ataxic effect may be attributed to reduced development of AFT to EtOH.

CONCLUSIONS: Our results suggest that apremilast increases the duration of EtOH intoxication by reducing AFT. Apremilast also reduces some aspects of general reward and increases EtOH's aversive properties, which might also contribute to its ability to reduce EtOH drinking.}, } @article {pmid29452828, year = {2018}, author = {Tooley, J and Marconi, L and Alipio, JB and Matikainen-Ankney, B and Georgiou, P and Kravitz, AV and Creed, MC}, title = {Glutamatergic Ventral Pallidal Neurons Modulate Activity of the Habenula-Tegmental Circuitry and Constrain Reward Seeking.}, journal = {Biological psychiatry}, volume = {83}, number = {12}, pages = {1012-1023}, pmid = {29452828}, issn = {1873-2402}, support = {R25 GM055036/GM/NIGMS NIH HHS/United States ; Z99 DK999999//Intramural NIH HHS/United States ; }, mesh = {Action Potentials/drug effects/genetics ; Animals ; Avoidance Learning/physiology ; Bacterial Proteins/genetics/metabolism ; Basal Forebrain/*cytology ; Channelrhodopsins/genetics/metabolism ; Choline O-Acetyltransferase/genetics/metabolism ; Conditioning, Operant/physiology ; Dopamine/metabolism ; Excitatory Amino Acid Agents/pharmacology ; Excitatory Postsynaptic Potentials/drug effects/genetics ; Female ; Glutamic Acid/*metabolism/pharmacology ; Habenula/*physiology ; Luminescent Proteins/genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons/*physiology ; Optogenetics ; Parvalbumins/genetics/metabolism ; Patch-Clamp Techniques ; *Reward ; Taste ; Transduction, Genetic ; Ventral Tegmental Area/*physiology ; Vesicular Glutamate Transport Protein 2/genetics/metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins/genetics/metabolism ; gamma-Aminobutyric Acid/metabolism ; }, abstract = {BACKGROUND: The ability to appropriately integrate and respond to rewarding and aversive stimuli is essential for survival. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. However, the VP is a heterogeneous structure, and how VP subpopulations integrate into larger reward networks to ultimately modulate these behaviors is not known. We identify a noncanonical population of glutamatergic VP neurons that play a unique role in responding to aversive stimuli and constraining inappropriate reward seeking.

METHODS: Using neurochemical, genetic, and electrophysiological approaches, we characterized glutamatergic VP neurons (n = 4-8 mice/group). We performed patch clamp and in vivo electrophysiology recordings in the lateral habenula, rostromedial tegmental nucleus, and ventral tegmental area to determine the effect of glutamatergic VP neuron activation in these target regions (n = 6-10 mice/group). Finally, we selectively optogenetically stimulated glutamatergic VP neurons in a real-time place preference task and ablated these neurons using a virally expressed caspase to determine their necessity for reward seeking.

RESULTS: Glutamatergic VP neurons exhibit little overlap with cholinergic or gamma-aminobutyric acidergic markers, the canonical VP subtypes, and exhibit distinct membrane properties. Glutamatergic VP neurons innervate and increase firing activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons. While nonselective optogenetic stimulation of the VP induced a robust place preference, selective activation of glutamatergic VP neurons induced a place avoidance. Viral ablation of glutamatergic VP neurons increased reward responding and abolished taste aversion to sucrose.

CONCLUSIONS: Glutamatergic VP neurons constitute a noncanonical subpopulation of VP neurons. These glutamatergic VP neurons increase activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons and adaptively constrain reward seeking.}, } @article {pmid29447835, year = {2018}, author = {Nakajima, S}, title = {Clay eating attenuates lithium-based taste aversion learning in rats: A remedial effect of kaolin on nausea.}, journal = {Physiology & behavior}, volume = {188}, number = {}, pages = {199-204}, doi = {10.1016/j.physbeh.2018.02.020}, pmid = {29447835}, issn = {1873-507X}, mesh = {Analysis of Variance ; Animals ; Antidiarrheals/*therapeutic use ; Antimanic Agents/toxicity ; Avoidance Learning/*drug effects ; Body Weight/drug effects ; Eating/drug effects ; Kaolin/*therapeutic use ; Lithium Chloride/toxicity ; Male ; Nausea/chemically induced/*drug therapy ; Rats ; Rats, Wistar ; Taste/*drug effects ; }, abstract = {Kaolin clay eating has been considered as a marker of nausea in rats, because a variety of treatments, which evoke nausea in humans, generate consumption of kaolin clay in rats. The present study with two experiments replicated kaolin clay ingestion induced by an injection of emetic lithium chloride (LiCl). The LiCl injection, however, did not generate eating of wooden objects in rats. The present study also provides a new finding that consumption of kaolin clay alleviates rats' taste aversion learning caused by an LiCl injection. This finding is congruent with the contention that consumption of kaolin clay is not only a useful index of, but also an effective remedy for, drug-induced nausea in rats.}, } @article {pmid29403379, year = {2017}, author = {Reed, C and Baba, H and Zhu, Z and Erk, J and Mootz, JR and Varra, NM and Williams, RW and Phillips, TJ}, title = {A Spontaneous Mutation in Taar1 Impacts Methamphetamine-Related Traits Exclusively in DBA/2 Mice from a Single Vendor.}, journal = {Frontiers in pharmacology}, volume = {8}, number = {}, pages = {993}, pmid = {29403379}, issn = {1663-9812}, support = {T32 DA007262/DA/NIDA NIH HHS/United States ; R01 DA034388/DA/NIDA NIH HHS/United States ; U01 DA041579/DA/NIDA NIH HHS/United States ; P50 DA018165/DA/NIDA NIH HHS/United States ; R24 AA020245/AA/NIAAA NIH HHS/United States ; I01 BX002106/BX/BLRD VA/United States ; }, abstract = {Major gene effects on traits associated with substance use disorders are rare. Previous findings in methamphetamine drinking (MADR) lines of mice, bred for high or low voluntary MA intake, and in null mutants demonstrate a major impact of the trace amine-associated receptor 1 (Taar1) gene on a triad of MA-related traits: MA consumption, MA-induced conditioned taste aversion and MA-induced hypothermia. While inbred strains are fundamentally genetically stable, rare spontaneous mutations can become fixed and result in new or aberrant phenotypes. A single nucleotide polymorphism in Taar1 that encodes a missense proline to threonine mutation in the second transmembrane domain (Taar1[m1J]) has been identified in the DBA/2J strain. MA is an agonist at this receptor, but the receptor produced by Taar1[m1J] does not respond to MA or endogenous ligands. In the present study, we used progeny of the C57BL/6J × DBA/2J F2 cross, the MADR lines, C57BL/6J × DBA/2J recombinant inbred strains, and DBA/2 mice sourced from four vendors to further examine Taar1-MA phenotype relations and to define the chronology of the fixation of the Taar1[m1J] mutation. Mice homozygous for Taar1[m1J] were found at high frequency early in selection for high MA intake in multiple replicates of the high MADR line, whereas Taar1[m1J] homozygotes were absent in the low MADR line. The homozygous Taar1[m1J] genotype is causally linked to increased MA intake, reduced MA-induced conditioned taste aversion, and reduced MA-induced hypothermia across models. Genotype-phenotype correlations range from 0.68 to 0.96. This Taar1 polymorphism exists in DBA/2J mice sourced directly from The Jackson Laboratory, but not DBA/2 mice sourced from Charles River (DBA/2NCrl), Envigo (formerly Harlan Sprague Dawley; DBA/2NHsd) or Taconic (DBA/2NTac). By genotyping archived samples from The Jackson Laboratory, we have determined that this mutation arose in 2001-2003. Our data strengthen the conclusion that the mutant Taar1[m1J] allele, which codes for a non-functional receptor protein, increases risk for multiple MA-related traits, including MA intake, in homozygous Taar1[m1J] individuals.}, } @article {pmid29326059, year = {2018}, author = {Guzmán-Ramos, K and Venkataraman, A and Morin, JP and Osorio-Gómez, D and Bermúdez-Rattoni, F}, title = {Differential requirement of de novo Arc protein synthesis in the insular cortex and the amygdala for safe and aversive taste long-term memory formation.}, journal = {Behavioural brain research}, volume = {342}, number = {}, pages = {89-93}, doi = {10.1016/j.bbr.2018.01.006}, pmid = {29326059}, issn = {1872-7549}, mesh = {Amygdala/drug effects/physiology ; Animals ; Avoidance Learning/drug effects ; Cerebral Cortex/drug effects/physiology ; Conditioning, Classical/physiology ; Cytoskeletal Proteins/biosynthesis/*metabolism ; Male ; Memory/physiology ; Memory, Long-Term/*physiology ; Nerve Tissue Proteins/biosynthesis/*metabolism ; Rats ; Rats, Wistar ; Saccharin/administration & dosage ; Taste/*drug effects/physiology ; }, abstract = {Several immediate early genes products are known to be involved in the facilitation of structural and functional modifications at distinct synapses activated through experience. The IEG-encoded protein Arc (activity regulated cytoskeletal-associated protein) has been widely implicated in long-term memory formation and stabilization. In this study, we sought to evaluate a possible role for de novo Arc protein synthesis in the insular cortex (IC) and in the amygdala (AMY) during long-term taste memory formation. We found that acute inhibition of Arc protein synthesis through the infusion of antisense oligonucleotides administered in the IC before a novel taste presentation, affected consolidation of a safe taste memory trace (ST) but spared consolidation of conditioned taste aversion (CTA). Conversely, blocking Arc synthesis within the AMY impaired CTA consolidation but had no effect on ST long-term memory formation. Our results suggest that Arc-dependent plasticity during taste learning is required within distinct structures of the medial temporal lobe, depending on the emotional valence of the memory trace.}, } @article {pmid29294381, year = {2018}, author = {Aonuma, H and Totani, Y and Kaneda, M and Nakamura, R and Watanabe, T and Hatakeyama, D and Dyakonova, VE and Lukowiak, K and Ito, E}, title = {Effects of 5-HT and insulin on learning and memory formation in food-deprived snails.}, journal = {Neurobiology of learning and memory}, volume = {148}, number = {}, pages = {20-29}, doi = {10.1016/j.nlm.2017.12.010}, pmid = {29294381}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Behavior, Animal/drug effects/*physiology ; Central Nervous System/drug effects/*metabolism ; *Cognitive Dysfunction/drug therapy/etiology/metabolism/physiopathology ; Conditioning, Psychological/drug effects/*physiology ; Food Deprivation/*physiology ; Hypoglycemic Agents/administration & dosage/*pharmacology ; Insulin/administration & dosage/*pharmacology ; Lymnaea/drug effects/metabolism/*physiology ; Memory, Long-Term/drug effects/*physiology ; Serotonin/*metabolism ; Taste Perception/drug effects/*physiology ; Time Factors ; }, abstract = {The pond snail Lymnaea stagnalis learns conditioned taste aversion (CTA) and consolidates it into long-term memory (LTM). How well they learn and form memory depends on the degree of food deprivation. Serotonin (5-HT) plays an important role in mediating feeding, and insulin enhances the memory consolidation process following CTA training. However, the relationship between these two signaling pathways has not been addressed. We measured the 5-HT content in the central nervous system (CNS) of snails subjected to different durations of food deprivation. One-day food-deprived snails, which exhibit the best learning and memory, had the lowest 5-HT content in the CNS, whereas 5-day food-deprived snails, which do not learn, had a high 5-HT content. Immersing 1-day food-deprived snails in 5-HT impaired learning and memory by causing an increase in 5-HT content, and that the injection of insulin into these snails reversed this impairment. We conclude that insulin rescues the CTA deficit and this may be due to a decrease in the 5-HT content in the CNS of Lymnaea.}, } @article {pmid29254662, year = {2018}, author = {Li, N and Song, G and Wang, Y and Zhu, Q and Han, F and Zhang, C and Zhou, Y}, title = {Blocking constitutive activity of GHSR1a in the lateral amygdala facilitates acquisition of conditioned taste aversion.}, journal = {Neuropeptides}, volume = {68}, number = {}, pages = {22-27}, doi = {10.1016/j.npep.2017.12.001}, pmid = {29254662}, issn = {1532-2785}, mesh = {Animals ; *Avoidance Learning ; Basolateral Nuclear Complex/*physiology ; *Conditioning, Classical ; Ghrelin/administration & dosage/physiology ; Male ; Mental Recall/drug effects ; Rats, Wistar ; Receptors, Ghrelin/antagonists & inhibitors/*physiology ; }, abstract = {Ghrelin is a circulating peptide hormone promoting feeding and regulating energy metabolism in human and rodents. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), which are widely distributed throughout the brain including the amygdala, a brain region important for regulating valenced behavior, such as aversion. Interestingly, GHSR1a was once characterized by highly constitutive, ligand-independent activity. However, the physiological importance of such ligand-independent signaling on aversive memory processing has not been tested yet. Here, we applied [D-Arg[1], D-Phe[5], D-Trp[7,9], Leu[11]]-Substance P (D-SP), a full inverse agonist for GHSR1a, into the lateral amygdala (LA) and investigated the effect of blocking GHSR1a constitutive activity on conditioned taste aversion (CTA) in rats. We found that intra-LA infusion of a single low dose of D-SP (8ng/0.5μl/side) facilitates CTA acquisition. Moreover, pre-administration of a high dose of D-SP into the LA abolishes the suppressive effect of exogenous ghrelin on CTA acquisition. In contrast, pre-administration of the same dose of D-SP does not affect the suppression of substance P, a potent neurokinin-1 (NK1) receptor ligand, on CTA. Therefore, our data indicated that the spontaneous or basal activity of GHSR1a signaling in the LA might interfere with CTA memory formation. D-SP decreases the constitutive activity of GHSR1a and thus facilitates CTA. Altogether, our present findings along with previous results support the idea that ghrelin/GHSR1a signaling in the LA circuit blocks conditioned taste aversion.}, } @article {pmid29184500, year = {2017}, author = {Juárez-Muñoz, Y and Ramos-Languren, LE and Escobar, ML}, title = {CaMKII Requirement for in Vivo Insular Cortex LTP Maintenance and CTA Memory Persistence.}, journal = {Frontiers in pharmacology}, volume = {8}, number = {}, pages = {822}, pmid = {29184500}, issn = {1663-9812}, abstract = {Calcium-calmodulin/dependent protein kinase II (CaMKII) plays an essential role in LTP induction, but since it has the capacity to remain persistently activated even after the decay of external stimuli it has been proposed that it can also be necessary for LTP maintenance and therefore for memory persistence. It has been shown that basolateral amygdaloid nucleus (Bla) stimulation induces long-term potentiation (LTP) in the insular cortex (IC), a neocortical region implicated in the acquisition and retention of conditioned taste aversion (CTA). Our previous studies have demonstrated that induction of LTP in the Bla-IC pathway before CTA training increased the retention of this task. Although it is known that IC-LTP induction and CTA consolidation share similar molecular mechanisms, little is known about the molecular actors that underlie their maintenance. The purpose of the present study was to evaluate the role of CaMKII in the maintenance of in vivo Bla-IC LTP as well as in the persistence of CTA long-term memory (LTM). Our results show that acute microinfusion of myr-CaMKIINtide, a selective inhibitor of CaMKII, in the IC of adult rats during the late-phase of in vivo Bla-IC LTP blocked its maintenance. Moreover, the intracortical inhibition of CaMKII 24 h after CTA acquisition impairs CTA-LTM persistence. Together these results indicate that CaMKII is a central key component for the maintenance of neocortical synaptic plasticity as well as for persistence of CTA-LTM.}, } @article {pmid29182614, year = {2017}, author = {Hurtado, MM and García, R and Puerto, A}, title = {Tiapride prevents the aversive but not the rewarding effect induced by parabrachial electrical stimulation in a place preference task.}, journal = {Acta neurobiologiae experimentalis}, volume = {77}, number = {3}, pages = {236-243}, pmid = {29182614}, issn = {1689-0035}, mesh = {Analysis of Variance ; Animals ; Antipsychotic Agents/*pharmacology ; Avoidance Learning/*drug effects ; Conditioning, Operant/*drug effects ; Dose-Response Relationship, Drug ; Electric Stimulation/methods ; Male ; Maze Learning/drug effects ; Parabrachial Nucleus/*physiology ; Random Allocation ; Rats ; Rats, Wistar ; *Reward ; Tiapride Hydrochloride/*pharmacology ; }, abstract = {The parabrachial complex has been related to the processing of both rewarding and aversive signals. This pontine area is activated after the gastrointestinal administration of rewarding nutrients, in taste aversion learning, and in response to the reinforcing and aversive effects of some drugs of abuse. Electrical stimulation of this region can induce, in different animals, preference or aversion behaviors towards a place in a rectangular three-chamber maze task. This study examined the effect of tiapride, a D2/D3 receptor antagonist, on the aversive or rewarding effects induced by electrical stimulation of the external lateral parabrachial subnucleus (NLPBe). As previously observed, administration of tiapride interrupted the aversive effect induced by NLPBe electrical stimulation. However, in contrast to the effects of dopamine antagonists on other rewarding systems, tiapride did not impair the place preference induced by NLPBe stimulation, an activation effect that is subject to tolerance. Tiapride administration also appeared to have no effect on the horizontal motor activity (crossings) of the electrically stimulated animals. We discuss the specific relevance of parabrachial reward with respect to other reinforcing brain components or systems, especially in relation to the preference effect of drugs of abuse, such as opiates, after dopamine antagonist administration.}, } @article {pmid29176267, year = {2018}, author = {Hojo, R and Takaya, M and Yasuda, A and Tsuchiya, M and Ogawa, Y}, title = {Examination of validity of a conditioned odor aversion (COA) procedure using low-dose of organic solvent as an applied procedure of the conditioned taste aversion.}, journal = {Industrial health}, volume = {56}, number = {2}, pages = {141-149}, pmid = {29176267}, issn = {1880-8026}, mesh = {Animals ; Avoidance Learning/physiology ; Conditioning, Classical/physiology ; Lithium Chloride/administration & dosage ; Male ; Rats, Sprague-Dawley ; Smell/*physiology ; Taste/*physiology ; *Xylenes ; }, abstract = {Smell of very low dose of chemical might evoke subjective physical symptoms in human by some process of learning named the aversion conditioning. But few scientific evidences of the hypothesis have been reported so far. Validity of conditioned odor aversion (COA) using low-doses of organic solvent as odor conditioned stimulus (CS) was examined. In conditioning phase, water-deprived male Sprague-Dawley rats were presented low, medium or high dose solution for 30 min followed by 0.3 M Lithium Chloride (LiCl) solution or saline injection. The xylene solution and drink water were simultaneously provided on the next day as two-bottle test. Consumption of medium dose of xylene solution was significantly decreased in LiCl injection group as compared with saline group. There was no difference between LiCl and saline injected animals in low group. Animals in high dose did not access to xylene even on the conditioning. These results indicate that animals showed high sensitivity for discrimination against concentration of xylene and that the medium dose of xylene functioned as the CS. We concluded that the COA used in the present study may be one of useful procedures to investigate olfaction of animal.}, } @article {pmid29126997, year = {2018}, author = {Molero-Chamizo, A}, title = {Changes in the time of day of conditioning with respect to the pre-exposure interfere with the latent inhibition of conditioned taste aversion in rats.}, journal = {Behavioural processes}, volume = {146}, number = {}, pages = {22-26}, doi = {10.1016/j.beproc.2017.11.003}, pmid = {29126997}, issn = {1872-8308}, mesh = {Animals ; Avoidance Learning/*physiology ; Conditioning, Classical/*physiology ; Cues ; Male ; Memory/physiology ; Rats ; Rats, Wistar ; Taste/*physiology ; Time Factors ; }, abstract = {In rats, the reduction of the magnitude of a conditioned taste aversion (CTA) that occurs after taste pre-exposures (that is, the latent inhibition of CTA) can be attenuated by contextual changes of the external cues in the conditioning stage. Similarly, circadian internal cues such as those induced by the time of day may also modulate the magnitude of the taste aversion. Under a long period of temporal-contextual habituation, the latent inhibition of CTA is reduced if the pre-exposure and conditioning stages occur at different times of day. However, it is unknown if this effect is consistent when different changes in the time of day of conditioning with respect to the pre-exposure are compared. In this study, the effect of two different changes in the time of day of conditioning (one from morning to evening, and one from evening to morning) on the latent inhibition of CTA was compared with the response of a typical latent inhibition group without temporal change between stages, and with control groups without pre-exposures. The results indicate that the latent inhibition of CTA of both groups with temporal change between pre-exposure and conditioning is significantly reduced when compared with the latent inhibition of the group without temporal change. These findings suggest that the temporal context may be a critical cue for the latent inhibition of CTA, and they show that different changes in the time of day of conditioning interfere similarly with this learning.}, } @article {pmid29124570, year = {2018}, author = {Kislal, S and Blizard, DA}, title = {Acquisition and retention of conditioned aversions to context and taste in laboratory mice.}, journal = {Learning & behavior}, volume = {46}, number = {2}, pages = {198-212}, pmid = {29124570}, issn = {1543-4508}, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Conditioning, Classical/drug effects/*physiology ; Extinction, Psychological/*physiology ; Lithium Chloride/pharmacology ; Male ; Mice ; Retention, Psychology/drug effects/*physiology ; Taste/drug effects/*physiology ; }, abstract = {We compared the rate of acquisition and strength of retention of conditioned context aversion (CCA) with conditioned taste aversion (CTA) using pigmented, genetically heterogeneous mice (derived from Large and Small strains). Extending previous findings, in Experiment 1, mice accustomed to drinking from large glass bottles in the colony room learned to avoid graduated tubes after a single conditioning trial when drinking from these novel tubes was paired with injections of LiCl. The results also showed that CCA could be developed even when there was a 30-minute delay between conditioned stimulus and unconditioned stimulus. Retention of the aversion lasted for 4 weeks in both Immediate and Delay groups. Studies of conditioned saccharin aversion were conducted in Experiment 2. CTA acquisition was very similar to that observed in CCA and duration of aversion retention was similar in the CCA and CTA Delay groups, although at least 2 weeks longer in the Immediate group. Thus, CCA acquisition and retention characteristics are closer to those seen for CTA than has previously been reported. In Experiment 3, we examined whether albino mice (which are known to have weaker visual abilities compared to pigmented mice) would develop CCA comparable to those of pigmented mice. The development of conditioned aversion and its duration of retention was similar in albinos and pigmented mice. Nonspecific aversion emerged as an important contributor to strength of aversion during retention trials in both CCA and CTA paradigms with pigmented (but not albino) mice and deserves additional scrutiny in this field of inquiry.}, } @article {pmid29124569, year = {2018}, author = {Nakajima, S}, title = {Running-based pica and taste avoidance in rats.}, journal = {Learning & behavior}, volume = {46}, number = {2}, pages = {182-197}, pmid = {29124569}, issn = {1543-4508}, mesh = {Animals ; Avoidance Learning/*physiology ; Behavior, Animal/*physiology ; Feeding Behavior/*physiology ; Male ; Motor Activity/*physiology ; *Pica ; Rats ; Taste/*physiology ; }, abstract = {Running in an activity wheel generates pica behavior (kaolin clay intake) in rats. Wheel running also results in Pavlovian conditioned avoidance of the taste solution consumed immediately before the running. Since pica has been considered a behavioral marker of nausea in rats, these findings suggest that wheel running induces nausea, which is the underlying physiological state for establishing taste avoidance. This article reports a replication of running-based pica in rats (Experiment 1) and concurrent demonstrations of running-based pica and taste avoidance in the same animals (Experiments 2 and 3). Also shown is that pica does not alleviate running-based taste avoidance (Experiment 3). Another finding is that pica is generated by a nausea-inducing lithium chloride injection but not by a pain-inducing hypertonic saline injection (Experiment 4). These results, when taken together, support the hypothesis that pica behavior generated by wheel running reflects nausea in rats.}, } @article {pmid29104056, year = {2018}, author = {Cheung, LC and Nguyen, M and Tang, E and von Ungern Sternberg, BS and Salman, S and Tuleu, C and Mohamed Ahmed, AHA and Soto, J and Lim, LY}, title = {Taste evaluation of a novel midazolam tablet for pediatric patients: In vitro drug dissolution, in vivo animal taste aversion and clinical taste perception profiles.}, journal = {International journal of pharmaceutics}, volume = {535}, number = {1-2}, pages = {194-200}, doi = {10.1016/j.ijpharm.2017.10.060}, pmid = {29104056}, issn = {1873-3476}, mesh = {Administration, Oral ; Adolescent ; Animals ; Child ; Child, Preschool ; *Chocolate ; Drug Compounding ; Drug Liberation ; Facial Expression ; Feeding Behavior/*drug effects ; Flavoring Agents/*chemistry ; Humans ; Hypnotics and Sedatives/*administration & dosage/chemistry ; Injections, Intravenous ; Male ; Midazolam/*administration & dosage/chemistry ; Prospective Studies ; Rats, Sprague-Dawley ; Tablets ; Taste Perception/*drug effects ; }, abstract = {Harmonized methodologies are urgently required for the taste evaluation of novel pediatric medicines. This study utilized in vitro, in vivo and clinical data to evaluate the palatability of a novel midazolam chocolate tablet. In vitro dissolution experiments showed the crushed tablet to release within 5 min 1.68 mg of midazolam into simulated saliva. This translated to a drug level of 0.84 mg/ml in the oral cavity, which would be higher than the midazolam bitterness detection threshold concentration of 0.03 mg/ml determined in a rat 'brief access taste aversion' (BATA) model. The visual analogue scale scores of patients aged 4-16 years prescribed with midazolam pre-surgery showed a clear preference for the midazolam chocolate tablets (3.35 ± 1.04, n = 20) compared to the control midazolam solution (1.47 ± 0.62, n = 17). The clinical data was in agreement with the in vivo rodent data in showing the novel chocolate tablet matrix to be effective at taste-masking the bitter midazolam.}, } @article {pmid29081083, year = {2017}, author = {Lee, MJ and Sung, HY and Jo, H and Kim, HW and Choi, MS and Kwon, JY and Kang, K}, title = {Ionotropic Receptor 76b Is Required for Gustatory Aversion to Excessive Na+ in Drosophila.}, journal = {Molecules and cells}, volume = {40}, number = {10}, pages = {787-795}, pmid = {29081083}, issn = {0219-1032}, mesh = {Animals ; Behavior, Animal/drug effects ; Caffeine/administration & dosage ; Drosophila Proteins/*genetics ; Drosophila melanogaster/genetics/physiology ; Neurons/*drug effects/physiology ; Receptors, Cell Surface/*genetics ; Receptors, Ionotropic Glutamate/*genetics ; Salts/administration & dosage ; Sodium Channels/*genetics ; Taste/*genetics ; }, abstract = {Avoiding ingestion of excessively salty food is essential for cation homeostasis that underlies various physiological processes in organisms. The molecular and cellular basis of the aversive salt taste, however, remains elusive. Through a behavioral reverse genetic screening, we discover that feeding suppression by Na[+]-rich food requires Ionotropic Receptor 76b (Ir76b) in Drosophila labellar gustatory receptor neurons (GRNs). Concentrated sodium solutions with various anions caused feeding suppression dependent on Ir76b. Feeding aversion to caffeine and high concentrations of divalent cations and sorbitol was unimpaired in Ir76b-deficient animals, indicating sensory specificity of Ir76b-dependent Na[+] detection and the irrelevance of hyperosmolarity-driven mechanosensation to Ir76b-mediated feeding aversion. Ir76b-dependent Na[+]-sensing GRNs in both L- and s-bristles are required for repulsion as opposed to the previous report where the L-bristle GRNs direct only low-Na[+] attraction. Our work extends the physiological implications of Ir76b from low-Na[+] attraction to high-Na[+] aversion, prompting further investigation of the physiological mechanisms that modulate two competing components of Na[+]-evoked gustation coded in heterogeneous Ir76b-positive GRNs.}, } @article {pmid29080021, year = {2017}, author = {Torrealba, F and Madrid, C and Contreras, M and Gómez, K}, title = {Plasticity in the Interoceptive System.}, journal = {Advances in experimental medicine and biology}, volume = {1015}, number = {}, pages = {59-74}, doi = {10.1007/978-3-319-62817-2_4}, pmid = {29080021}, issn = {0065-2598}, mesh = {Animals ; Avoidance Learning/physiology ; Cerebral Cortex/*physiology ; Interoception/*physiology ; Learning/*physiology ; Neuronal Plasticity/*physiology ; Rats ; }, abstract = {The most outstanding manifestations of the plastic capacities of brain circuits and their neuronal and synaptic components in the adult CNS are learning and memory. A reduced number of basic plastic mechanisms underlie learning capacities at many levels and regions of the brain. The interoceptive system is no exception, and some of the most studied behavioral changes that involve learning and memory engage the interoceptive pathways at many levels of their anatomical and functional organization.In this chapter, we will review four examples of learning, mostly in rats, where the interoceptive system has a role. In the case of conditioned taste aversion, the interoceptive system is of outstanding importance. In drug addiction, the role of the insular cortex - the highest level of the interoceptive system- is unusual and complex, as many forebrain regions are engaged by the process of addiction. In the third example, neophobia, the gustatory region of the insular cortex plays a major role. Finally, the role of different areas of the insular cortex in different processes of aversive memory, particularly fear conditioning, will be reviewed.}, } @article {pmid29056353, year = {2018}, author = {Rodriguez, JA and Fehrentz, JA and Martinez, J and Ben Haj Salah, K and Wellman, PJ}, title = {The GHR-R antagonist JMV 2959 neither induces malaise nor alters the malaise property of LiCl in the adult male rat.}, journal = {Physiology & behavior}, volume = {183}, number = {}, pages = {46-48}, doi = {10.1016/j.physbeh.2017.10.017}, pmid = {29056353}, issn = {1873-507X}, mesh = {Animals ; Appetite/drug effects ; Avoidance Learning/drug effects ; Conditioning, Psychological/drug effects ; Feeding Behavior/*drug effects/psychology ; Glycine/*analogs & derivatives/pharmacology ; Lithium Chloride/*pharmacology ; Male ; Nicotine/pharmacology ; Psychotropic Drugs/*pharmacology ; Random Allocation ; Rats, Sprague-Dawley ; Receptors, Ghrelin/*antagonists & inhibitors ; *Reinforcement, Psychology ; Saccharin ; Sodium, Dietary ; Taste Perception/drug effects ; Triazoles/*pharmacology ; }, abstract = {The orexigenic peptide ghrelin (GHR) interacts with ghrelin receptors (GHR-Rs) to modulate brain reinforcement and feeding circuits. Pharmacological inactivation of GHR-Rs via administration of the drug JMV 2959 attenuates the rewarding/reinforcing effects of several drugs of abuse including alcohol, morphine, amphetamine and nicotine. One view of these results is that inactivation of GHR-Rs taps into brain reinforcement/feeding circuits acted upon by drugs of abuse. An alternate explanation is that JMV 2959 may induce malaise, which in turn may limit reinforcement as well as food ingestion. This is a variable of interest given that nicotine alone can induce malaise which may be enhanced by JMV 2959. In the present study, we assessed the capacity of JMV 2959 to produce malaise using a conditioned taste aversion (CTA) task. Adult male rats were allowed to consume a 0.1% sodium saccharin solution and then injected IP with either vehicle, 0.4mg/kg nicotine, 3mg/kg JMV 2959, a combination of 0.4mg/kg nicotine and 3mg/kg JMV 2959, or 32mg/kg lithium chloride (a positive control known to support induction of CTA). Lithium chloride produced a robust avoidance of the saccharin solution in subsequent 2 bottle (water and saccharin) tests, whereas JMV 2959 alone did not induce CTA. The combination of JMV 2959 and nicotine induced a moderate degree of CTA that was similar to that produced by nicotine alone. These results suggest that JMV 2959 is unlikely to limit either reinforcement or food ingestion via induction of malaise.}, } @article {pmid29037662, year = {2018}, author = {Ward, M and Norman, H and D'Souza, MS}, title = {Effects of pharmacological manipulation of the kappa opioid receptors on the aversive effects of nicotine.}, journal = {Behavioural brain research}, volume = {338}, number = {}, pages = {56-65}, doi = {10.1016/j.bbr.2017.10.011}, pmid = {29037662}, issn = {1872-7549}, mesh = {3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/*pharmacology ; Animals ; Avoidance Learning/*drug effects ; Conditioning, Operant/*drug effects ; Male ; Naltrexone/*analogs & derivatives/pharmacology ; Narcotic Antagonists/*pharmacology ; Nicotine/*pharmacology ; Rats ; Rats, Wistar ; Receptors, Opioid, kappa/*antagonists & inhibitors ; Taste ; }, abstract = {Nicotine, an addictive component of tobacco smoke, produces both rewarding and aversive effects. Increasing the aversive effects of nicotine may help in promoting smoking cessation. However, neural targets mediating the aversive effects of nicotine have not been fully identified. In this study, we evaluated the role of kappa opioid receptors (KORs) in the aversive effects of nicotine (0.4 mg/kg, base; s.c.) using the nicotine-induced conditioned taste aversion (CTA) model in Wistar rats. The KORs were activated using the selective KOR agonist (±)U-50,488H (0, 0.03, 0.15 & 0.3mg/kg; s.c.) and inhibited using the KOR antagonist nor-binaltorphimine (nor-BNI; 0, 15 & 30mg/kg; s.c.) in separate groups of rats using a between-subjects design. Pretreatment with the KOR agonist (±)U-50,488H (0.3mg/kg) significantly increased aversion for the nicotine-associated solution. Additionally, (±)U-50,488H (0.3mg/kg) on its own induced aversion to the flavored solution associated with it even in the absence of nicotine, suggesting that the KOR agonist induced increase in nicotine-induced aversion was an additive effect. Interestingly, administration of the KOR antagonist nor-BNI (30mg/kg) prior to conditioning with nicotine/saline, but not after conditioning with nicotine/saline, attenuated nicotine-induced aversive effects compared to saline controls. Taken together, these data suggest a role for KORs in the aversive effects of nicotine.}, } @article {pmid29030219, year = {2018}, author = {Song, G and Zhu, Q and Han, F and Liu, S and Zhao, C and Zhou, Y}, title = {Local infusion of ghrelin into the lateral amygdala blocks extinction of conditioned taste aversion in rats.}, journal = {Neuroscience letters}, volume = {662}, number = {}, pages = {71-76}, doi = {10.1016/j.neulet.2017.10.012}, pmid = {29030219}, issn = {1872-7972}, mesh = {Amygdala/drug effects/*physiology ; Animals ; *Avoidance Learning ; *Conditioning, Classical ; *Extinction, Psychological ; Ghrelin/pharmacology/*physiology ; Male ; Microinjections ; Phosphatidylinositol 3-Kinase/metabolism ; Rats, Wistar ; Taste/drug effects/*physiology ; }, abstract = {Ghrelin is an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents. Our previous study showed that ghrelin locally infused into the lateral amygdala (LA) activates its receptor GHS-R1a and blocks acquisition of conditioned taste aversion (CTA) in rats. In this study, we further investigated the effect of ghrelin/GHS-R1a signaling on extinction of CTA. We found that local infusion of ghrelin (5μM, 0.5μl/side) into the LA not only interfered with CTA memory formation, but also the extinction of CTA memory. Pre-administration of GHS-R1a antagonist blocked ghrelin's effect on both CTA acquisition and extinction. However, pre-treatment with PI3K inhibitor only abolished the inhibitory effect of ghrelin on acquisition, but not on extinction. Altogether, our data indicated that ghrelin/GHS-R1a signaling in the LA circuit modulates both acquisition and extinction of CTA, the two forms of taste aversion processes with distinct mechanisms may also share certain molecular and circuit components in common.}, } @article {pmid29021746, year = {2017}, author = {Vandaele, Y and Pribut, HJ and Janak, PH}, title = {Lever Insertion as a Salient Stimulus Promoting Insensitivity to Outcome Devaluation.}, journal = {Frontiers in integrative neuroscience}, volume = {11}, number = {}, pages = {23}, pmid = {29021746}, issn = {1662-5145}, abstract = {Flexible and efficient decision-making in complex environments can be achieved through constant interactions between the goal-directed and habitual systems. While goal-directed behavior is considered dependent upon Response-Outcome (R-O) associations, habits instead rely on Stimulus-Response (S-R) associations. However, the stimuli that support the S-R association underlying habitual responding in typical instrumental procedures are poorly defined. To resolve this issue, we designed a discrete-trials procedure, in which rats must wait for lever insertion and complete a sequence of five lever presses to obtain a reward (20% sucrose or grain-based pellets). Lever insertion thus constituted an audio-visual stimulus signaling the opportunity for reward. Using sensory-specific satiety-induced devaluation, we found that rats trained with grain-based pellets remained sensitive to outcome devaluation over the course of training with this procedure whereas rats trained with a solution of 20% sucrose rapidly developed habit, and that insensitivity to outcome devaluation in rats trained with sucrose did not result from a bias in general satiety. Importantly, although rats trained with pellets were sensitive to satiety-induced devaluation, their performance was not affected by degradation of instrumental contingency and devaluation by conditioned taste aversion (CTA), suggesting that these rats may also have developed habitual responding. To test whether the discrete-trials procedure biases subjects towards habitual responding, we compared discrete-trials to free-running instrumental responding, and found that rats trained with sucrose in a fixed-ratio 5 (FR5) procedure with continuous presentation of the lever were goal-directed. Together, these results demonstrate that discrete presentations of a stimulus predictive of reward availability promoted the formation of S-R habit in rats trained with liquid sucrose. Further research is necessary to explain inconsistencies in sensitivity to outcome devaluation when rats are trained with grain-based pellets.}, } @article {pmid28955210, year = {2017}, author = {Sunada, H and Totani, Y and Nakamura, R and Sakakibara, M and Lukowiak, K and Ito, E}, title = {Two Strains of Lymnaea stagnalis and the Progeny from Their Mating Display Differential Memory-Forming Ability on Associative Learning Tasks.}, journal = {Frontiers in behavioral neuroscience}, volume = {11}, number = {}, pages = {161}, pmid = {28955210}, issn = {1662-5153}, abstract = {The pond snail Lymnaea stagnalis learns and forms long-term memory (LTM) following both operant conditioning of aerial respiratory behavior and classical conditioning of taste aversive behavior. In the present study, we examined whether there are interstrain differences in the ability to form LTM following these two types of conditioning. A strain of Lymnaea (TC1) collected in Alberta, Canada exhibits superior memory-forming ability following aerial respiratory operant conditioning compared to a laboratory-reared strain of Lymnaea from Netherlands known as the Dutch strain. We asked whether the offspring of the Canadian TC1 and Dutch snails (i.e., filial 1 (F1) cross snails) would have the superior memory ability and found, rather, that their memory ability was average like the Dutch snails. That is, the Canadian TC1 snails have superior ability for LTM formation following aerial respiratory operant conditioning, but the Dutch and the generated F1 cross have average ability for memory forming. We next examined the Canadian TC1, Dutch and F1 cross snails for their ability to learn and form memory following conditioned taste aversion (CTA). All three populations showed similar associative CTA responses. However, both LTM formation and the ratio of good-to-poor performers in the memory retention test were much better in the Dutch snails than the Canadian TC1 and F1 cross snails. The memory abilities of the Canadian TC1 and F1 cross snails were average. Our present findings, therefore, suggest that snails of different strains have different memory abilities, and the F1 cross snails do not inherit the memory ability from the smart strain. To our knowledge, there have been a limited number of studies examining differences in memory ability among invertebrate strains, with the exception of studies using mutant flies.}, } @article {pmid28861596, year = {2017}, author = {Molero-Chamizo, A and Rivera-Urbina, GN}, title = {Effects of lesions in different nuclei of the amygdala on conditioned taste aversion.}, journal = {Experimental brain research}, volume = {235}, number = {11}, pages = {3517-3526}, pmid = {28861596}, issn = {1432-1106}, mesh = {Animals ; Avoidance Learning/*physiology ; Basolateral Nuclear Complex/pathology/*physiology ; Behavior, Animal/physiology ; Central Amygdaloid Nucleus/pathology/*physiology ; Conditioning, Classical/*physiology ; Corticomedial Nuclear Complex/pathology/*physiology ; Male ; Rats ; Rats, Wistar ; Taste Perception/*physiology ; }, abstract = {Conditioned taste aversion (CTA) is an adaptive learning that depends on brain mechanisms not completely identified. The amygdala is one of the structures that make up these mechanisms, but the involvement of its nuclei in the acquisition of CTA is unclear. Lesion studies suggest that the basolateral complex of the amygdala, including the basolateral and lateral amygdala, could be involved in CTA. The central amygdala has also been considered as an important nucleus for the acquisition of CTA in some studies. However, to the best of our knowledge, the effect of lesions of the basolateral complex of the amygdala on the acquisition of CTA has not been directly compared with the effect of lesions of the central and medial nuclei of the amygdala. The aim of this study is to compare the effect of lesions of different nuclei of the amygdala (the central and medial amygdala and the basolateral complex) on the acquisition of taste aversion in male Wistar rats. The results indicate that lesions of the basolateral complex of the amygdala reduce the magnitude of the CTA when compared with lesions of the other nuclei and with animals without lesions. These findings suggest that the involvement of the amygdala in the acquisition of CTA seems to depend particularly on the integrity of the basolateral complex of the amygdala.}, } @article {pmid28856957, year = {2019}, author = {Kwok, DW and Boakes, RA}, title = {Situational relevance: Context as a factor in serial overshadowing of taste aversion learning.}, journal = {Quarterly journal of experimental psychology (2006)}, volume = {72}, number = {2}, pages = {263-273}, doi = {10.1080/17470218.2017.1338739}, pmid = {28856957}, issn = {1747-0226}, mesh = {Animals ; Avoidance Learning/*physiology ; Behavior, Animal/*physiology ; Conditioning, Classical/*physiology ; Male ; Rats ; Rats, Wistar ; Taste Perception/*physiology ; }, abstract = {In a serial overshadowing procedure, a target stimulus, A, is followed after an interval by a potentially interfering stimulus, B, and this is then followed by an unconditioned stimulus (US). An untested proposal from over four decades ago was that the degree to which B overshadows conditioning of A depends on whether or not the two events take place in the same context. To test this, two experiments used a 1-trial long-delay conditioned taste aversion (CTA) procedure: sucrose served as the target taste (A) and dilute hydrochloric acid (HCl) as the overshadowing taste (B), with lithium chloride injection providing the US. In Experiment 1, these tastes were novel: weaker overshadowing by HCl of an aversion to sucrose was found when the two tastes were presented in different contexts. Experiment 2 tested whether the effect of pre-exposure to HCl, thereby rendering it less effective in overshadowing a sucrose aversion, was also context dependent. In the conditioning session, rats again received either context-same or context-different presentations of sucrose and HCl. However, for some rats, HCl was pre-exposed in the same context to which it was later presented during conditioning (Consistent), while others were pre-exposed to HCl in a different context to the one in which it was presented during conditioning (Inconsistent). The Inconsistent group produced greater overshadowing than the Consistent group and thus confirmed that the latent inhibition effect was also context dependent. This study confirms the concept of situational relevance.}, } @article {pmid28807538, year = {2017}, author = {Arthurs, J and Lin, JY and Ocampo, R and Reilly, S}, title = {Lactose malabsorption and taste aversion learning.}, journal = {Physiology & behavior}, volume = {180}, number = {}, pages = {39-44}, pmid = {28807538}, issn = {1873-507X}, support = {R01 DC006456/DC/NIDCD NIH HHS/United States ; R56 DC006456/DC/NIDCD NIH HHS/United States ; }, mesh = {Adjuvants, Immunologic/toxicity ; Analysis of Variance ; Animals ; Avoidance Learning/drug effects/*physiology ; Conditioning, Classical/drug effects ; Drinking Behavior/drug effects ; Eating/drug effects/*physiology ; Lactose/*metabolism ; Lithium Chloride/toxicity ; Male ; Rats ; Rats, Sprague-Dawley ; Saccharin/administration & dosage ; Sweetening Agents/administration & dosage ; Taste/drug effects/*physiology ; Water Deprivation ; }, abstract = {Consumption of foods can be suppressed by two feeding system defense mechanisms: conditioned taste aversion (CTA) or taste avoidance learning (TAL). There is a debate in the literature about which form of intake suppression is caused by various aversive stimuli. For instance, illness-inducing stimuli like lithium chloride are the gold standard for producing CTA and external (or peripheral) painful stimuli, such as footshock, are the traditional model of TAL. The distinction between CTA and TAL, which have identical effects on intake, is based on differential effects on palatability. That is, CTA involves a decrease in both intake and palatability, whereas TAL suppresses intake without influencing palatability. We evaluated whether lactose, which causes gastrointestinal pain in adult rats, produces CTA or TAL. Using lick pattern analysis to simultaneously measure intake and palatability (i.e., lick cluster size and initial lick rate), we found that pairing saccharin with intragastric infusions of lactose suppressed both the intake and palatability of saccharin. These results support the conclusion that gastrointestinal pain produced by lactose malabsorption produces a CTA, not TAL as had previously been suggested. Furthermore, these findings encourage the view that the CTA mechanism is broadly tuned to defend against the ingestion of foods with aversive post-ingestive effects.}, } @article {pmid28803978, year = {2017}, author = {Sasaki, T and Yasoshima, Y and Matsui, S and Yokota-Hashimoto, H and Kobayashi, M and Kitamura, T}, title = {Intraperitoneal injection of d-serine inhibits high-fat diet intake and preference in male mice.}, journal = {Appetite}, volume = {118}, number = {}, pages = {120-128}, doi = {10.1016/j.appet.2017.08.011}, pmid = {28803978}, issn = {1095-8304}, mesh = {Animals ; Brain/drug effects/metabolism ; Conditioning, Classical ; *Diet, High-Fat ; *Feeding Behavior ; Injections, Intraperitoneal ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, N-Methyl-D-Aspartate/agonists/metabolism ; Serine/*pharmacology ; Taste ; }, abstract = {d-serine is a co-agonist of the N-methyl d-aspartate (NMDA) receptor, an important modulator of glutamatergic excitatory synaptic transmission. We previously reported that oral d-serine ingestion inhibited the intake of highly preferred food and promoted the intake of less preferred food in mice. Here, we analyzed the effects of intraperitoneal (IP) d-serine injections on feeding behavior in mice. We assessed the effects of d-serine during both the acquisition and maintenance of a preference for high-fat diets (HFDs). Aversiveness of IP d-serine was analyzed in the conditioned taste aversion paradigm. The effects on food intake were assessed by providing liquid meals with different fat contents. Finally, we measured brain d-serine and l-serine levels after d-serine administration. We found that IP-injected d-serine effectively inhibited the acquisition of a HFD preference, but failed to prevent expression of a previously learned HFD preference. IP-injected d-serine was not sufficient to condition taste aversion. The effect on HFD preference acquisition was associated with increases in d-serine levels in the cerebral cortex, hypothalamus, and cerebellum. IP-injected d-serine most effectively inhibited the intake of liquid meals with high fat content. This effect was dose-dependent, but the responses varied significantly among male C57BL/6J mice. The differential responses to d-serine were consistent among multiple trials in each mouse. In summary, IP-injected d-serine inhibited HFD intake and the acquisition of an HFD preference. Individual mice with the same genetic background showed different sensitivities to d-serine; thus, d-serine sensitivity may be associated with unidentified traits.}, } @article {pmid28716589, year = {2017}, author = {Miranda, MI and Rangel-Hernández, JA and Vera-Rivera, G and García-Medina, NE and Soto-Alonso, G and Rodríguez-García, G and Núñez-Jaramillo, L}, title = {The role of dopamine D2 receptors in the nucleus accumbens during taste-aversive learning and memory extinction after long-term sugar consumption.}, journal = {Neuroscience}, volume = {359}, number = {}, pages = {142-150}, doi = {10.1016/j.neuroscience.2017.07.009}, pmid = {28716589}, issn = {1873-7544}, mesh = {Animals ; *Avoidance Learning ; Extinction, Psychological/*physiology ; Male ; Mental Recall/physiology ; Nucleus Accumbens/*physiology ; Rats, Wistar ; Receptors, Dopamine D2/*physiology ; Sugars/*administration & dosage ; Taste ; }, abstract = {The nucleus accumbens (NAcc) is a forebrain region that may significantly contribute to the integration of taste and visceral signals during food consumption. Changes in dopamine release in the NAcc have been observed during consumption of a sweet taste and during compulsive consumption of dietary sugars, suggesting that NAcc dopaminergic transmission is strongly correlated with taste familiarity and the hedonic value content. NAcc core and shell nuclei are differentially involved during and after sugar exposure and, particularly, previous evidence suggests that dopamine D2 receptors could be related with the strength of the latent inhibition (LI) of conditioned taste aversion (CTA), which depends on the length of the taste stimulus pre-exposure. Thus, the objective of this work was to evaluate, after long-term exposure to sugar, the function of dopaminergic D2 receptors in the NAcc core during taste memory retrieval preference test, and during CTA. Adult rats were exposed during 14days to 10% sugar solution as a single liquid ad libitum. NAcc core bilateral injections of D2 dopamine receptor antagonist, haloperidol (1μg/μL), were made before third preference test and CTA acquisition. We found that sugar was similarly preferred after 3 acute presentations or 14days of continued sugar consumption and that haloperidol did not disrupt this appetitive memory retrieval. Nevertheless, D2 receptors antagonism differentially affects aversive memory formation after acute or long-term sugar consumption. These results demonstrate that NAcc dopamine D2 receptors have a differential function during CTA depending on the degree of sugar familiarity.}, } @article {pmid28693705, year = {2017}, author = {Molero-Chamizo, A and Rivera-Urbina, GN}, title = {Effects of temporal contexts and contextual habituation on latent inhibition.}, journal = {Psicothema}, volume = {29}, number = {3}, pages = {346-351}, doi = {10.7334/psicothema2016.312}, pmid = {28693705}, issn = {1886-144X}, mesh = {Animals ; *Habituation, Psychophysiologic ; *Inhibition, Psychological ; Male ; Rats ; Rats, Wistar ; Taste ; Time Factors ; }, abstract = {BACKGROUND: Latent inhibition of conditioned taste aversion (CTA) is sensitive to external and internal cues. Time of day can serve as an internal cue, and latent inhibition may be reduced if the pre-exposure and conditioning stages occur at different times of day. This contextual cue attributed to a change in the time of day may reveal a temporal specificity of latent inhibition. Although the habituation period to spatial contexts is a determinant variable for the spatial specificity of latent inhibition of CTA, the influence of contextual-temporal familiarity (time of day) on latent inhibition of CTA has not been explored through direct comparisons between different periods of habituation to the temporal context.

METHOD: Two different periods of contextual habituation (short vs. long) previous to taste pre-exposures were compared in Wistar rats to analyze the influence of these periods on the temporal specificity of latent inhibition of CTA.

RESULTS: A long period of habituation, in relation to a short period, facilitated the effect of a change of the time of day between pre-exposure and conditioning on the magnitude of taste aversion.

CONCLUSIONS: A long habituation to temporal contexts facilitates the temporal specificity of latent inhibition of CTA.}, } @article {pmid28689966, year = {2017}, author = {Münster, M and Mohamed-Ahmed, AHA and Immohr, LI and Schoch, C and Schmidt, C and Tuleu, C and Breitkreutz, J}, title = {Comparative in vitro and in vivo taste assessment of liquid praziquantel formulations.}, journal = {International journal of pharmaceutics}, volume = {529}, number = {1-2}, pages = {310-318}, doi = {10.1016/j.ijpharm.2017.06.084}, pmid = {28689966}, issn = {1873-3476}, mesh = {2-Hydroxypropyl-beta-cyclodextrin/*chemistry ; Animals ; Electronic Nose ; Male ; Praziquantel/*pharmacology ; Rats, Sprague-Dawley ; Solubility ; *Taste ; beta-Cyclodextrins/*chemistry ; }, abstract = {The taste of pharmaceuticals strongly affects the compliance of patients. This study investigated the applicability of the electronic tongue and rodent brief-access taste aversion (BATA) model for the bitter compound praziquantel (PZQ) and taste masked liquid formulations for PZQ. In a comparative study maltodextrin (MD) Kleptose[®] linecaps 17 was selected as an alternative taste masking agent to two cyclodextrins; hydroxypropyl-beta-cyclodextrin (HP-β-CD) and sulfobutyl ether-beta-cyclodextrin (SBE-β-CD). A phase solubility study showed the highest affinity and solubilization capabilities for SBE-β-CD over HP-β-CD and MD, suggesting the highest taste masking ability for SBE-β-CD. No reliable results were achieved for PZQ with the Insent electronic tongue. Thus this system was not used for further evaluation of solutions with MD and CDs to confirm the results of the solubility study. In contrast the BATA model demonstrated conclusive responses for the aversiveness of PZQ. The concentration of PZQ inhibiting 50% of water lick numbers (called IC50 value) was 0.06mg/ml. In contrast to the phase solubility study, the MD enabled an equal taste masking effect in vivo in comparison to both CDs. Moreover HP-β-CD showed superior taste masking capabilities for PZQ compared to SBE-β-CD as the SBE-β-CD itself was less acceptable for the rodents than HP-β-CD. In conclusion, the BATA model was identified as a more efficient taste assessment tool for the pure PZQ and liquid formulations in contrast to the electronic tongue and the phase solubility study.}, } @article {pmid28687346, year = {2018}, author = {Keating, AV and Soto, J and Tuleu, C and Forbes, C and Zhao, M and Craig, DQM}, title = {Solid state characterisation and taste masking efficiency evaluation of polymer based extrudates of isoniazid for paediatric administration.}, journal = {International journal of pharmaceutics}, volume = {536}, number = {2}, pages = {536-546}, doi = {10.1016/j.ijpharm.2017.07.008}, pmid = {28687346}, issn = {1873-3476}, mesh = {Animals ; Antitubercular Agents/administration & dosage/*chemistry ; Child ; Drug Compounding ; Drug Liberation ; Electronic Nose ; Hot Temperature ; Humans ; Isoniazid/administration & dosage/*chemistry ; Male ; Polyethylene Glycols/administration & dosage/*chemistry ; Polymethacrylic Acids/administration & dosage/*chemistry ; Polyvinyls/administration & dosage/*chemistry ; Rats, Sprague-Dawley ; Saliva, Artificial/chemistry ; Solubility ; *Taste ; }, abstract = {Hot melt extrusion has gained considerable attention as a novel technique for taste masking of bitter APIs. The aim of this study was to investigate whether hot melt extrusion could be used to develop taste masked formulations of isoniazid and also to evaluate and correlate different taste assessment methods Two polymers with different physico-chemical properties, Soluplus and Eudragit E-PO were chosen as carriers for the drug. Eudragit E-PO has already been widely used for taste masking due to its selective release properties, while Soluplus has not been studied in this regard but provides a useful comparator of a polymer that should release the drug reasonably efficiently. Polymeric formulations of isoniazid were produced with drug loadings of 20% and 30% w/w. The solid state characteristics of the formulations were assessed by differential scanning calorimetry and powder X-ray diffraction. The taste of isoniazid was assessed using the rodent Brief Access Taste Aversion (BATA) model, while formulations were assessed using the electronic tongue and dissolution under simulated oral conditions. Investigation into the drug loading effect with these two polymers showed that all Soluplus based extrudates with drug loading up to 30% w/w were fully amorphous while Eudragit E-PO based extrudates contained crystalline drug as demonstrated by both DSC and PXRD, dependent on loading. BATA testing of isoniazid gave an IC50 value, i.e. the dose of drug which inhibits 50% of licks, of 11.1mg/mL. Taste assessment of the formulations using both simulated oral drug release and the electronic tongue demonstrated that Eudragit E-PO based formulations had a better taste masking efficiency than Soluplus. This is due to the fact that significantly less isoniazid is released from the Eudragit E-PO based formulations under oral conditions.}, } @article {pmid28684275, year = {2017}, author = {Roman, CW and Sloat, SR and Palmiter, RD}, title = {A tale of two circuits: CCK[NTS] neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions.}, journal = {Neuroscience}, volume = {358}, number = {}, pages = {316-324}, pmid = {28684275}, issn = {1873-7544}, support = {/HHMI/Howard Hughes Medical Institute/United States ; R01 DA024908/DA/NIDA NIH HHS/United States ; T32 DK007247/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Appetite/*genetics ; Avoidance Learning/physiology ; Channelrhodopsins/genetics/metabolism ; Cholecystokinin/genetics/*metabolism ; Conditioning, Operant/physiology ; Eating/genetics ; Luminescent Proteins/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motivation/*physiology ; Neural Pathways/*physiology ; Oncogene Proteins v-fos/metabolism ; Optogenetics ; Parabrachial Nucleus/*physiology ; Paraventricular Hypothalamic Nucleus/*metabolism ; Solitary Nucleus/*cytology ; Taste/physiology ; Transduction, Genetic ; }, abstract = {Cholecystokinin (CCK)-expressing neurons within the nucleus of the solitary tract (CCK[NTS]) of the mouse are responsive to satiety signals and their chemogenetic activation suppresses appetite. Optogenetic activation of CCK[NTS] axon terminals within either the parabrachial nucleus (PBN) or the paraventricular nucleus of the hypothalamus (PVH) is sufficient to suppress feeding. An interesting dichotomy has been revealed when assessing the motivational valence of these two circuits. Activating CCK[NTS] cell bodies is aversive as demonstrated by conditioned taste aversion and place-preference assays. Activation of the CCK[NTS]→PBN pathway is also aversive; however, stimulating the CCK[NTS]→PVH pathway is appetitive when assayed using a real-time, place-preference task. Thus, these two projections from CCK[NTS] neurons reduce food intake through opposite motivational states; one pathway signals positive valence (CCK[NTS]→PVH) and the other signals negative valence (CCK[NTS]→PBN).}, } @article {pmid28667676, year = {2017}, author = {Shoshan, N and Segev, A and Abush, H and Mizrachi Zer-Aviv, T and Akirav, I}, title = {Cannabinoids prevent the differential long-term effects of exposure to severe stress on hippocampal- and amygdala-dependent memory and plasticity.}, journal = {Hippocampus}, volume = {27}, number = {10}, pages = {1093-1109}, doi = {10.1002/hipo.22755}, pmid = {28667676}, issn = {1098-1063}, mesh = {Amidohydrolases/antagonists & inhibitors/metabolism ; Amygdala/*drug effects/pathology/physiopathology ; Animals ; Avoidance Learning/drug effects/physiology ; Benzamides/pharmacology ; Benzoxazines/pharmacology ; Bromine/*pharmacology ; Cannabinoid Receptor Modulators/pharmacology ; Cannabinoids/*pharmacology ; Carbamates/pharmacology ; Disease Models, Animal ; Drug Combinations ; Electroshock ; Enzyme Inhibitors/pharmacology ; Fear/drug effects/physiology ; Glutamates/*pharmacology ; Hippocampus/*drug effects/pathology/physiopathology ; Magnesium/*pharmacology ; Male ; Memory/drug effects/physiology ; Morpholines/pharmacology ; Naphthalenes/pharmacology ; Neuronal Plasticity/drug effects/physiology ; Piperidines/pharmacology ; Pyrazoles/pharmacology ; Rats, Sprague-Dawley ; Receptors, Cannabinoid/*metabolism ; Stress Disorders, Post-Traumatic/*drug therapy/pathology/physiopathology/psychology ; }, abstract = {Exposure to excessive or uncontrolled stress is a major factor associated with various diseases including posttraumatic stress disorder (PTSD). The consequences of exposure to trauma are affected not only by aspects of the event itself, but also by the frequency and severity of trauma reminders. It was suggested that in PTSD, hippocampal-dependent memory is compromised while amygdala-dependent memory is strengthened. Several lines of evidence support the role of the endocannabinoid (eCB) system as a modulator of the stress response. In this study we aimed to examine cannabinoids modulation of the long-term effects (i.e., 1 month) of exposure to a traumatic event on memory and plasticity in the hippocampus and amygdala. Following exposure to the shock and reminders model of PTSD in an inhibitory avoidance light-dark apparatus rats demonstrated: (i) enhanced fear retrieval and impaired inhibitory extinction (Ext), (ii) no long-term potentiation (LTP) in the CA1, (iii) impaired hippocampal-dependent short-term memory in the object location task, (iv) enhanced LTP in the amygdala, and (v) enhanced amygdala-dependent conditioned taste aversion memory. The cannabinoid CB1/2 receptor agonist WIN55-212,2 (0.5mg/kg, i.p.) and the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3mg/kg, i.p.), administered 2 hr after shock exposure prevented these opposing effects on hippocampal- and amygdala-dependent processes. Moreover, the effects of WIN55-212,2 and URB597 on Ext and acoustic startle were prevented by co-administration of a low dose of the CB1 receptor antagonist AM251 (0.5mg/kg, i.p.), suggesting that the preventing effects of both drugs are mediated by CB1 receptors. Exposure to shock and reminders increased CB1 receptor levels in the CA1 and basolateral amygdala 1 month after shock exposure and this increase was also prevented by administering WIN55-212,2 or URB597. Taken together, these findings suggest the involvement of the eCB system, and specifically CB1 receptors, in the opposite effects of severe stress on memory and plasticity in the hippocampus and amygdala.}, } @article {pmid28663116, year = {2017}, author = {Fernández, MS and Báez, B and Bordón, A and Espinosa, L and Martínez, E and Pautassi, RM}, title = {Short-term selection for high and low ethanol intake yields differential sensitivity to ethanol's motivational effects and anxiety-like responses in adolescent Wistar rats.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {79}, number = {Pt B}, pages = {220-233}, doi = {10.1016/j.pnpbp.2017.06.027}, pmid = {28663116}, issn = {1878-4216}, mesh = {Alcohol-Related Disorders/physiopathology ; Animals ; Anxiety/*physiopathology ; Central Nervous System Depressants/*adverse effects ; Ethanol/*adverse effects ; Feeding Behavior/physiology ; Female ; *Genetic Predisposition to Disease ; Male ; Motivation/*drug effects/physiology ; Motor Activity/physiology ; Phenotype ; Rats, Wistar ; Saccharin ; Selective Breeding ; Time Factors ; }, abstract = {Alcohol use disorders are modulated by genetic factors, but the identification of specific genes and their concomitant biological changes that are associated with a higher risk for these disorders has proven difficult. Alterations in the sensitivity to the motivational effects of ethanol may be one way by which genes modulate the initiation and escalation of ethanol intake. Rats and mice have been selectively bred for high and low ethanol consumption during adulthood. However, selective breeding programs for ethanol intake have not focused on adolescence. This phase of development is associated with the initiation and escalation of ethanol intake and characterized by an increase in the sensitivity to ethanol's appetitive effects and a decrease in the sensitivity to ethanol's aversive effects compared with adulthood. The present study performed short-term behavioral selection to select rat lines that diverge in the expression of ethanol drinking during adolescence. A progenitor nucleus of Wistar rats (F0) and filial generation 1 (F1), F2, and F3 adolescent rats were derived from parents that were selected for high (STDRHI) and low (STDRLO) ethanol consumption during adolescence and were tested for ethanol intake and responsivity to ethanol's motivational effects. STDRHI rats exhibited significantly greater ethanol intake and preference than STDRLO rats. Compared with STDRLO rats, STDRHI F2 and F3 rats exhibited a blunted response to ethanol in the conditioned taste aversion test. F2 and F3 STDRHI rats but not STDRLO rats exhibited ethanol-induced motor stimulation. STDRHI rats exhibited avoidance of the white compartment of the light-dark box, a reduction of locomotion, and a reduction of saccharin consumption, suggesting an anxiety-prone phenotype. The results suggest that the genetic risk for enhanced ethanol intake during adolescence is associated with lower sensitivity to the aversive effects of ethanol, heightened reactivity to ethanol's stimulating effects, and enhanced innate anxiety.}, } @article {pmid28649917, year = {2019}, author = {Dwyer, DM and Gasalla, P and López, M}, title = {Partial reinforcement and conditioned taste aversion: No evidence for resistance to extinction.}, journal = {Quarterly journal of experimental psychology (2006)}, volume = {72}, number = {2}, pages = {274-284}, doi = {10.1080/17470218.2017.1347191}, pmid = {28649917}, issn = {1747-0226}, mesh = {Animals ; Avoidance Learning/*physiology ; Behavior, Animal/*physiology ; Conditioning, Classical/*physiology ; Extinction, Psychological/physiology ; Generalization, Psychological/*physiology ; Male ; Rats ; *Reinforcement, Psychology ; Taste Perception/*physiology ; }, abstract = {The partial reinforcement extinction effect (PREE) is the observation that, following training in which a response is followed by reward on only a subset of trials, the response is more resistant to extinction following the total removal of reward than it is after training in which reward is presented on all trials. The PREE is almost ubiquitous in instrumental conditioning procedures but only inconsistently observed in Pavlovian conditioning. In his classic review of animal learning, Mackintosh attributes the bulk of the PREE to generalisation decrement relating to the fact that partial reinforcement typically ensures that acquisition of responding has taken place in conditions similar to that of extinction (e.g., in the absence of the reinforcer). We report here that extinction of a conditioned taste aversion is not retarded by partial reinforcement in terms of either consumption of the taste or hedonic reactions to it (assessed through the analysis of licking microstructure). These results are consistent with Mackintosh's analysis of the PREE and the way in which it might differ between instrumental and Pavlovian conditioning.}, } @article {pmid28623169, year = {2017}, author = {Blednov, YA and Borghese, CM and Ruiz, CI and Cullins, MA and Da Costa, A and Osterndorff-Kahanek, EA and Homanics, GE and Harris, RA}, title = {Mutation of the inhibitory ethanol site in GABAA ρ1 receptors promotes tolerance to ethanol-induced motor incoordination.}, journal = {Neuropharmacology}, volume = {123}, number = {}, pages = {201-209}, pmid = {28623169}, issn = {1873-7064}, support = {R37 AA010422/AA/NIAAA NIH HHS/United States ; R37 AA006399/AA/NIAAA NIH HHS/United States ; R01 AA006399/AA/NIAAA NIH HHS/United States ; U01 AA013520/AA/NIAAA NIH HHS/United States ; U01 AA020889/AA/NIAAA NIH HHS/United States ; R01 AA010422/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcoholic Intoxication/*metabolism ; Animals ; Ataxia/*chemically induced/metabolism ; CRISPR-Cas Systems ; Central Nervous System Depressants/*pharmacology ; Cerebellum/drug effects/metabolism ; Ethanol/*pharmacology ; Female ; Humans ; Male ; Mice, Transgenic ; Motor Activity/drug effects/physiology ; Mutation ; Oocytes ; RNA, Messenger/metabolism ; Receptors, GABA-A/genetics/*metabolism ; Recovery of Function/physiology ; Xenopus laevis ; }, abstract = {Genes encoding the ρ1/2 subunits of GABAA receptors have been associated with alcohol (ethanol) dependence in humans, and ρ1 was also shown to regulate some of the behavioral effects of ethanol in animal models. Ethanol inhibits GABA-mediated responses in wild-type (WT) ρ1, but not ρ1(T6'Y) mutant receptors expressed in Xenopus laevis oocytes, indicating the presence of an inhibitory site for ethanol in the second transmembrane helix. In this study, we found that ρ1(T6'Y) receptors expressed in oocytes display overall normal responses to GABA, the endogenous GABA modulator (zinc), and partial agonists (β-alanine and taurine). We generated ρ1 (T6'Y) knockin (KI) mice using CRISPR/Cas9 to test the behavioral importance of the inhibitory actions of ethanol on this receptor. Both ρ1 KI and knockout (KO) mice showed faster recovery from acute ethanol-induced motor incoordination compared to WT mice. Both KI and KO mutant strains also showed increased tolerance to motor impairment produced by ethanol. The KI mice did not differ from WT mice in other behavioral actions, including ethanol intake and preference, conditioned taste aversion to ethanol, and duration of ethanol-induced loss of righting reflex. WT and KI mice did not differ in levels of ρ1 or ρ2 mRNA in cerebellum or in ethanol clearance. Our findings indicate that the inhibitory site for ethanol in GABAA ρ1 receptors regulates acute functional tolerance to moderate ethanol intoxication. We note that low sensitivity to alcohol intoxication has been linked to risk for development of alcohol dependence in humans.}, } @article {pmid28606627, year = {2017}, author = {He, AB and Chang, YC and Meng, AWY and Huang, ACW}, title = {Re-evaluation of the reward comparison hypothesis for alcohol abuse.}, journal = {Behavioural brain research}, volume = {332}, number = {}, pages = {218-222}, doi = {10.1016/j.bbr.2017.06.006}, pmid = {28606627}, issn = {1872-7549}, mesh = {Alcoholism/*psychology ; Animals ; Central Nervous System Depressants/*pharmacology ; Conditioning, Psychological/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Ethanol/*pharmacology ; Male ; *Models, Psychological ; Psychological Tests ; Random Allocation ; Rats, Wistar ; *Reward ; Saccharin ; Space Perception/drug effects ; }, abstract = {This study examined whether various doses of ethanol induced reward or aversion and then evaluated Grigson's reward comparison hypothesis (1997). Rats were given a 0.1% saccharin solution (conditioned stimulus 1 [CS1]) 15min prior to administration of a 0, 0.05, 0.125, 0.20, 0.35, or 0.50g/kg dose of ethanol (unconditioned stimulus [US]). The rats were then exposed to a paired compartment (CS2) for 30min. The low dose of 0.05g/kg ethanol did not induce conditioned suppression (i.e., conditioned taste aversion [CTA]) or conditioned place preference (CPP). The dose of 0.125g/kg ethanol induced CPP but not CTA. High doses of ethanol, including 0.35g/kg and 0.50g/kg, produced CTA but not CPP. The middle dose of 0.20g/kg ethanol simultaneously induced CTA and CPP. As a result, the reward comparison hypothesis cannot explain the present finding that the middle dose of ethanol induced CTA and CPP. Meanwhile, the high doses of ethanol induced motivationally aversive CTA but not rewarding CPP. The reward comparison hypothesis should be updated further.}, } @article {pmid28605507, year = {2017}, author = {Eddy, MC and Eschle, BK and Delay, ER}, title = {Comparison of the Tastes of L-Alanine and Monosodium Glutamate in C57BL/6J Wild Type and T1r3 Knockout Mice.}, journal = {Chemical senses}, volume = {42}, number = {7}, pages = {563-573}, doi = {10.1093/chemse/bjx037}, pmid = {28605507}, issn = {1464-3553}, mesh = {Alanine/*pharmacology ; Animals ; Discriminant Analysis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptors, G-Protein-Coupled/deficiency/genetics ; Sodium Glutamate/*pharmacology ; Taste/*drug effects ; Taste Threshold/drug effects ; }, abstract = {Previous research showed that L-alanine and monosodium L-glutamate elicit similar taste sensations in rats. This study reports the results of behavioral experiments designed to compare the taste capacity of C57BL/6J wild type and T1r3- mice for these 2 amino acids. In conditioned taste aversion (CTA) experiments, wild-type mice exhibited greater sensitivity than knockout mice for both L-amino acids, although knockout mice were clearly able to detect both amino acids at 50 mM and higher concentrations. Generalization of CTA between L-alanine and L-glutamate was bidirectionally equivalent for both mouse genotypes, indicating that both substances elicited similar tastes in both genotypes. This was verified by the discrimination experiments in which both mouse genotypes performed at or near chance levels at 75 and 150 mM. Above 150 mM, discrimination performance improved, suggesting the taste qualities of the 2 L-amino acids are not identical. No differences between knockout and wild-type mice in discrimination ability were detected. These results indicate that while the T1r3 receptor is important for tasting L-alanine and L-glutamate, other receptors are also important for tasting these amino acids.}, } @article {pmid28552029, year = {2017}, author = {Bala, M and Gupta, V and Prasad, J}, title = {A standardized Hippophae extract (SBL-1) counters neuronal tissue injuries and changes in neurotransmitters: implications in radiation protection.}, journal = {Pharmaceutical biology}, volume = {55}, number = {1}, pages = {1833-1842}, pmid = {28552029}, issn = {1744-5116}, mesh = {Amygdala/metabolism/pathology/radiation effects ; Animals ; Antioxidants/chemistry/standards/therapeutic use ; Behavior, Animal/radiation effects ; Brain Chemistry/radiation effects ; Cerebral Cortex/metabolism/pathology/radiation effects ; Cobalt Radioisotopes ; Conditioning, Classical ; *Dietary Supplements ; Hippocampus/metabolism/pathology/radiation effects ; Hippophae/*chemistry ; Male ; Neurons/*metabolism/pathology/radiation effects ; Neuroprotective Agents/chemistry/standards/therapeutic use ; Oxidative Stress/radiation effects ; Plant Extracts/chemistry/standards/*therapeutic use ; Plant Leaves/*chemistry ; Radiation Injuries, Experimental/metabolism/pathology/physiopathology/*prevention & control ; Radiation-Protective Agents/chemistry/standards/*therapeutic use ; Random Allocation ; Rats, Sprague-Dawley ; Taste Disorders/etiology/prevention & control ; }, abstract = {CONTEXT: Effects of a radioprotective, standardized leaf extract (code SBL-1) from traditional medicinal plant, sea buckthorn [Hippophae rhamnoides L. (Elaeagnaceae)], on neurotransmitters and brain injuries in rats showing radiation-induced conditioned taste aversion (CTA), are not known. Understanding CTA in rats is important because its process is considered parallel to nausea and vomiting in humans.

OBJECTIVE: This study investigated the levels of neurotransmitters, antioxidant defences and histological changes in rats showing radiation CTA, and their modification by SBL-1.

MATERIALS AND METHODS: The inbred male Sprague-Dawley rats (age 65 days, weighing 190 ± 10 g) were used. Saccharin-preferring rats were selected using standard procedure and divided into groups. Group I (untreated control) was administered sterile water, group II was [60]Co-γ-irradiated (2 Gy), and group III was administered SBL-1 before irradiation. Observations were recorded up to day 5.

RESULTS: Irradiation (2 Gy) caused (i) non-recoverable CTA (≥ 64.7 ± 5.0%); (ii) degenerative changes in cerebral cortex, amygdala and hippocampus; (iii) increases in brain dopamine (DA, 63.4%), norepinephrine (NE, 157%), epinephrine (E, 233%), plasma NE (103%) and E (160%); and (iv) decreases in brain superoxide dismutase (67%), catalase (60%) and glutathione (51%). SBL-1 treatment (12 mg/kg body weight) 30 min before irradiation (i) countered brain injuries, (ii) reduced CTA (38.7 ± 3.0%, day 1) and (iii) normalized brain DA, NE, E, superoxide dismutase, catalase and CTA from day 3 onwards.

DISCUSSION AND CONCLUSION: Radiation CTA was coupled with brain injuries, disturbances in neurotransmitters and antioxidant defences. SBL-1 pretreatment countered these disturbances, indicating neuroprotective action.}, } @article {pmid28549583, year = {2017}, author = {Sun, H and Yan, J and Sun, B and Song, L and Yan, J}, title = {Taste sensitivity to sucrose is lower in outbred Sprague-Dawley phenotypic obesity-prone rats than obesity-resistant rats.}, journal = {Biochemical and biophysical research communications}, volume = {489}, number = {2}, pages = {155-163}, doi = {10.1016/j.bbrc.2017.05.117}, pmid = {28549583}, issn = {1090-2104}, mesh = {Animals ; Behavior, Animal/drug effects ; Body Weight/drug effects ; *Diet, High-Fat ; Energy Intake/drug effects ; Male ; Obesity/*drug therapy/physiopathology ; Phenotype ; Rats ; Rats, Sprague-Dawley ; Sucrose/administration & dosage/*pharmacology ; Taste/*drug effects ; Taste Threshold/drug effects ; }, abstract = {The purpose of the present study was to better understand the role of sweet taste perception in dietary behavior and body weight in outbred Sprague-Dawley phenotypic obesity-prone and obesity-resistant rats by measuring sucrose taste sensitivity using a conditioned taste aversion paradigm. Rats were given a high fat diet for 2 weeks and were assigned as obesity-prone (P, upper tertile) or obesity-resistant (R, lower tertile) based on weight gain. Each group was then given either chow (C, 10% fat) or the high fat diet (F, 46% fat) for the remainder of the experiment (∼18 weeks) such that there were four groups - obesity-prone on chow (C-P), obesity-prone on high fat (H-P), obesity-resistant on chow (C-R), obesity-resistant on high fat (H-R). The sucrose sensitivity of phenotypic obesity-prone rats is lower than that of obesity-resistant rats in either H-fed or C-fed group, and all H-fed rats were more sensitivity than their C-fed counterparts (H-P vs. C-P; H-R vs. C-R). Body weight gain and total calories intake of phenotypic obesity-prone rats are more than that of obesity-resistant rats. The results suggest that lower sucrose taste sensitivity may contribute to body weight gain and total calories intake of phenotypic obesity-prone rats compared to obesity-resistant rats, and there is correlation between the change in the sweet taste threshold and diet treatment.}, } @article {pmid28544245, year = {2017}, author = {Abegg, K and Bernasconi, L and Hutter, M and Whiting, L and Pietra, C and Giuliano, C and Lutz, TA and Riediger, T}, title = {Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity-related metabolic disease.}, journal = {Diabetes, obesity & metabolism}, volume = {19}, number = {12}, pages = {1740-1750}, doi = {10.1111/dom.13020}, pmid = {28544245}, issn = {1463-1326}, mesh = {Animals ; Anti-Obesity Agents/adverse effects/pharmacology/*therapeutic use ; Arcuate Nucleus of Hypothalamus/drug effects/metabolism/pathology ; Diabetes Mellitus, Type 2/*drug therapy/metabolism/pathology/physiopathology ; Diet, High-Fat/adverse effects ; Drug Inverse Agonism ; Energy Intake/drug effects ; HEK293 Cells ; Humans ; Hyperlipidemias/etiology/*prevention & control ; Hypoglycemic Agents/adverse effects/pharmacology/*therapeutic use ; Islets of Langerhans/drug effects/metabolism/pathology ; Liver/drug effects/metabolism/pathology ; Mice ; Neurons/drug effects/metabolism/pathology ; Non-alcoholic Fatty Liver Disease/etiology/*prevention & control ; Obesity/*drug therapy/metabolism/pathology/physiopathology ; Random Allocation ; Rats ; Rats, Zucker ; Receptors, Ghrelin/*agonists/antagonists & inhibitors/metabolism ; Weight Gain/drug effects ; }, abstract = {AIMS: Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand-independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR-IA) might be effective for the treatment of obesity-related metabolic disease, we tested 2 novel synthetic compounds GHSR-IA1 and GHSR-IA2.

MATERIALS AND METHODS: In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR-IA1 and GHSR-IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet-induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids.

RESULTS: Both compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR-IA1 increased metabolic rate in chow-fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR-IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair-fed and vehicle-treated mice. GHSR-IA2-treated DIO mice showed decreased blood lipids. GHSR-IA1 treatment markedly decreased HS in DIO mice.

CONCLUSIONS: Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity-related metabolic disorders including diabetes mellitus.}, } @article {pmid28476409, year = {2017}, author = {Rorabaugh, B and Seeley, S and Evans, M and Marengo, C and D'Souza, M}, title = {Differential behavioral effects of nicotine in adult male and female rats with a history of prenatal methamphetamine exposure.}, journal = {Neuroscience letters}, volume = {651}, number = {}, pages = {116-122}, doi = {10.1016/j.neulet.2017.05.002}, pmid = {28476409}, issn = {1872-7972}, mesh = {Animals ; Avoidance Learning/drug effects ; Behavior, Animal/*drug effects ; Central Nervous System Stimulants/*administration & dosage ; Conditioning, Classical ; Female ; Locomotion/drug effects ; Male ; Methamphetamine/*administration & dosage ; Nicotine/*administration & dosage ; Pregnancy ; Prenatal Exposure Delayed Effects/*psychology ; Rats, Sprague-Dawley ; }, abstract = {The goal of the current study was to assess the effects of prenatal methamphetamine (MA)/saline exposure on nicotine-induced stimulant and aversive effects in both male and female adult rats. The aversive effects of nicotine were assessed using the nicotine-induced conditioned taste aversion model (0.4mg/kg, base), while the stimulant effects of nicotine were measured by assessing changes in spontaneous locomotor activity after subcutaneous administration of different doses of nicotine (0, 0.1 & 0.4mg/kg, base). The aversive effects of nicotine were significantly decreased in male, but not in female rats with a history of prenatal MA exposure compared to respective saline controls. No influence of prenatal MA exposure was observed on nicotine-induced increase in locomotor activity in either male or female rats. In conclusion, males with a history of prenatal MA exposure may be more vulnerable to nicotine addiction due to a decrease in nicotine-induced aversive effects.}, } @article {pmid28450080, year = {2017}, author = {Aonuma, H and Kaneda, M and Hatakeyama, D and Watanabe, T and Lukowiak, K and Ito, E}, title = {Weak involvement of octopamine in aversive taste learning in a snail.}, journal = {Neurobiology of learning and memory}, volume = {141}, number = {}, pages = {189-198}, doi = {10.1016/j.nlm.2017.04.010}, pmid = {28450080}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Central Nervous System/*metabolism ; Food Deprivation/physiology ; Lymnaea/drug effects/physiology ; Octopamine/*metabolism/pharmacology ; Phentolamine/pharmacology ; Receptors, Biogenic Amine/agonists/antagonists & inhibitors ; Signal Transduction/drug effects/physiology ; Taste/*drug effects/physiology ; }, abstract = {The pond snail Lymnaea stagnalis is capable of learning taste aversion by pairing presentations of a sucrose solution and an electric shock and consolidating it into long-term memory (LTM), which is referred to as conditioned taste aversion (CTA). We asked here if the neurotransmitter octopamine is involved in CTA. We first determined the levels of octopamine and its catabolites in the central nervous system (CNS) of snails with varying degrees of food deprivation, because CTA grades are correlated with degrees of food deprivation. We next manipulated the octopamine signaling using both an agonist and an antagonist of octopamine receptors and correlated their respective effects with CTA grades. We found that snails with the least amount of food-deprivation obtained the best CTA grade and had low levels of octopamine; whereas the most severely food-deprived snails did not form CTA and had the highest CNS octopamine levels. In modestly food-deprived snails, octopamine application increased the basal level of feeding response to a sucrose solution, and it did not obstruct CTA formation. Application of phentolamine, an octopamine receptor antagonist, to the most severely food-deprived snails decreased the basal level of feeding elicited by sucrose, but it did not enhance CTA formation. We conclude that octopamine involvement in CTA formation in Lymnaea is at best weak, and that the changes in CNS octopamine content are an epiphenomenon.}, } @article {pmid28432009, year = {2017}, author = {Sheth, C and Furlong, TM and Keefe, KA and Taha, SA}, title = {The lateral hypothalamus to lateral habenula projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption.}, journal = {Behavioural brain research}, volume = {328}, number = {}, pages = {195-208}, pmid = {28432009}, issn = {1872-7549}, support = {R01 MH094870/MH/NIMH NIH HHS/United States ; }, mesh = {Alcohol Drinking/pathology/*physiopathology ; Animals ; Basal Forebrain/pathology/*physiopathology ; Central Nervous System Depressants/administration & dosage ; Drug-Seeking Behavior/physiology ; Ethanol/administration & dosage ; Habenula/pathology/*physiopathology ; Hypothalamic Area, Lateral/pathology/*physiopathology ; Male ; Neural Pathways/pathology/physiopathology ; Rats, Long-Evans ; Self Administration ; Volition ; }, abstract = {The lateral habenula (LHb) is an epithalamic brain region implicated in aversive processing via negative modulation of midbrain dopamine (DA) and serotonin (5-HT) systems. Given the role of the LHb in inhibiting DA and 5-HT systems, it is thought to be involved in various psychiatric pathologies, including drug addiction. In support, it has been shown that LHb plays a critical role in cocaine- and ethanol-related behaviors, most likely by mediating drug-induced aversive conditioning. In our previous work, we showed that LHb lesions increased voluntary ethanol consumption and operant ethanol self-administration and blocked yohimbine-induced reinstatement of ethanol self-administration. LHb lesions also attenuated ethanol-induced conditioned taste aversion suggesting that a mechanism for the increased intake of ethanol may be reduced aversion learning. However, whether afferents to the LHb are required for mediating effects of the LHb on these behaviors remained to be investigated. Our present results show that lesioning the fiber bundle carrying afferent inputs to the LHb, the stria medullaris (SM), increases voluntary ethanol consumption, suggesting that afferent structures projecting to the LHb are important for mediating ethanol-directed behaviors. We then chose two afferent structures as the focus of our investigation. We specifically studied the role of the inputs from the lateral hypothalamus (LH) and ventral pallidum (VP) to the LHb in ethanol-directed behaviors. Our results show that the LH-LHb projection is necessary for regulating voluntary ethanol consumption. These results are an important first step towards understanding the functional role of afferents to LHb with regard to ethanol consumption.}, } @article {pmid28383939, year = {2017}, author = {Gasalla, P and Soto, A and Dwyer, DM and López, M}, title = {Blocking of flavor-nausea learning by non-flavor cues: Assessment through orofacial reactivity responses.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {43}, number = {2}, pages = {171-182}, doi = {10.1037/xan0000135}, pmid = {28383939}, issn = {2329-8464}, mesh = {Animals ; *Avoidance Learning ; Conditioning, Classical ; *Cues ; Nausea ; Rats ; Taste ; }, abstract = {We investigated, using orofacial reactivity assessment, whether nonflavor context cues can elicit conditioned aversive reactions, and also whether context cues interfere, through blocking, with the reduction in taste palatability during taste aversion conditioning. Experiment 1 showed that a context previously paired with LiCl evoked aversive orofacial reactions, and also attenuated the reduction in palatability of a saccharin solution which was paired with LiCl in that context. In Experiment 2, this blocking effect was abolished when the rats were given nonreinforced exposure to the previously LiCl-paired context (context extinction) before aversive conditioning of the saccharin in compound with the context. These results confirm that context stimuli can elicit conditioned aversive reactions in the absence of any flavor component, and demonstrate that context cues can interfere with the affective aspects of taste aversion learning. Thus nonflavor cues appear to engage the same processes as taste cues in aversion learning. These results are consistent with the idea that taste aversion learning is governed by general associative mechanisms and the special properties of nausea, rather than by a selective mechanism for poison-avoidance. (PsycINFO Database Record}, } @article {pmid28382659, year = {2017}, author = {Egervari, G and Rahman, T}, title = {Increased firing of lateral habenula neurons mediates ethanol aversion: potential implications for substance use disorders.}, journal = {The Journal of physiology}, volume = {595}, number = {13}, pages = {4135-4136}, pmid = {28382659}, issn = {1469-7793}, mesh = {*Ethanol ; *Habenula ; Humans ; Neurons ; Substance-Related Disorders ; Taste ; }, } @article {pmid31976952, year = {2017}, author = {Keenan, M}, title = {The Fuzzy Outline of an Operant.}, journal = {The Behavior analyst}, volume = {40}, number = {1}, pages = {187-191}, pmid = {31976952}, issn = {0738-6729}, } @article {pmid28323090, year = {2017}, author = {Soto, A and Gasalla, P and Begega, A and López, M}, title = {c-Fos activity in the insular cortex, nucleus accumbens and basolateral amygdala following the intraperitoneal injection of saccharin and lithium chloride.}, journal = {Neuroscience letters}, volume = {647}, number = {}, pages = {32-37}, doi = {10.1016/j.neulet.2017.03.025}, pmid = {28323090}, issn = {1872-7972}, mesh = {Animals ; Avoidance Learning ; Basolateral Nuclear Complex/*metabolism ; Cerebral Cortex/*metabolism ; Injections, Intraperitoneal ; Lithium Chloride/*administration & dosage ; Male ; Nucleus Accumbens/*metabolism ; Proto-Oncogene Proteins c-fos/*metabolism ; Rats, Wistar ; Saccharin/*administration & dosage ; *Taste ; }, abstract = {This study examined c-Fos expression in selected brain areas consequent to intraperitoneal (IP) administration of saccharin and lithium chloride. Rats were tested for aversion to the saccharin as measured by flavor consumption and orofacial reactions in the taste reactivity (TR) test. It was found that intraperitoneal conditioning resulted in the reduction in voluntary consumption but not in the production of aversive orofacial responses to the saccharin. The immunohistochemistry quantification revealed increased c-Fos activity in the insular cortex, the shell and core regions of the nucleus accumbens, and the basolateral nucleus of the amygdala. These results show that a conditioned taste aversion can be induced without direct oropharyngeal gustatory stimulation at the time of conditioning. In addition, this study provide evidence of increased neural activity in response to intraperitoneal saccharin injections.}, } @article {pmid28234597, year = {2017}, author = {Huang, TN and Hsueh, YP}, title = {Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice.}, journal = {Journal of psychiatry & neuroscience : JPN}, volume = {42}, number = {1}, pages = {37-47}, pmid = {28234597}, issn = {1488-2434}, mesh = {Amygdala/enzymology/pathology ; Animals ; *Association ; Autism Spectrum Disorder/*enzymology/pathology ; Conditioning, Psychological/physiology ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Extinction, Psychological/physiology ; Fear/physiology ; Guanylate Kinases/genetics/*metabolism ; Intellectual Disability/*enzymology/pathology ; Male ; Memory/*physiology ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Transgenic ; Receptors, N-Methyl-D-Aspartate/metabolism ; T-Box Domain Proteins ; Taste Perception/physiology ; }, abstract = {BACKGROUND: Human genetic studies have indicated that mutations in calcium/calmodulin-dependent serine protein kinase (CASK) result in X-linked mental retardation and autism-spectrum disorders. We aimed to establish a mouse model to study how Cask regulates mental ability.

METHODS: Because Cask encodes a multidomain scaffold protein, a possible strategy to dissect how CASK regulates mental ability and cognition is to disrupt specific protein-protein interactions of CASK in vivo and then investigate the impact of individual specific protein interactions. Previous in vitro analyses indicated that a rat CASK T724A mutation reduces the interaction between CASK and T-brain-1 (TBR1) in transfected COS cells. Because TBR1 is critical for glutamate receptor, ionotropic, N-methyl-D-aspartate receptor subunit 2B (Grin2b) expression and is a causative gene for autism and intellectual disability, we then generated CASK T740A (corresponding to rat CASK T724A) mutant mice using a gene-targeting approach. Immunoblotting, coimmunoprecipitation, histological methods and behavioural assays (including home cage, open field, auditory and contextual fear conditioning and conditioned taste aversion) were applied to investigate expression of CASK and its related proteins, the protein-protein interactions of CASK, and anatomic and behavioural features of CASK T740A mice.

RESULTS: The CASK T740A mutation attenuated the interaction between CASK and TBR1 in the brain. However, CASK T740A mice were generally healthy, without obvious defects in brain morphology. The most dramatic defect among the mutant mice was in extinction of associative memory, though acquisition was normal.

LIMITATIONS: The functions of other CASK protein interactions cannot be addressed using CASK T740A mice.

CONCLUSION: Disruption of the CASK and TBR1 interaction impairs extinction, suggesting the involvement of CASK in cognitive flexibility.}, } @article {pmid28222821, year = {2017}, author = {Albanell, E and Manuelian, CL and Rovai, M and Salama, AAK and Caja, G}, title = {Using long-term averted goats for selective grazing in olive groves.}, journal = {Animal : an international journal of animal bioscience}, volume = {11}, number = {10}, pages = {1832-1838}, doi = {10.1017/S1751731117000362}, pmid = {28222821}, issn = {1751-732X}, mesh = {Animal Feed ; Animal Husbandry ; Animals ; Avoidance Learning ; Conditioning, Psychological ; *Feeding Behavior ; Fruit ; Goats/*physiology/psychology ; Lithium Chloride/*administration & dosage ; Male ; *Olea ; Plant Leaves ; Taste ; }, abstract = {Conditioned taste aversion (CTA) is a useful tool to modify animal feed preferences, allowing the implementation of selective grazing to control weeds in tree orchards without damaging the trees or affecting fruit production. LiCl is commonly used for inducing CTA. However, studies investigating the long-term persistence of CTA by LiCl in small ruminants are scarce. With this aim, we evaluated the efficiency of two LiCl doses (AV1 and AV2, 175 and 200 mg/kg BW, respectively) and a control (C, 0 mg/kg BW) for averting non-lactating dairy goats (n=15) to olive tree leaves. Aversion induction was reinforced on day 9 in those goats that consumed >10 g of olive leaves. Mid-term aversion effectiveness was assessed by five double-choice feeding tests (days 16, 24, 31, 38 and 53) of 30 min each, where 100 g of olive leaves were offered side-by-side with 390 g of Italian rye-grass (as-fed). Long-term aversion effectiveness was assessed in C, AV1 and AV2 goats by grazing for 30 min in paddocks with a simulated olive tree (days 59, 90, 121, 182 and 420). Moreover, C and AV2 goats were compared under on-field conditions (days 143, 211 and 363) in a commercial olive grove also for 30 min. The CTA proved to be established with a single LiCl dose in all goats and persisted for 4 and 55 days in AV1 and AV2 goats, respectively (P<0.001). However, 80% AV1 and 20% AV2 goats needed to be reinforced at day 9. When grazing under simulated olive tree and commercial olive grove conditions, the CTA goats, especially AV2 group, avoided the contact with the olive trees and minimally used a bipedal stance to feed leaves, than control goats. On average, time proportion spent consuming olive leaves and sprouts was much greater (P<0.05) for C (50.7±9.1%) than for AV1 (14.4±3.9%) and AV2 (3.1±0.9%). In conclusion, the 200 mg LiCl/kg BW dose was more effective than the 175 mg LiCl/kg BW dose for inducing an effective long-term CTA to olive tree leaves in goats.}, } @article {pmid28218622, year = {2017}, author = {Gaykema, RP and Newmyer, BA and Ottolini, M and Raje, V and Warthen, DM and Lambeth, PS and Niccum, M and Yao, T and Huang, Y and Schulman, IG and Harris, TE and Patel, MK and Williams, KW and Scott, MM}, title = {Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight.}, journal = {The Journal of clinical investigation}, volume = {127}, number = {3}, pages = {1031-1045}, pmid = {28218622}, issn = {1558-8238}, support = {R00 DA024719/DA/NIDA NIH HHS/United States ; R01 DK101946/DK/NIDDK NIH HHS/United States ; F32 DK102294/DK/NIDDK NIH HHS/United States ; T32 GM007055/GM/NIGMS NIH HHS/United States ; R01 DK100699/DK/NIDDK NIH HHS/United States ; R01 NS075157/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Body Weight/*physiology ; Eating/*physiology ; Gluconeogenesis/genetics ; Hypothalamo-Hypophyseal System/*metabolism ; Mice ; Mice, Transgenic ; Neurons/*metabolism ; Pituitary-Adrenal System/*metabolism ; Proglucagon/genetics/*metabolism ; Rhombencephalon/metabolism ; }, abstract = {Peptides derived from pre-proglucagon (GCG peptides) act in both the periphery and the CNS to change food intake, glucose homeostasis, and metabolic rate while playing a role in anxiety behaviors and physiological responses to stress. Although the actions of GCG peptides produced in the gut and pancreas are well described, the role of glutamatergic GGC peptide-secreting hindbrain neurons in regulating metabolic homeostasis has not been investigated. Here, we have shown that chemogenetic stimulation of GCG-producing neurons reduces metabolic rate and food intake in fed and fasted states and suppresses glucose production without an effect on glucose uptake. Stimulation of GCG neurons had no effect on corticosterone secretion, body weight, or conditioned taste aversion. In the diet-induced obese state, the effects of GCG neuronal stimulation on gluconeogenesis were lost, while the food intake-lowering effects remained, resulting in reductions in body weight and adiposity. Our work suggests that GCG peptide-expressing neurons can alter feeding, metabolic rate, and glucose production independent of their effects on hypothalamic pituitary-adrenal (HPA) axis activation, aversive conditioning, or insulin secretion. We conclude that GCG neurons likely stimulate separate populations of downstream cells to produce a change in food intake and glucose homeostasis and that these effects depend on the metabolic state of the animal.}, } @article {pmid28216206, year = {2017}, author = {Lückemann, L and Unteroberdörster, M and Kirchhof, J and Schedlowski, M and Hadamitzky, M}, title = {Applications and limitations of behaviorally conditioned immunopharmacological responses.}, journal = {Neurobiology of learning and memory}, volume = {142}, number = {Pt A}, pages = {91-98}, doi = {10.1016/j.nlm.2017.02.012}, pmid = {28216206}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*drug effects ; Conditioning, Classical/*drug effects ; Humans ; Immunosuppressive Agents/*pharmacology ; Memory/*drug effects ; Memory Consolidation/*drug effects ; Rats ; }, abstract = {The importance of placebo responses for the treatment of various medical conditions has increasingly been recognized, whereas knowledge and systematic application in clinical settings are still sparse. One possible application for placebo responses in pharmacotherapy is given by learning paradigms, such as behaviorally conditioned immunosuppression, aiming at drug dose reduction while maintaining therapeutic efficacy of drug treatment. In an established learning paradigm of conditioned taste aversion/avoidance (CTA) in both, rats and humans, respectively, a novel-tasting drinking solution (conditioned stimulus, CS) is paired with an injection of the immunosuppressive drug cyclosporine A (CsA) as unconditioned stimulus (US). The conditioned response, evoked by re-presenting the CS alone at a later time, is reflected by avoidance behavior of consuming the solution (conditioned taste aversion; CTA) and a diminished interleukin (IL)-2 and interferon (IFN)-γ cytokine production as well as mRNA expression of rat splenic T cells or human peripheral T lymphocytes, closely mimicking the immunosuppressive effects of CsA. However, due to unreinforced CS-re-exposure conditioned responses progressively decreases over time (extinction), reflecting a considerable challenge for potential clinical applications of this learned immunosuppression. The present article discusses and critically reviews actual approaches, applications but also limitations of learning paradigms in immune pharmacotherapy.}, } @article {pmid28164781, year = {2017}, author = {Kim, H and Kirkhart, C and Scott, K}, title = {Long-range projection neurons in the taste circuit of Drosophila.}, journal = {eLife}, volume = {6}, number = {}, pages = {}, pmid = {28164781}, issn = {2050-084X}, support = {R01 DC013280/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; *Brain Mapping ; Drosophila melanogaster/*anatomy & histology/*physiology ; Neural Pathways/*anatomy & histology/*physiology ; Neurons/*physiology ; *Taste Perception ; }, abstract = {Taste compounds elicit innate feeding behaviors and act as rewards or punishments to entrain other cues. The neural pathways by which taste compounds influence innate and learned behaviors have not been resolved. Here, we identify three classes of taste projection neurons (TPNs) in Drosophila melanogaster distinguished by their morphology and taste selectivity. TPNs receive input from gustatory receptor neurons and respond selectively to sweet or bitter stimuli, demonstrating segregated processing of different taste modalities. Activation of TPNs influences innate feeding behavior, whereas inhibition has little effect, suggesting parallel pathways. Moreover, two TPN classes are absolutely required for conditioned taste aversion, a learned behavior. The TPNs essential for conditioned aversion project to the superior lateral protocerebrum (SLP) and convey taste information to mushroom body learning centers. These studies identify taste pathways from sensory detection to higher brain that influence innate behavior and are essential for learned responses to taste compounds.}, } @article {pmid28148214, year = {2017}, author = {Sunada, H and Lukowiak, K and Ito, E}, title = {Cerebral Giant Cells are Necessary for the Formation and Recall of Memory of Conditioned Taste Aversion in Lymnaea.}, journal = {Zoological science}, volume = {34}, number = {1}, pages = {72-80}, doi = {10.2108/zs160152}, pmid = {28148214}, issn = {0289-0003}, mesh = {Animals ; Giant Cells/*physiology ; Lymnaea/*cytology/*physiology ; Memory/physiology ; Neurons/*physiology ; Taste/*physiology ; }, abstract = {The pond snail Lymnaea stagnalis can acquire conditioned taste aversion (CTA) as a long-term memory. CTA is caused by the temporal pairing of a stimulus, such as sucrose (the conditioned stimulus; CS), with another stimulus, such as electric shock (the unconditioned stimulus; US). Previous studies have demonstrated changes in both cellular and molecular properties in a pair of neurons known as the cerebral giant cells (CGCs), suggesting that these neurons play a key role in CTA. Here we examined the necessity of the pair of CGC somata for the learning, memory formation and memory recall of CTA by using the soma ablation technique. There was no difference in the feeding response elicited by the CS before and after ablation of the CGC somata. Ablation of the CGC somata before taste-aversion training resulted in the learning acquisition, but the memory formation was not observed 24 h later. We next asked whether memory was present when the CGC somata were ablated 24 h after taste-aversion training. The memory was present before performing the somata ablation. However, when we tested snails five days after somata ablation, the memory recall was not present. Together the data show that: 1) the somata of the CGCs are not necessary for learning acquisition; 2) the somata are necessary for memory formation; and 3) the somata are necessary for memory recall. That is, these results demonstrate that the CGCs function in the long-term memory of CTA in Lymnaea.}, } @article {pmid28127358, year = {2016}, author = {Veysi, A and Vatandoost, H and Yaghoobi-Ershadi, MR and Jafari, R and Arandian, MH and Hosseini, M and Fadaei, R and Ramazanpour, J and Heidari, K and Sadjadi, A and Shirzadi, MR and Akhavan, AA}, title = {Rodenticide Comparative Effect of Klerat® and Zinc Phosphide for Controlling Zoonotic Cutaneous Leishmaniasis in Central Iran.}, journal = {Iranian journal of parasitology}, volume = {11}, number = {4}, pages = {471-479}, pmid = {28127358}, issn = {1735-7020}, abstract = {BACKGROUND: Zoonotic cutaneous leishmaniasis (ZCL) is a neglected disease with public health importance that is common in many rural areas of Iran. In recent years, behavioral resistance and/or bait shyness against the common rodenticide among reservoir hosts of ZCL have been reported. The aim of this study was to evaluate the effectiveness of Klerat® and zinc phosphide against natural reservoir of ZCL.

METHODS: This survey was carried out in four villages located 45 to 95 km far from Esfahan City Esfahan province, central Iran from April to November 2011. The rodent burrows were counted destroyed and reopened holes baited around all villages. Effect of rodent control operation on the main vector density and incidence of ZCL were evaluated.

RESULTS: The reduction rate of rodent burrows after intervention calculated to be at 62.8% in Klerat® and 58.15% in zinc phosphide treated areas. Statistical analysis showed no difference between the densities of the vector in indoors and outdoors in intervention and control areas. The incidence of the disease between treated and control areas after intervention was statistically different (P< 0.05).

CONCLUSION: Klerat® could be a suitable alternative for zinc phosphide in a specific condition such as behavior resistance or occurrence of bait shyness.}, } @article {pmid28126819, year = {2017}, author = {Yokose, J and Okubo-Suzuki, R and Nomoto, M and Ohkawa, N and Nishizono, H and Suzuki, A and Matsuo, M and Tsujimura, S and Takahashi, Y and Nagase, M and Watabe, AM and Sasahara, M and Kato, F and Inokuchi, K}, title = {Overlapping memory trace indispensable for linking, but not recalling, individual memories.}, journal = {Science (New York, N.Y.)}, volume = {355}, number = {6323}, pages = {398-403}, doi = {10.1126/science.aal2690}, pmid = {28126819}, issn = {1095-9203}, mesh = {Amygdala/cytology/*physiology ; Animals ; Conditioning, Classical/drug effects/*physiology ; Cues ; Fear ; Freezing Reaction, Cataleptic ; Mental Recall/*physiology ; Mice ; Neurons/physiology ; Saccharin/pharmacology ; }, abstract = {Memories are not stored in isolation from other memories but are integrated into associative networks. However, the mechanisms underlying memory association remain elusive. Using two amygdala-dependent behavioral paradigms-conditioned taste aversion (CTA) and auditory-cued fear conditioning (AFC)-in mice, we found that presenting the conditioned stimulus used for the CTA task triggered the conditioned response of the AFC task after natural coreactivation of the memories. This was accompanied through an increase in the overlapping neuronal ensemble in the basolateral amygdala. Silencing of the overlapping ensemble suppressed CTA retrieval-induced freezing. However, retrieval of the original CTA or AFC memory was not affected. A small population of coshared neurons thus mediates the link between memories. They are not necessary for recalling individual memories.}, } @article {pmid28095308, year = {2017}, author = {Sanchís-Ollé, M and Ortega-Sánchez, JA and Belda, X and Gagliano, H and Nadal, R and Armario, A}, title = {Lithium-induced malaise does not interfere with adaptation of the hypothalamic-pituitary-adrenal axis to stress.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {75}, number = {}, pages = {77-83}, doi = {10.1016/j.pnpbp.2017.01.006}, pmid = {28095308}, issn = {1878-4216}, mesh = {Adaptation, Physiological/*drug effects ; Adrenocorticotropic Hormone/blood ; Animals ; Antimanic Agents/*adverse effects ; Body Weight/drug effects ; Corticosterone/blood ; Disease Models, Animal ; Hypothalamo-Hypophyseal System/*drug effects ; Lithium Chloride/*adverse effects ; Male ; Pituitary-Adrenal System/*drug effects ; Radioimmunoassay ; Rats ; Rats, Sprague-Dawley ; Saccharin/metabolism ; Stress, Psychological/*drug therapy/metabolism ; Time Factors ; }, abstract = {We have recently demonstrated that adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to repeated exposure to a stressor does not follow the rules of habituation and can be fully expressed after a single experience with severe stressors. In the present work we tested the hypothesis that adaptation could be impaired if animals experience malaise during initial exposure to the stressor. To this end, animals were allowed to drink saccharin for 30min before being exposed for 3h to immobilization on boards (IMO), a severe stressor; then they were given either saline or lithium ip after the first hour of IMO. Stress-naïve rats followed exactly the same procedure except IMO. Exposure to IMO caused a strong activation of the HPA axis whereas the effect of lithium was modest. Both IMO and lithium administration resulted in conditioned taste aversion to saccharin when evaluated 4days later. When all animals were exposed to IMO 6days later, reduced HPA response and less impact on body weight was observed in the two groups previously exposed to IMO as compared with stress-naïve rats. Therefore, lithium administration during the first IMO exposure did not affect adaptation of the HPA axis and weight gain. These results indicate that malaise per se only weakly activated the HPA axis and argue against the hypothesis that signs of physical malaise during exposure to the stressor could impair HPA adaptation.}, } @article {pmid28040488, year = {2017}, author = {Yamaguchi, E and Yasoshima, Y and Shimura, T}, title = {Systemic administration of anorexic gut peptide hormones impairs hedonic-driven sucrose consumption in mice.}, journal = {Physiology & behavior}, volume = {171}, number = {}, pages = {158-164}, doi = {10.1016/j.physbeh.2016.12.034}, pmid = {28040488}, issn = {1873-507X}, mesh = {Analysis of Variance ; Animals ; Antimanic Agents/pharmacology ; Avoidance Learning/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Eating/*drug effects ; Gastrointestinal Hormones/*pharmacology ; Glucagon-Like Peptide 1/pharmacology ; Lithium Chloride/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Peptide Fragments/pharmacology ; Peptide YY/pharmacology ; Philosophy ; Sincalide/pharmacology ; Sucrose/*administration & dosage ; Sweetening Agents/*administration & dosage ; Taste/drug effects ; Time Factors ; }, abstract = {A number of reports suggest that gut hormones such as cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY(3-36) (PYY3-36), which are released postprandially, suppress homeostatic food intake and result in satiety and the termination of feeding. However, it remains unclear whether these peptide hormones also suppress non-homeostatic consumption of palatable foods or fluids. To examine whether gut hormones reduce hedonically motivated sugar consumption, we assessed the effects of intraperitoneal administration of these gut hormones on the consumption of a highly palatable sucrose solution, using a mouse model we previously established for binge-like sucrose overconsumption (Yasoshima and Shimura, 2015). To reduce homeostatic hunger, chow was available at nighttime prior to testing. After a limited-access training procedure for 10days, during which access to both sucrose and chow were controlled, on the test day, control mice injected with saline consumed significantly more sucrose than during the pre-training period. In contrast, sucrose consumption on the test day in the mice injected with CCK-8 (2 and 4μg/kg), GLP-1 (500 and 1000nmol/kg), or PYY3-36 (12.5 and 25nmol/kg) was significantly less than that in saline-injected mice. In a separate cohort of mice, the higher doses of CCK-8 and GLP-1 and a greater dose of PYY3-36 (50nmol/kg) did not produce conditioned taste aversion to saccharin, suggesting that the doses of exogenous hormones in the present study do not cause aversive visceral distress. The present findings suggest that the systemic administration of these three gut hormones suppresses hedonic-driven sugar consumption due to the anorexic, but not aversive-visceral, effects of these hormones.}, } @article {pmid28034786, year = {2017}, author = {Rodríguez-Durán, LF and Martínez-Moreno, A and Escobar, ML}, title = {Bidirectional modulation of taste aversion extinction by insular cortex LTP and LTD.}, journal = {Neurobiology of learning and memory}, volume = {142}, number = {Pt A}, pages = {85-90}, doi = {10.1016/j.nlm.2016.12.014}, pmid = {28034786}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*physiology ; Cerebral Cortex/*physiology ; Conditioning, Classical/*physiology ; Extinction, Psychological/*physiology ; Long-Term Potentiation/*physiology ; Long-Term Synaptic Depression/*physiology ; Male ; Rats ; Rats, Wistar ; Taste/*physiology ; }, abstract = {The history of activity of a given neuron has been proposed to bidirectionally influence its future response to synaptic inputs. In particular, induction of synaptic plasticity expressions such as long-term potentiation (LTP) and long-term depression (LTD) modifies the performance of several behavioral tasks. Our previous studies in the insular cortex (IC), a neocortical region that has been related to acquisition and retention of conditioned taste aversion (CTA), have demonstrated that induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC pathway before CTA training enhances the retention of this task. In addition, we reported that CTA training triggers a persistent impairment in the ability to induce in vivo LTP in the IC. The aim of the present study was to investigate whether LTD can be induced in the Bla-IC projection in vivo, as well as, whether the extinction of CTA is bidirectionally modified by previous synaptic plasticity induction in this pathway. Thus, rats received 900 train pulses (five 250μs pulses at 250Hz) delivered at 1Hz in the Bla-IC projection in order to induce LTD or 10 trains of 100Hz/1s with an intertrain interval of 20s in order to induce LTP. Seven days after surgery, rats were trained in the CTA task including the extinction trials. Our results show that the Bla-IC pathway is able to express in vivo LTD in an N-Methyl-D-aspartate (NMDA) receptor-dependent manner. Induction of LTD in the Bla-IC projection previous to CTA training facilitates the extinction of this task. Conversely, LTP induction enhances CTA retention. The present results show the bidirectional modulation of CTA extinction in response to IC-LTP and LTD, providing evidence of the homeostatic adaptation of taste learning.}, } @article {pmid27984199, year = {2017}, author = {Yasoshima, Y and Shimura, T}, title = {Midazolam impairs the retrieval of conditioned taste aversion via opioidergic transmission in mice.}, journal = {Neuroscience letters}, volume = {636}, number = {}, pages = {64-69}, doi = {10.1016/j.neulet.2016.10.055}, pmid = {27984199}, issn = {1872-7972}, mesh = {Animals ; Avoidance Learning/*drug effects ; Conditioning, Classical ; Eating/drug effects ; Male ; Mice, Inbred C57BL ; Midazolam/*pharmacology ; Naloxone/pharmacology ; Narcotic Antagonists/pharmacology ; Receptors, Opioid/*agonists/physiology ; *Taste ; }, abstract = {Midazolam is a benzodiazepine agonist that affects the acquisition, retention, and retrieval of malaise-induced conditioned taste aversion (CTA) in rats. Our previous study suggested that the palatability-enhancing rather than amnesic effects of midazolam were responsible for impaired retrieval of conditioned aversion to palatable conditioned stimuli (CSs). However, it remains unclear whether this effect is opioid-dependent. In the present study, we examined the involvement of opioid signaling with the ability of peripheral midazolam administration to transiently impair CTA retrieval in mice. CTA was established by pairing 5mM saccharin ingestion (conditioned stimulus, CS) with an intraperitoneal (i.p.) injection of 0.15M lithium chloride (LiCl, 2% body weight) (unconditioned stimulus) for two consecutive days. Conditioned mice that received midazolam (1.5mg/kg, i.p.) before the first retention test consumed significantly more saccharin (CS) than conditioned mice that received vehicle (phosphate-buffered physiological saline, PBS; i.p.). On the next day, both conditioned groups showed strong aversions to the CS. Next, naloxone, an opioid receptor antagonist, was peripherally administered prior to the midazolam injection before the retention test. Pre-administration of naloxone but not PBS attenuated midazolam-induced increases in CS intake. Finally, we examined aversive orofacial taste reactions (TRs) to an oral infusion of the CS with pre-administration of naloxone or PBS prior to midazolam using a taste reactivity test. Conditioned mice that received midazolam showed significantly longer latencies to express aversive orofacial TRs than those that received PBS. Pre-administration of naloxone eliminated the effect of midazolam on latency to express aversive TRs. Taken together, these data suggest that midazolam activates opioidergic transmission and opioid-dependent palatability enhancement of the CS to eliminate conditioned aversion to a sweet taste.}, } @article {pmid27980072, year = {2017}, author = {Osorio-Gómez, D and Guzmán-Ramos, K and Bermúdez-Rattoni, F}, title = {Memory trace reactivation and behavioral response during retrieval are differentially modulated by amygdalar glutamate receptors activity: interaction between amygdala and insular cortex.}, journal = {Learning & memory (Cold Spring Harbor, N.Y.)}, volume = {24}, number = {1}, pages = {14-23}, pmid = {27980072}, issn = {1549-5485}, mesh = {6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology ; Amygdala/drug effects/*metabolism ; Analysis of Variance ; Animals ; Avoidance Learning/drug effects/*physiology ; Cerebral Cortex/*physiology ; Dopamine/metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/metabolism ; Male ; Mental Recall/drug effects/*physiology ; Neural Pathways/drug effects/*physiology ; Norepinephrine/metabolism ; Rats ; Rats, Wistar ; Receptors, Glutamate/*metabolism ; Taste/drug effects/physiology ; Valine/analogs & derivatives/pharmacology ; }, abstract = {The insular cortex (IC) is required for conditioned taste aversion (CTA) retrieval. However, it remains unknown which cortical neurotransmitters levels are modified upon CTA retrieval. Using in vivo microdialysis, we observed that there were clear elevations in extracellular glutamate, norepinephrine, and dopamine in and around the center of the gustatory zone of the IC during CTA retrieval. Additionally, it has been reported that the amygdala-IC interaction is highly involved in CTA memory establishment. Therefore, we evaluated the effects of infusions of an AMPA receptor antagonist (CNQX) and a NMDA receptor antagonist (APV) into the amygdala on CTA retrieval and IC neurotransmitter levels. Infusion of APV into the amygdala impaired glutamate augmentation within the IC, whereas dopamine and norepinephrine levels augmentation persisted and a reliable CTA expression was observed. Conversely, CNQX infusion into the amygdala impaired the aversion response, as well as norepinephrine and dopamine augmentations in the IC. Interestingly, CNQX infusion did not affect glutamate elevation in the IC. To evaluate the functional meaning of neurotransmitters elevations within the IC on CTA response, we infused specific antagonists for the AMPA, NMDA, D1, and β-adrenergic receptor before retrieval. Results showed that activation of AMPA, D1, and β-adrenergic receptors is necessary for CTA expression, whereas NMDA receptors are not involved in the aversion response.}, } @article {pmid27940259, year = {2017}, author = {Nilsson, A and Wilhelms, DB and Mirrasekhian, E and Jaarola, M and Blomqvist, A and Engblom, D}, title = {Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.}, journal = {Brain, behavior, and immunity}, volume = {61}, number = {}, pages = {236-243}, pmid = {27940259}, issn = {1090-2139}, mesh = {Animals ; Anorexia/chemically induced/genetics/*metabolism ; Avoidance Learning/drug effects/*physiology ; Cyclooxygenase 2/*genetics/metabolism ; Cyclooxygenase 2 Inhibitors ; Fever/chemically induced/genetics/*metabolism ; Inflammation/chemically induced/genetics/*metabolism ; Lipopolysaccharides ; Mice ; Taste/drug effects/*physiology ; }, abstract = {Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.}, } @article {pmid27924869, year = {2016}, author = {Li, WG and Liu, MG and Deng, S and Liu, YM and Shang, L and Ding, J and Hsu, TT and Jiang, Q and Li, Y and Li, F and Zhu, MX and Xu, TL}, title = {ASIC1a regulates insular long-term depression and is required for the extinction of conditioned taste aversion.}, journal = {Nature communications}, volume = {7}, number = {}, pages = {13770}, pmid = {27924869}, issn = {2041-1723}, mesh = {Acid Sensing Ion Channels/deficiency/*metabolism ; Amino Acid Sequence ; Animals ; Avoidance Learning/drug effects ; Cerebral Cortex/drug effects/*metabolism ; *Conditioning, Classical/drug effects ; Electric Stimulation ; *Extinction, Psychological/drug effects ; Glutamates/metabolism ; Glycine/analogs & derivatives/pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism ; *Long-Term Potentiation/drug effects ; Male ; Memory/drug effects ; Mice, Inbred C57BL ; Peptides/chemistry ; Resorcinols/pharmacology ; Signal Transduction/drug effects ; Synaptic Transmission/drug effects ; Taste/drug effects/*physiology ; }, abstract = {Acid-sensing ion channel 1a (ASIC1a) has been shown to play important roles in synaptic plasticity, learning and memory. Here we identify a crucial role for ASIC1a in long-term depression (LTD) at mouse insular synapses. Genetic ablation and pharmacological inhibition of ASIC1a reduced the induction probability of LTD without affecting that of long-term potentiation in the insular cortex. The disruption of ASIC1a also attenuated the extinction of established taste aversion memory without altering the initial associative taste learning or its long-term retention. Extinction of taste aversive memory led to the reduced insular synaptic efficacy, which precluded further LTD induction. The impaired LTD and extinction learning in ASIC1a null mice were restored by virus-mediated expression of wild-type ASIC1a, but not its ion-impermeable mutant, in the insular cortices. Our data demonstrate the involvement of an ASIC1a-mediated insular synaptic depression mechanism in extinction learning, which raises the possibility of targeting ASIC1a to manage adaptive behaviours.}, } @article {pmid27906463, year = {2016}, author = {Gaillard, D and Stratford, JM}, title = {Measurement of Behavioral Taste Responses in Mice: Two-Bottle Preference, Lickometer, and Conditioned Taste-Aversion Tests.}, journal = {Current protocols in mouse biology}, volume = {6}, number = {4}, pages = {380-407}, pmid = {27906463}, issn = {2161-2617}, support = {P30 DC004657/DC/NIDCD NIH HHS/United States ; R01 DC012383/DC/NIDCD NIH HHS/United States ; R01 DC012931/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; *Avoidance Learning ; Biological Assay/instrumentation/*methods ; *Conditioning, Classical ; *Food Preferences ; *Mice ; *Taste ; *Taste Perception ; }, abstract = {The natural like and dislike of foods based on taste is one of the most easily observed behaviors in animals. Animals eat palatable foods and reject aversive foods, which makes measurement of taste perception possible using various behavioral techniques. Three different methods to accurately measure taste behavior are described here. First, two-bottle preference tests evaluate whether a taste compound (tastant) is preferred over water. Second, lickometer tests quantify the like and dislike for multiple concentrations of the same tastant or multiple tastants at the same time. Finally, conditioned taste aversion tests accurately determine the perceived taste threshold for palatable tastants. Together, these diverse methods enable researchers to observe and measure behavioral taste responses in mice to any tastant. © 2016 by John Wiley & Sons, Inc.}, } @article {pmid27865867, year = {2017}, author = {Chan, J and Ni, Y and Zhang, P and Zhang, J and Chen, Y}, title = {D1-like dopamine receptor dysfunction in the lateral habenula nucleus increased anxiety-like behavior in rat.}, journal = {Neuroscience}, volume = {340}, number = {}, pages = {542-550}, doi = {10.1016/j.neuroscience.2016.11.005}, pmid = {27865867}, issn = {1873-7544}, mesh = {Animals ; Anxiety/*metabolism ; Catheters, Indwelling ; Depression/metabolism ; Dopamine Agents/pharmacology ; Habenula/drug effects/*metabolism ; Learning/drug effects/physiology ; Male ; Memory/drug effects/physiology ; Rats, Sprague-Dawley ; Receptors, Dopamine D1/agonists/antagonists & inhibitors/*metabolism ; Receptors, Dopamine D2/agonists/metabolism ; }, abstract = {Lateral habenula (LHb) is important for emotional processing. It is a link node between forebrain and midbrain. LHb is reciprocally connected with ventral tegmental area, acting as a regulatory center for the dopaminergic system. However, the role of dopamine receptors in the LHb in emotional processing is less clear. In the present study, the expression of dopamine D1 and D2 receptors in LHb was testified by western blot. In addition, D1- or D2-like receptor agonist or antagonist was bilaterally administered into the LHb, anxiety-like and depressive-like behaviors were tested 15min later in rats. In addition, the effects of LHb dopamine receptor activation and inactivation on aversive learning and memory were assessed. Our results showed that: (1) activation and inhibition of D1R but not D2R in LHb increased anxiety-like behavior but decreased depressive-like behavior in rats. (2) D1R activation and inactivation in LHb impaired aversive memory acquisition but not consolidation in rats, D1R agonist also impaired aversive memory retrieval in rats. These results might provide new clues about how LHb was involved in emotional processing.}, } @article {pmid27847246, year = {2017}, author = {Molero-Chamizo, A}, title = {Modulation of the magnitude of conditioned taste aversion in rats with excitotoxic lesions of the basolateral amygdala.}, journal = {Neurobiology of learning and memory}, volume = {137}, number = {}, pages = {56-64}, doi = {10.1016/j.nlm.2016.11.009}, pmid = {27847246}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Basolateral Nuclear Complex/drug effects/*physiology ; Conditioning, Classical/drug effects/*physiology ; Hippocampus/drug effects/*physiology ; Male ; N-Methylaspartate/*toxicity ; Rats ; Rats, Wistar ; Taste/physiology ; }, abstract = {The amygdala is one of the structures involved in the acquisition of conditioned taste aversion (CTA). Nevertheless, the specific roles that the nuclei of this structure play in CTA learning are controversial. Electrolytic lesions applied to the basolateral nucleus of the amygdala can eliminate or reduce the acquisition of this learning. This effect has been attributed to the involvement of fibers that pass through this nucleus and connect with other structures that are critical for CTA. Excitotoxic lesions may allow a clearer insight as to the potential involvement of this nucleus in the acquisition of CTA. The few studies to date that have used this paradigm have shown effects on taste aversion learning after applying extensive lesions to the amygdala. Thus, the aim of the present study was to determine the effect of selective excitotoxic lesions of the basolateral amygdala on the acquisition of CTA. The effects of these lesions on learning were compared with the effects observed in animals with sham lesions and animals with lesions of the hippocampus, which is a structure apparently not involved in CTA. The results revealed a decreased aversion in animals with basolateral lesions compared with both the sham and hippocampus-lesioned groups. Based on these findings, the role of this specific nucleus of the amygdala in the acquisition of taste aversion is briefly discussed.}, } @article {pmid27837417, year = {2017}, author = {Molero-Chamizo, A}, title = {Circadian-temporal context and latent inhibition of conditioned taste aversion: Effect of restriction in the intake of the conditioned taste stimulus.}, journal = {Learning & behavior}, volume = {45}, number = {2}, pages = {157-163}, pmid = {27837417}, issn = {1543-4508}, mesh = {Animals ; *Avoidance Learning ; *Conditioning, Classical ; Conditioning, Psychological ; Rats ; Rats, Wistar ; Taste ; *Taste Perception ; }, abstract = {Latent inhibition of conditioned taste aversion (CTA) is sensitive to changes in the temporal context. A change in the time of day of conditioning with respect to the time of day of the preexposure can disrupt the latent inhibition. This contextual change in the time of day may reveal a temporal specificity of latent inhibition. The optimum procedure to induce this temporal specificity is not well established. For example, it has been shown that a long period of habituation to temporal contexts is one factor that can determine the effect. However, the experimental conditions on the conditioning day that facilitate this phenomenon are unknown. The aim of this study is to elucidate whether a restriction in the intake of the conditioned taste stimulus affects the temporal specificity of latent inhibition. Two main groups of Wistar rats were tested in a latent inhibition of CTA paradigm, in which the temporal specificity of this phenomenon was analyzed by a change in the time of day of conditioning. The intake of the taste stimulus was restricted in the conditioning day in one of the groups, but this restriction was not applied in the other group. The results indicated temporal specificity of latent inhibition only in the group without restriction, but not in the group with limitation in the intake of the taste stimulus during conditioning. These findings can help to elucidate the characteristics of the procedure to induce temporal specificity of latent inhibition.}, } @article {pmid27825896, year = {2017}, author = {Inui, T and Shimura, T}, title = {Activation of mu-opioid receptors in the ventral pallidum decreases the negative hedonic evaluation of a conditioned aversive taste in rats.}, journal = {Behavioural brain research}, volume = {320}, number = {}, pages = {391-399}, doi = {10.1016/j.bbr.2016.10.051}, pmid = {27825896}, issn = {1872-7549}, mesh = {Adjuvants, Immunologic/pharmacology ; Analgesics, Opioid/pharmacology ; Animals ; Avoidance Learning/*drug effects ; Conditioning, Classical/drug effects/physiology ; Conditioning, Psychological/drug effects ; Drinking/drug effects ; Drug Delivery Systems ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology ; Globus Pallidus/drug effects/*metabolism ; Lithium Chloride/pharmacology ; Male ; Microinjections ; Rats ; Rats, Wistar ; Receptors, Opioid, mu/genetics/*metabolism ; Saccharin/administration & dosage ; Taste/drug effects/*physiology ; Taste Perception/*drug effects/physiology ; }, abstract = {Conditioned taste aversion (CTA) causes a shift in the hedonic evaluation of a conditioned stimulus (CS) from positive to negative, and reduces the CS intake. Mu-opioid receptors (MORs) in the ventral pallidum (VP) are known to be involved in the hedonic evaluation of positive rewarding stimuli; however, their involvement in evaluation of a negative aversive stimulus is still unclear. To explore the neural mechanisms of the negative hedonic evaluation of the CS in CTA, we examined the effects of the activation of VP MORs on the behavioral responses of rats to a CS. Rats implanted with guide cannulae into the bilateral VP received a pairing of 5mM saccharin solution as a CS with an intraperitoneal injection of 0.15M lithium chloride as an unconditioned stimulus. On the test day, after microinjections of MOR agonist [D-Ala[2], N-MePhe[4], Gly-ol]-enkephalin (DAMGO) into the VP, we observed the behavioral responses to the intraorally infused CS solution. The DAMGO injections caused a larger number of ingestive taste reactivity responses to the CS solution. We also measured the consumption of the CS solution in a separate group of rats, using a single-bottle test. The DAMGO injected rats drank a higher volume of the CS solution than the saline injected rats. These results indicate that the activation of MORs in the VP results in the attenuation of aversion to the CS solution, thereby inducing the larger CS intake. Therefore, it is likely that VP MORs are involved in not only positive but also negative hedonic evaluation.}, } @article {pmid27815244, year = {2016}, author = {Aonuma, H and Kaneda, M and Hatakeyama, D and Watanabe, T and Lukowiak, K and Ito, E}, title = {Relationship between the grades of a learned aversive-feeding response and the dopamine contents in Lymnaea.}, journal = {Biology open}, volume = {5}, number = {12}, pages = {1869-1873}, pmid = {27815244}, issn = {2046-6390}, abstract = {The pond snail Lymnaea learns conditioned taste aversion (CTA) and remembers not to respond to food substances that initially cause a feeding response. The possible relationship between how well snails learn to follow taste-aversion training and brain dopamine contents is not known. We examined this relationship and found the following: first, snails in the act of eating just before the commencement of CTA training were poor learners and had the highest dopamine contents in the brain; second, snails which had an ad libitum access to food, but were not eating just before training, were average learners and had lower dopamine contents; third, snails food-deprived for one day before training were the best learners and had significantly lower contents of dopamine compared to the previous two cohorts. There was a negative correlation between the CTA grades and the brain dopamine contents in these three cohorts. Fourth, snails food-deprived for five days before training were poor learners and had higher dopamine contents. Thus, severe hunger increased the dopamine content in the brain. Because dopamine functions as a reward transmitter, CTA in the severely deprived snails (i.e. the fourth cohort) was thought to be mitigated by a high dopamine content.}, } @article {pmid27663886, year = {2016}, author = {Licursi, M and Alberto, CO and Dias, A and Hirasawa, K and Hirasawa, M}, title = {High-fat diet-induced downregulation of anorexic leukemia inhibitory factor in the brain stem.}, journal = {Obesity (Silver Spring, Md.)}, volume = {24}, number = {11}, pages = {2361-2367}, doi = {10.1002/oby.21647}, pmid = {27663886}, issn = {1930-739X}, support = {RNL‐132870//CIHR/Canada ; }, mesh = {Animals ; Anorexia/*physiopathology ; Body Weight/drug effects ; Brain Stem/*metabolism ; Diet, High-Fat/*adverse effects ; *Down-Regulation ; Eating/drug effects ; Hypothalamus/metabolism ; Inflammation/metabolism ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Leukemia Inhibitory Factor/administration & dosage/*physiology ; Male ; RNA, Messenger/metabolism ; Rats ; Solitary Nucleus/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVE: High-fat diet (HFD) is known to induce low-grade hypothalamic inflammation. Whether inflammation occurs in other brain areas remains unknown. This study tested the effect of short-term HFD on cytokine gene expression and identified leukemia inhibitory factor (LIF) as a responsive cytokine in the brain stem. Thus, functional and cellular effects of LIF in the brain stem were investigated.

METHODS: Male rats were fed chow or HFD for 3 days, and then gene expression was analyzed in different brain regions for IL-1β, IL-6, TNF-α, and LIF. The effect of intracerebroventricular injection of LIF on chow intake and body weight was also tested. Patch clamp recording was performed in the nucleus tractus solitarius (NTS).

RESULTS: HFD increased pontine TNF-α mRNA while downregulating LIF in all major parts of the brain stem, but not in the hypothalamus or hippocampus. LIF injection into the cerebral aqueduct suppressed food intake without conditioned taste aversion, suggesting that LIF can induce anorexia via lower brain regions without causing malaise. In the NTS, a key brain stem nucleus for food intake regulation, LIF induced acute changes in neuronal excitability.

CONCLUSIONS: HFD-induced downregulation of anorexic LIF in the brain stem may provide a permissive condition for HFD overconsumption. This may be at least partially mediated by the NTS.}, } @article {pmid27594096, year = {2016}, author = {Mahiout, S and Pohjanvirta, R}, title = {Aryl hydrocarbon receptor agonists trigger avoidance of novel food in rats.}, journal = {Physiology & behavior}, volume = {167}, number = {}, pages = {49-59}, doi = {10.1016/j.physbeh.2016.08.033}, pmid = {27594096}, issn = {1873-507X}, mesh = {Analysis of Variance ; Animals ; Avoidance Learning/*drug effects ; Benzo(a)pyrene/metabolism/pharmacology ; Carbazoles/pharmacology ; Cytochrome P-450 CYP1A1/genetics/metabolism ; Cytochrome P-450 CYP2B1/genetics/metabolism ; Dose-Response Relationship, Drug ; Eating/drug effects ; Feeding Behavior/*drug effects ; Food Preferences/*drug effects ; Male ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Aryl Hydrocarbon/*agonists/metabolism ; Taste/*drug effects ; Time Factors ; beta-Naphthoflavone/pharmacology ; }, abstract = {The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of dioxins, but also plays important physiological roles, which are only beginning to unfold. Previous studies have surprisingly unveiled that low doses of the potent AHR agonist TCDD induce a strong and persistent avoidance of novel food items in rats. Here, we further examined the involvement of the AHR in the avoidance response in Sprague-Dawley rats with three established AHR agonists: 6-formylindolo(3,2-b)carbazole (FICZ), β-naphthoflavone (BNF) and benzo[a]pyrene (BaP); with a novel selective AHR modulator (C2); and with an activator of another nuclear receptor, CAR: 2,4,6-tryphenyldioxane-1,3 (TPD). As sensitive indices of AHR or CAR activity, we used Cyp1a1 and Cyp2b1 gene expression, as they are, respectively, the drug-metabolizing enzymes specifically regulated by them. We further attempted to address the roles played by enhanced neophobia and conditioned taste aversion (CTA) in the avoidance behaviour. All AHR agonists triggered practically total avoidance of novel chocolate, but the durations varied. Likewise, acutely subtoxic doses of C2, differing by 25-fold, all elicited a similar outcome. In contrast, TPD did not influence chocolate consumption at all. If rats were initially accustomed to chocolate for 6h after single FICZ or BNF exposure, avoidance was still clearly present two weeks later when chocolate was offered again. Hence, the avoidance response appears to specifically involve the AHR instead of being triggered by induction of intestinal or hepatic nuclear receptor signalling in general. It is also shared by both endogenous and exogenous AHR activators. Moreover, this behavioural change in rats seems to contain elements of both CTA and enhanced neophobia, but further clarification of this is still required.}, } @article {pmid27733615, year = {2016}, author = {Levitan, D and Fortis-Santiago, Y and Figueroa, JA and Reid, EE and Yoshida, T and Barry, NC and Russo, A and Katz, DB}, title = {Memory Retrieval Has a Dynamic Influence on the Maintenance Mechanisms That Are Sensitive to ζ-Inhibitory Peptide (ZIP).}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {36}, number = {41}, pages = {10654-10662}, pmid = {27733615}, issn = {1529-2401}, support = {R01 DC006666/DC/NIDCD NIH HHS/United States ; T32 MH019929/MH/NIMH NIH HHS/United States ; T32 NS007292/NS/NINDS NIH HHS/United States ; }, mesh = {Amnesia/chemically induced/psychology ; Animals ; Anisomycin/pharmacology ; Avoidance Learning/*drug effects ; Cell-Penetrating Peptides ; Conditioning, Classical/drug effects ; Female ; Lipopeptides/administration & dosage/*pharmacology ; Memory/*drug effects ; Mental Recall/*drug effects ; Microinjections ; Protein Synthesis Inhibitors/pharmacology ; Rats ; Rats, Long-Evans ; Somatosensory Cortex/anatomy & histology/drug effects ; Taste/*drug effects ; }, abstract = {UNLABELLED: In neuroscientists' attempts to understand the long-term storage of memory, topics of particular importance and interest are the cellular and system mechanisms of maintenance (e.g., those sensitive to ζ-inhibitory peptide, ZIP) and those induced by memory retrieval (i.e., reconsolidation). Much is known about each of these processes in isolation, but less is known concerning how they interact. It is known that ZIP sensitivity and memory retrieval share at least some molecular targets (e.g., recycling α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA, receptors to the plasma membrane); conversely, the fact that sensitivity to ZIP emerges only after consolidation ends suggests that consolidation (and by extension reconsolidation) and maintenance might be mutually exclusive processes, the onset of one canceling the other. Here, we use conditioned taste aversion (CTA) in rats, a cortically dependent learning paradigm, to test this hypothesis. First, we demonstrate that ZIP infusions into gustatory cortex begin interfering with CTA memory 43-45 h after memory acquisition-after consolidation ends. Next, we show that a retrieval trial administered after this time point interrupts the ability of ZIP to induce amnesia and that ZIP's ability to induce amnesia is reengaged only 45 h after retrieval. This pattern of results suggests that memory retrieval and ZIP-sensitive maintenance mechanisms are mutually exclusive and that the progression from one to the other are similar after acquisition and retrieval. They also reveal concrete differences between ZIP-sensitive mechanisms induced by acquisition and retrieval: the latency with which ZIP-sensitive mechanisms are expressed differ for the two processes.

SIGNIFICANCE STATEMENT: Memory retrieval and the molecular mechanisms that are sensitive to ζ-inhibitory peptide (ZIP) are the few manipulations that have been shown to effect memory maintenance. Although much is known about their effect on maintenance separately, it is unknown how they interact. Here, we describe a model for the interaction between memory retrieval and ZIP-sensitive mechanisms, showing that retrieval trials briefly (i.e., for 45 h) interrupt these mechanisms. ZIP sensitivity emerges across a similar time window after memory acquisition and retrieval; the maintenance mechanisms that follow acquisition and retrieval differ, however, in the latency with which the impact of ZIP is expressed.}, } @article {pmid27733609, year = {2016}, author = {Ramírez-Lugo, L and Peñas-Rincón, A and Ángeles-Durán, S and Sotres-Bayon, F}, title = {Choice Behavior Guided by Learned, But Not Innate, Taste Aversion Recruits the Orbitofrontal Cortex.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {36}, number = {41}, pages = {10574-10583}, pmid = {27733609}, issn = {1529-2401}, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Choice Behavior/drug effects/*physiology ; GABA Agonists/pharmacology ; Learning/drug effects/*physiology ; Male ; Memory/drug effects ; Muscimol/pharmacology ; Prefrontal Cortex/drug effects/*physiology ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Rats, Wistar ; Receptors, GABA-A/drug effects ; Receptors, GABA-B/drug effects ; Taste/drug effects/*physiology ; Taste Perception ; }, abstract = {UNLABELLED: The ability to select an appropriate behavioral response guided by previous emotional experiences is critical for survival. Although much is known about brain mechanisms underlying emotional associations, little is known about how these associations guide behavior when several choices are available. To address this, we performed local pharmacological inactivations of several cortical regions before retrieval of an aversive memory in choice-based versus no-choice-based conditioned taste aversion (CTA) tasks in rats. Interestingly, we found that inactivation of the orbitofrontal cortex (OFC), but not the dorsal or ventral medial prefrontal cortices, blocked retrieval of choice CTA. However, OFC inactivation left retrieval of no-choice CTA intact, suggesting its role in guiding choice, but not in retrieval of CTA memory. Consistently, OFC activity increased in the choice condition compared with no-choice, as measured with c-Fos immunolabeling. Notably, OFC inactivation did not affect choice behavior when it was guided by innate taste aversion. Consistent with an anterior insular cortex (AIC) involvement in storing taste memories, we found that AIC inactivation impaired retrieval of both choice and no-choice CTA. Therefore, this study provides evidence for OFC's role in guiding choice behavior and shows that this is dissociable from AIC-dependent taste aversion memory. Together, our results suggest that OFC is required and recruited to guide choice selection between options of taste associations relayed from AIC.

SIGNIFICANCE STATEMENT: Survival and mental health depend on being able to choose stimuli not associated with danger. This is particularly important when danger is associated with stimuli that we ingest. Although much is known about the brain mechanisms that underlie associations with dangerous taste stimuli, very little is known about how these stored emotional associations guide behavior when it involves choice. By combining pharmacological and immunohistochemistry tools with taste-guided tasks, our study provides evidence for the key role of orbitofrontal cortex activity in choice behavior and shows that this is dissociable from the adjacent insular cortex-dependent taste aversion memory. Understanding the brain mechanisms that underlie the impact that emotional associations have on survival choice behaviors may lead to better treatments for mental disorders characterized by emotional decision-making deficits.}, } @article {pmid27721985, year = {2016}, author = {Levitan, D and Gal-Ben-Ari, S and Heise, C and Rosenberg, T and Elkobi, A and Inberg, S and Sala, C and Rosenblum, K}, title = {The differential role of cortical protein synthesis in taste memory formation and persistence.}, journal = {NPJ science of learning}, volume = {1}, number = {}, pages = {16001}, pmid = {27721985}, issn = {2056-7936}, support = {GGP13187/TI_/Telethon/Italy ; }, abstract = {The current dogma suggests that the formation of long-term memory (LTM) is dependent on protein synthesis but persistence of the memory trace is not. However, many of the studies examining the effect of protein synthesis inhibitors (PSIs) on LTM persistence were performed in the hippocampus, which is known to have a time-dependent role in memory storage, rather than the cortex, which is considered to be the main structure to store long-term memories. Here we studied the effect of PSIs on LTM formation and persistence in male Wistar Hola (n ≥ 5) rats by infusing the protein synthesis inhibitor, anisomycin (100 μg, 1 μl), into the gustatory cortex (GC) during LTM formation and persistence in conditioned taste aversion (CTA). We found that local anisomycin infusion to the GC before memory acquisition impaired LTM formation (P = 8.9E - 5), but had no effect on LTM persistence when infused 3 days post acquisition (P = 0.94). However, when we extended the time interval between treatment with anisomycin and testing from 3 days to 14 days, LTM persistence was enhanced (P = 0.01). The enhancement was on the background of stable and non-declining memory, and was not recapitulated by another amnesic agent, APV (10 μg, 1 μl), an N-methyl-d-aspartate receptor antagonist (P = 0.54). In conclusion, CTA LTM remains sensitive to the action of PSIs in the GC even 3 days following memory acquisition. This sensitivity is differentially expressed between the formation and persistence of LTM, suggesting that increased cortical protein synthesis promotes LTM formation, whereas decreased protein synthesis promotes LTM persistence.}, } @article {pmid27682823, year = {2017}, author = {Tandon, S and Keefe, KA and Taha, SA}, title = {Excitation of lateral habenula neurons as a neural mechanism underlying ethanol-induced conditioned taste aversion.}, journal = {The Journal of physiology}, volume = {595}, number = {4}, pages = {1393-1412}, pmid = {27682823}, issn = {1469-7793}, support = {R01 MH094870/MH/NIMH NIH HHS/United States ; }, mesh = {Alcohol Drinking/*physiopathology ; Animals ; Conditioning, Operant ; Ethanol/*toxicity ; *Evoked Potentials, Somatosensory ; Habenula/cytology/*physiology ; Male ; Neurons/*physiology ; Rats ; Rats, Long-Evans ; Taste Disorders/etiology/*physiopathology ; *Taste Perception ; }, abstract = {KEY POINTS: The lateral habenula (LHb) has been implicated in regulation of drug-seeking behaviours through aversion-mediated learning. In this study, we recorded neuronal activity in the LHb of rats during an operant task before and after ethanol-induced conditioned taste aversion (CTA) to saccharin. Ethanol-induced CTA caused significantly higher baseline firing rates in LHb neurons, as well as elevated firing rates in response to cue presentation, lever press and saccharin taste. In a separate cohort of rats, we found that bilateral LHb lesions blocked ethanol-induced CTA. Our results strongly suggest that excitation of LHb neurons is required for ethanol-induced CTA, and point towards a mechanism through which LHb firing may regulate voluntary ethanol consumption.

ABSTRACT: Ethanol, like other drugs of abuse, has both rewarding and aversive properties. Previous work suggests that sensitivity to ethanol's aversive effects negatively modulates voluntary alcohol intake and thus may be important in vulnerability to developing alcohol use disorders. We previously found that rats with lesions of the lateral habenula (LHb), which is implicated in aversion-mediated learning, show accelerated escalation of voluntary ethanol consumption. To understand neural encoding in the LHb contributing to ethanol-induced aversion, we recorded neural firing in the LHb of freely behaving, water-deprived rats before and after an ethanol-induced (1.5 g kg[-1] 20% ethanol, i.p.) conditioned taste aversion (CTA) to saccharin taste. Ethanol-induced CTA strongly decreased motivation for saccharin in an operant task to obtain the tastant. Comparison of LHb neural firing before and after CTA induction revealed four main differences in firing properties. First, baseline firing after CTA induction was significantly higher. Second, firing evoked by cues signalling saccharin availability shifted from a pattern of primarily inhibition before CTA to primarily excitation after CTA induction. Third, CTA induction reduced the magnitude of lever press-evoked inhibition. Finally, firing rates were significantly higher during consumption of the devalued saccharin solution after CTA induction. Next, we studied sham- and LHb-lesioned rats in our operant CTA paradigm and found that LHb lesion significantly attenuated CTA effects in the operant task. Our data demonstrate the importance of LHb excitation in regulating expression of ethanol-induced aversion and suggest a mechanism for its role in modulating escalation of voluntary ethanol intake.}, } @article {pmid27660150, year = {2017}, author = {St John, SJ}, title = {The Perceptual Characteristics of Sodium Chloride to Sodium-Depleted Rats.}, journal = {Chemical senses}, volume = {42}, number = {2}, pages = {93-103}, pmid = {27660150}, issn = {1464-3553}, mesh = {Amiloride/pharmacology ; Animals ; Appetite/drug effects/*physiology ; Male ; Rats ; Rats, Sprague-Dawley ; Sodium/*deficiency ; Sodium Chloride/*analysis ; Sodium Chloride, Dietary/administration & dosage/*pharmacology ; Sucrose/analysis/pharmacology ; Taste/*drug effects/*physiology ; Taste Perception/drug effects/physiology ; }, abstract = {Three experiments assessed potential changes in the rat's perception of sodium chloride (NaCl) during a state of sodium appetite. In Experiment 1, sodium-sufficient rats licking a range of NaCl concentrations (0.028-0.89M) in 15s trials showed an inverted U-shaped concentration response function peaking at 0.281M. Depleted rats (furosemide) showed an identical function, merely elevated, suggesting altered qualitative or hedonic perception but no change in perceived intensity. In Experiment 2, sodium-depleted rats were tested with NaCl, sodium gluconate, and potassium chloride (KCl; 0.028-0.89M) similar to Experiment 1. KCl was licked at the same rate as water except for a slight elevation at 0.158; sodium gluconate and NaCl were treated similarly, but rats showed more licking for hypertonic sodium gluconate than hypertonic NaCl. Sodium-depleted rats were also tested with NaCl mixed in amiloride (10-300 μM). Amiloride reduced licking but did not alter the shape of the concentration-response function. Collectively, these results suggest that transduction of sodium by epithelial sodium channels (which are blocked by amiloride and are more dominant in sodium gluconate than NaCl transduction) is crucial for the perception of sodium during physiological sodium depletion. In Experiment 3, sodium-deplete rats were tested with NaCl as in Experiment 1 but after taste aversion conditioning to 0.3M NaCl or sucrose. Rats conditioned to avoid NaCl but not sucrose failed to express a sodium appetite, strongly suggesting that NaCl does not undergo a change in taste quality during sodium appetite-rats show no confusion between sucrose and NaCl in this paradigm.}, } @article {pmid27643793, year = {2017}, author = {Ellis, JM and Galloway, AT and Webb, RM and Martz, DM}, title = {Measuring adult picky eating: The development of a multidimensional self-report instrument.}, journal = {Psychological assessment}, volume = {29}, number = {8}, pages = {955-966}, doi = {10.1037/pas0000387}, pmid = {27643793}, issn = {1939-134X}, mesh = {Adult ; Anxiety Disorders/diagnosis/psychology ; Diagnostic and Statistical Manual of Mental Disorders ; Feeding and Eating Disorders/*diagnosis/*psychology ; Female ; Food Preferences/psychology ; Humans ; Male ; Psychometrics/*statistics & numerical data ; Quality of Life/psychology ; *Self Report ; *Surveys and Questionnaires ; Taste ; Young Adult ; }, abstract = {A brief multidimensional measure of adult picky eating (PE) behavior was developed using a large U.S. adult sample. In addition, the study explored associations between specific aspects of adult PE behavior and psychosocial impairment in effort to support the inclusion of adults in the Diagnostic and Statistical Manual for Mental Disorders-Fifth Edition (DSM-5) avoidant-restrictive food intake disorder (ARFID). The study included 3 phases of qualitative and quantitative data collection. Participants were 1,663 U.S. adults who completed online surveys. Exploratory and confirmatory factor analyses were used to develop PE subscales. Associations among the PE subscales and measures of psychosocial impairment were examined. Exploratory and confirmatory factor analysis supported a 16-item 4-factor model of adult PE that included subscales of meal presentation, food variety, meal disengagement, and taste aversion. The measure also demonstrated convergence with previous measures of PE. The meal disengagement and meal presentation subscales demonstrated significant associations with social eating anxiety, anxiety sensitivity, eating related quality of life (QOL), and psychological flexibility. Meal disengagement alone was significantly associated with depressive symptoms. The Adult Picky Eating Questionnaire (APEQ) demonstrated sound psychometric properties and may be used to further investigate adult PE behavior. The relationships between adult PE and psychological impairment, particularly social anxiety, support the inclusion of ARFID in the DSM-5. (PsycINFO Database Record}, } @article {pmid27624788, year = {2016}, author = {Katagawa, Y and Yasuo, T and Suwabe, T and Yamamura, T and Gen, K and Sako, N}, title = {Recognition by Rats of Binary Taste Solutions and Their Components.}, journal = {Chemical senses}, volume = {41}, number = {9}, pages = {795-801}, doi = {10.1093/chemse/bjw093}, pmid = {27624788}, issn = {1464-3553}, abstract = {This behavioral study investigated how rats conditioned to binary mixtures of preferred and aversive taste stimuli, respectively, responded to the individual components in a conditioned taste aversion (CTA) paradigm. The preference of stimuli was determined based on the initial results of 2 bottle preference test. The preferred stimuli included 5mM sodium saccharin (Sacc), 0.03M NaCl (Na), 0.1M Na, 5mM Sacc + 0.03M Na, and 5mM Sacc + 0.2mM quinine hydrochloride (Q), whereas the aversive stimuli tested were 1.0M Na, 0.2mM Q, 0.3mM Q, 5mM Sacc + 1.0M Na, and 5mM Sacc + 0.3mM Q. In CTA tests where LiCl was the unconditioned stimulus, the number of licks to the preferred binary mixtures and to all tested preferred components were significantly less than in control rats. No significant difference resulted between the number of licks to the aversive binary mixtures or to all tested aversive components. However, when rats pre-exposed to the aversive components contained of the aversive binary mixtures were conditioned to these mixtures, the number of licks to all the tested stimuli was significantly less than in controls. Rats conditioned to components of the aversive binary mixtures generalized to the binary mixtures containing those components. These results suggest that rats recognize and remember preferred and aversive taste mixtures as well as the preferred and aversive components of the binary mixtures, and that pre-exposure before CTA is an available method to study the recognition of aversive taste stimuli.}, } @article {pmid27579495, year = {2017}, author = {Ward-Fear, G and Thomas, J and Webb, JK and Pearson, DJ and Shine, R}, title = {Eliciting conditioned taste aversion in lizards: Live toxic prey are more effective than scent and taste cues alone.}, journal = {Integrative zoology}, volume = {12}, number = {2}, pages = {112-120}, doi = {10.1111/1749-4877.12226}, pmid = {27579495}, issn = {1749-4877}, mesh = {Animals ; *Avoidance Learning ; *Bufo marinus ; Cues ; Introduced Species ; Lithium Chloride ; Lizards/*physiology ; *Odorants ; Predatory Behavior ; *Taste ; Toxins, Biological/*toxicity ; Western Australia ; }, abstract = {Conditioned taste aversion (CTA) is an adaptive learning mechanism whereby a consumer associates the taste of a certain food with symptoms caused by a toxic substance, and thereafter avoids eating that type of food. Recently, wildlife researchers have employed CTA to discourage native fauna from ingesting toxic cane toads (Rhinella marina), a species that is invading tropical Australia. In this paper, we compare the results of 2 sets of CTA trials on large varanid lizards ("goannas," Varanus panoptes). One set of trials (described in this paper) exposed recently-captured lizards to sausages made from cane toad flesh, laced with a nausea-inducing chemical (lithium chloride) to reinforce the aversion response. The other trials (in a recently-published paper, reviewed herein) exposed free-ranging lizards to live juvenile cane toads. The effectiveness of the training was judged by how long a lizard survived in the wild before it was killed (fatally poisoned) by a cane toad. Both stimuli elicited rapid aversion to live toads, but the CTA response did not enhance survival rates of the sausage-trained goannas after they were released into the wild. In contrast, the goannas exposed to live juvenile toads exhibited higher long-term survival rates than did untrained conspecifics. Our results suggest that although it is relatively easy to elicit short-term aversion to toad cues in goannas, a biologically realistic stimulus (live toads, encountered by free-ranging predators) is most effective at buffering these reptiles from the impact of invasive toxic prey.}, } @article {pmid27579475, year = {2016}, author = {Drgonova, J and Walther, D and Hartstein, GL and Bukhari, MO and Baumann, MH and Katz, J and Hall, FS and Arnold, ER and Flax, S and Riley, A and Rivero-Martin, O and Lesch, KP and Troncoso, J and Ranscht, B and Uhl, GR}, title = {Cadherin 13: human cis-regulation and selectively-altered addiction phenotypes and cerebral cortical dopamine in knockout mice.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {22}, number = {}, pages = {537-547}, pmid = {27579475}, issn = {1528-3658}, support = {R21 HL102680/HL/NHLBI NIH HHS/United States ; }, abstract = {The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered Cdh13 expression as models for common human variation at this locus. Constitutive cdh13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine conditioned taste aversion. Reduced adult Cdh13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical Cdh13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly-quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5 choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.}, } @article {pmid27566473, year = {2017}, author = {Deguchi, T and Tsutsui, S and Iwahashi, H and Nakagawa, Y and Yoshida, M}, title = {Efficacy and safety of novel high-frequency multi-train stimulation for recording transcranial motor evoked potentials in a rat model.}, journal = {Journal of clinical monitoring and computing}, volume = {31}, number = {5}, pages = {1053-1058}, pmid = {27566473}, issn = {1573-2614}, support = {26462248//Grants-in-Aid for Scientific Research in the Japanese Society for the Promotion of Science/United States ; 26462248//Grants-in-Aid for Scientific Research in the Japanese Society for the Promotion of Science/United States ; }, mesh = {Anesthesia, General ; Animals ; Behavior, Animal ; Brain ; Disease Models, Animal ; Electric Stimulation/*methods ; Evoked Potentials, Motor/*physiology ; Humans ; Male ; Monitoring, Intraoperative/*methods ; Muscle, Skeletal ; Neurophysiology ; Patient Safety ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Recently, low-frequency multi-train stimulation (MTS) was shown to effectively enhance transcranial motor-evoked potentials (TcMEPs). In contrast, high- frequency double-train stimulation was reported to elicit a marked facilitation. The aim of this study was to evaluate the efficacy of high-frequency MTS in the augmentation of potentials. In addition, we investigated the safety of high-frequency MTS, behaviorally and histologically. TcMEPs were recorded from the triceps surae muscle in 38 rats. A multipulse stimulus was delivered repeatedly at different rates (2, 5, 10, 20, and 50 Hz), and was defined as MTS. A conditioned taste aversion method was used to investigate the effect of high-frequency MTS on learning and memory function. Subsequently, animals were sacrificed, and the brains were removed and examined using the standard hematoxylin-eosin method. Compared with conventional single train stimulation, TcMEP amplitudes increased 1.3, 2.1, 1.9, and 2.0 times on average with 5, 10, 20, and 50 Hz stimulation, respectively. The aversion index was >0.8 in all animals after they received 100 high-frequency MTSs. Histologically, no pathological changes were evident in the rat brains. High-frequency MTS shows potential to effectively enhance TcMEP responses, and to be used safely in transcranial brain stimulation.}, } @article {pmid27553426, year = {2017}, author = {Kwok, DWS and Harris, JA and Boakes, RA}, title = {Timing of interfering events in one-trial serial overshadowing of a taste aversion.}, journal = {Learning & behavior}, volume = {45}, number = {2}, pages = {124-134}, pmid = {27553426}, issn = {1543-4508}, mesh = {Animals ; *Avoidance Learning ; Conditioning, Classical ; Lithium Chloride ; Rats ; *Taste ; Taste Perception ; }, abstract = {This set of experiments examined the question of when a stimulus would be most effective in overshadowing the acquisition of long-delay taste aversion learning. In Experiment 1 rats drank sucrose, the target solution, followed by a hydrochloric acid (HCl) solution before lithium injection some time later; HCl was presented either early or late in the interval. The late condition produced greater overshadowing than the early condition. The importance of the HCl-injection interval was confirmed by Experiment 2, in which the sucrose-injection interval was varied. Experiment 3 found that even placement in a different context - an event that normally produces little overshadowing of a CTA - produced one-trial overshadowing of a sucrose aversion as long as the context was novel and exposure to it occurred immediately before lithium injection. No current theoretical account of one-trial overshadowing predicts that a late event produces more overshadowing than an early event. This result can, however, be accommodated within a modified version of the Rescorla-Wagner model.}, } @article {pmid27549757, year = {2016}, author = {Sheth, C and Furlong, TM and Keefe, KA and Taha, SA}, title = {Lesion of the rostromedial tegmental nucleus increases voluntary ethanol consumption and accelerates extinction of ethanol-induced conditioned taste aversion.}, journal = {Psychopharmacology}, volume = {233}, number = {21-22}, pages = {3737-3749}, pmid = {27549757}, issn = {1432-2072}, support = {R01 MH094870/MH/NIMH NIH HHS/United States ; }, mesh = {Adrenergic alpha-2 Receptor Antagonists/pharmacology ; Animals ; Central Nervous System Depressants/*pharmacology ; Conditioning, Classical/drug effects ; Conditioning, Operant ; Ethanol/*pharmacology ; Habenula ; Male ; Quinine ; Rats ; Rats, Long-Evans ; Saccharin ; Self Administration ; Sweetening Agents ; Taste/*drug effects ; *Tegmentum Mesencephali ; Yohimbine/pharmacology ; }, abstract = {RATIONALE: Ethanol has rewarding and aversive properties, and the balance of these properties influences voluntary ethanol consumption. Preclinical and clinical evidence show that the aversive properties of ethanol limit intake. The neural circuits underlying ethanol-induced aversion learning are not fully understood. We have previously shown that the lateral habenula (LHb), a region critical for aversive conditioning, plays an important role in ethanol-directed behaviors. However, the neurocircuitry through which LHb exerts its actions is unknown.

OBJECTIVE: In the present study, we investigate a role for the rostromedial tegmental nucleus (RMTg), a major LHb projection target, in regulating ethanol-directed behaviors.

METHODS: Rats received either sham or RMTg lesions and were studied during voluntary ethanol consumption; operant ethanol self-administration, extinction, and yohimbine-induced reinstatement of ethanol-seeking; and ethanol-induced conditioned taste aversion (CTA).

RESULTS: RMTg lesions increased voluntary ethanol consumption and accelerated extinction of ethanol-induced CTA.

CONCLUSIONS: The RMTg plays an important role in regulating voluntary ethanol consumption, possibly by mediating ethanol-induced aversive conditioning.}, } @article {pmid27535568, year = {2017}, author = {Okusha, Y and Hirai, Y and Maezawa, H and Hisadome, K and Inoue, N and Yamazaki, Y and Funahashi, M}, title = {Effects of intraperitoneally administered L-histidine on food intake, taste, and visceral sensation in rats.}, journal = {The journal of physiological sciences : JPS}, volume = {67}, number = {4}, pages = {467-474}, pmid = {27535568}, issn = {1880-6562}, mesh = {Animals ; Appetite Depressants/*administration & dosage ; Area Postrema/drug effects/metabolism/physiopathology ; Brain/*drug effects/metabolism/physiopathology ; Eating/*drug effects ; Feeding Behavior/*drug effects ; Histidine/*administration & dosage ; Injections, Intraperitoneal ; Nausea/chemically induced/physiopathology ; Proto-Oncogene Proteins c-fos/metabolism ; Rats, Sprague-Dawley ; Solitary Nucleus/drug effects/metabolism/physiopathology ; Taste/*drug effects ; Time Factors ; Vagotomy ; Visceral Pain/*chemically induced/physiopathology/psychology ; }, abstract = {To evaluate relative factors for anorectic effects of L-histidine, we performed behavioral experiments for measuring food and fluid intake, conditioned taste aversion (CTA), taste disturbance, and c-Fos immunoreactive (Fos-ir) cells before and after i.p. injection with L-histidine in rats. Animals were injected with saline (9 ml/kg, i.p.) for a control group, and saline (9 ml/kg, i.p.) containing L-histidine (0.75, 1.5, 2.0 g/kg) for a L-histidine group. Injection of L-histidine decreased the average value of food intake, and statistically significant anorectic effects were found in animals injected with 1.5 or 2.0 g/kg L-histidine but not with 0.75 g/kg L-histidine. Taste abnormalities were not detected in any of the groups. Animals injected with 2.0 g/kg L-histidine were revealed to present with nausea by the measurement of CTA. In this group, a significant increase in the number of Fos-ir cells was detected both in the area postrema and the nucleus tractus solitarius (NTS). In the 0.75 g/kg L-histidine group, a significant increase in the number of Fos-ir cells was detected only in the NTS. When the ventral gastric branch vagotomy was performed, recovery from anorexia became faster than the sham-operated group, however, vagotomized rats injected with 2.0 g/kg L-histidine still acquired CTA. These data indicate that acute anorectic effects induced by highly concentrated L-histidine are partly caused by induction of nausea and/or visceral discomfort accompanied by neuronal activities in the NTS and the area postrema. We suggest that acute and potent effects of L-histidine on food intake require substantial amount of L-histidine in the diet.}, } @article {pmid27521755, year = {2016}, author = {Kosaki, Y and Watanabe, S}, title = {Impaired Pavlovian predictive learning between temporally phasic but not static events in autism-model strain mice.}, journal = {Neurobiology of learning and memory}, volume = {134 Pt B}, number = {}, pages = {304-316}, doi = {10.1016/j.nlm.2016.08.001}, pmid = {27521755}, issn = {1095-9564}, mesh = {Animals ; Association Learning/*physiology ; Autism Spectrum Disorder/*physiopathology ; Behavior, Animal/*physiology ; Conditioning, Classical/*physiology ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred C57BL ; }, abstract = {Autism-spectrum disorder (ASD) is a multi-aspect developmental disorder characterised by various social and non-social behavioural abnormalities. Using BTBR T+ tf mouse strain (BTBR), a promising animal model displaying a number of behavioural and neural characteristics associated with ASD, we tested the hypothesis that at the core of various symptoms of ASD lies a fundamental deficit in predictive learning between events. In five experiments, we conducted a variety of Pavlovian conditioning tasks, some requiring the establishment of associations between temporally phasic events and others involving static events. BTBR mice were impaired in the acquisition of conditioned magazine approach responses with an appetitive unconditioned stimulus (US) (Experiment 1) and conditioned freezing with an electric shock US (Experiment 2). Both of these tasks had temporally phasic conditioned stimuli (CSs). Conversely, these mice showed normal acquisition of conditioned place preference (CPP), whether the US was a systemic injection of methamphetamine (Experiment 3A) or the presence of food (Experiment 3B). Experiment 4 showed normal acquisition of conditioned taste aversion (CTA) to a flavour-taste compound CS, although BTBR mice still exhibited an abnormal stimulus selection when learning for each element of the compound CS was assessed separately. Experiment 5 revealed a weaker latent inhibition of CTA in BTBR mice. The BTBR mouse's impaired predictive learning between phasic events and intact associations between static events are discussed in terms of dysfunctional contingency-based, but not contiguity-based learning, which may accompany abnormal selective attention to relevant cues. We propose that such dysfunctional contingency learning mechanisms may underlie the development of various social and non-social symptoms of ASD.}, } @article {pmid27511277, year = {2016}, author = {Schier, LA and Spector, AC}, title = {Post-oral sugar detection rapidly and chemospecifically modulates taste-guided behavior.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {311}, number = {4}, pages = {R742-R755}, pmid = {27511277}, issn = {1522-1490}, support = {F32 DC013494/DC/NIDCD NIH HHS/United States ; R01 DC009821/DC/NIDCD NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Appetite Regulation/*physiology ; Avoidance Learning/*physiology ; Conditioning, Classical ; Dietary Sucrose/*metabolism/pharmacology ; Eating/*physiology ; Feeding Behavior/drug effects/*physiology ; Male ; Postprandial Period/physiology ; Rats ; Rats, Sprague-Dawley ; Taste/*physiology ; Taste Perception ; }, abstract = {Several recent studies have shown that post-oral sugar sensing rapidly stimulates ingestion. Here, we explored the specificity with which early-phase post-oral sugar sensing influenced ingestive motivation. In experiment 1, rats were trained to associate the consumption of 0.3 M sucrose with injections of LiCl (3.0 meq/kg ip, conditioned taste aversion) or given equivalent exposures to the stimuli, but in an unpaired fashion. Then, all rats were subjected to two brief-access tests to assess appetitive and consummatory responses to the taste properties of sucrose (0.01-1.0 M), 0.12 M NaCl, and dH2O (in 10-s trials in randomized blocks). Intraduodenal infusions of either 0.3 M sucrose or equiosmolar 0.15 M NaCl (3.0 ml) were administered, beginning just before each test. For unpaired rats, intraduodenal sucrose specifically enhanced licking for 0.03-1.0 M sucrose, with no effect on trial initiation, relative to intraduodenal NaCl. Rats with an aversion to sucrose suppressed licking responses to sucrose in a concentration-dependent manner, as expected, but the intraduodenal sucrose preload did not appear to further influence licking responses; instead, intraduodenal sucrose attenuated trial initiation. Using a serial taste reactivity (TR) paradigm, however, experiment 2 demonstrated that intraduodenal sucrose preloads suppressed ingestive oromotor responses to intraorally delivered sucrose in rats with a sucrose aversion. Finally, experiment 3 showed that intraduodenal sucrose preloads enhanced preferential licking to some representative tastants tested (sucrose, Polycose, and Intralipid), but not others (NaCl, quinine). Together, the results suggest that the early phase-reinforcing efficacy of post-oral sugar is dependent on the sensory and motivational properties of the ingesta.}, } @article {pmid27491591, year = {2016}, author = {Gasalla, P and Begega, A and Soto, A and Dwyer, DM and López, M}, title = {Functional brain networks underlying latent inhibition of conditioned disgust in rats.}, journal = {Behavioural brain research}, volume = {315}, number = {}, pages = {36-44}, doi = {10.1016/j.bbr.2016.07.051}, pmid = {27491591}, issn = {1872-7549}, mesh = {Animals ; Avoidance Learning/*physiology ; Brain/*enzymology ; Conditioning, Classical/*physiology ; Electron Transport Complex IV/*metabolism ; *Inhibition, Psychological ; Lithium Chloride/adverse effects ; Male ; Neural Pathways/*physiology ; Rats ; Rats, Wistar ; Saccharin/administration & dosage ; *Taste ; }, abstract = {The present experiment examined the neuronal networks involved in the latent inhibition of conditioned disgust by measuring brain oxidative metabolism. Rats were given nonreinforced intraoral (IO) exposure to saccharin (exposed groups) or water (non-exposed groups) followed by a conditioning trial in which the animals received an infusion of saccharin paired (or unpaired) with LiCl. On testing, taste reactivity responses displayed by the rats during the infusion of the saccharin were examined. Behavioral data showed that preexposure to saccharin attenuated the development of LiCl-induced conditioned disgust reactions, indicating that the effects of taste aversion on hedonic taste reactivity had been reduced. With respect to cumulative oxidative metabolic activity across the whole study period, the parabrachial nucleus was the only single region examined which showed differential activity between groups which received saccharin-LiCl pairings with and without prior non-reinforced saccharin exposure, suggesting a key role in the effects of latent inhibition of taste aversion learning. In addition, many functional connections between brain regions were revealed through correlational analysis of metabolic activity, in particular an accumbens-amygdala interaction that may be involved in both positive and negative hedonic responses.}, } @article {pmid27485658, year = {2016}, author = {Preissmann, D and Dépré, M and Schenk, F and Gisquet-Verrier, P}, title = {Anxiety modulates cognitive deficits in a perinatal glutathione deficit animal model of schizophrenia.}, journal = {Brain research}, volume = {1648}, number = {Pt A}, pages = {459-468}, doi = {10.1016/j.brainres.2016.07.042}, pmid = {27485658}, issn = {1872-6240}, mesh = {Animals ; Anxiety/*chemically induced/complications ; Avoidance Learning/drug effects ; Behavior, Animal/drug effects ; Buthionine Sulfoximine/*administration & dosage/analogs & derivatives ; Cognitive Dysfunction/*chemically induced/complications ; *Disease Models, Animal ; Glutathione/*deficiency ; Locomotion/drug effects ; Male ; Prepulse Inhibition/drug effects ; Rats ; Rats, Wistar ; Reflex, Startle/drug effects ; Schizophrenia/chemically induced/*complications ; *Schizophrenic Psychology ; }, abstract = {In this study, we investigated long-term repercussion of early glutathione deficit by l-buthionine-(S,R)-sulfoximine (BSO) injections as a rat model of schizophrenia. BSO rats were tested through various behavioral tasks requiring animals to take into account previously delivered information. We showed that relative to controls, BSO rats (1) were less active and more anxious in an Elevated Plus Maze test, allowing us to split them into two subgroups with high and low anxiety levels; (2) demonstrated normal abilities of behavioral flexibility tested with a rat-adapted version of the Wisconsin Card Sorting Test (WCST), with even higher abilities in anxious BSO rats suggesting reduced interference of previously acquired rules; (3) did not forage normally in radial arm mazes and mainly used clockwise strategies; (4) exhibited a lack of habituation during a startle response task; and (5) showed a normal prepulse inhibition of the startle response (PPI) and a normal conditioned taste aversion (CTA). All these results indicate that early glutathione deficit provokes persistent changes in adulthood and improves the validity of this animal model of schizophrenia. They further suggest difficulties binding temporally separated events (WCST), except when the salience of this information is very strong (CTA). We propose that the transient glutathione deficit during cerebral development could alter a "cognitive binding" process in interaction with the emotional state that could possibly account for the disruption of integrative function that characterizes schizophrenia.}, } @article {pmid27481223, year = {2016}, author = {Rosenberg, T and Elkobi, A and Rosenblum, K}, title = {mAChR-dependent decrease in proteasome activity in the gustatory cortex is necessary for novel taste learning.}, journal = {Neurobiology of learning and memory}, volume = {135}, number = {}, pages = {115-124}, doi = {10.1016/j.nlm.2016.07.029}, pmid = {27481223}, issn = {1095-9564}, mesh = {Animals ; Behavior, Animal/drug effects/physiology ; Cerebral Cortex/drug effects/metabolism/*physiology ; Learning/drug effects/*physiology ; Male ; Muscarinic Antagonists/*pharmacology ; Proteasome Endopeptidase Complex/*metabolism ; Rats ; Rats, Wistar ; Receptors, Muscarinic/*metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/*metabolism ; Scopolamine/pharmacology ; Taste Perception/drug effects/*physiology ; }, abstract = {Regulation of protein degradation via the ubiquitin proteasome system is crucial for normal learning and synaptic plasticity processes. While some studies reveal that increased proteasome degradation is necessary for different types of learning, others suggest the proteasome to be a negative regulator of plasticity. We aim to understand the molecular and cellular processes taking place in the gustatory cortex (GC), which underlie appetitive and aversive forms of taste learning. Previously, we have shown that N-methyl d-aspartic acid receptor (NMDAR)-dependent upregulation of proteasome activity 4h after novel taste learning is necessary for the association of novel taste with malaise and formation of conditioned taste aversion (CTA). Here, we first identify a correlative increase in proteasome activity in the GC immediately after novel taste learning and study the upstream and downstream effectors of this modulated proteasome activity. Interestingly, proteasome-mediated degradation was reduced in the GC, 20min after novel taste consumption in a muscarinic acetylcholine receptor (mAChR)-dependent and NMDAR-independent manner. This reduction in protein degradation led to an increased amount of p70 S6 kinase (p70S6k), which was abolished in the presence of mAChR antagonist scopolamine. Infusion of lactacystin, a proteasome inhibitor, to the GC precluded the amnestic effect of scopolamine. This study shows for the first time that following novel taste learning there is a cortical, mAChR-dependent reduced proteasome activity that enables the memory of taste familiarity. Moreover, inhibition of degradation in the GC attenuates novel taste learning and of p70 S6 kinase correlative increased expression. These results shed light on the complex regulation of protein synthesis and degradation machineries in the cortex following novel taste experience.}, } @article {pmid27472892, year = {2016}, author = {Sheng, Y and Soto, J and Orlu Gul, M and Cortina-Borja, M and Tuleu, C and Standing, JF}, title = {New generalized poisson mixture model for bimodal count data with drug effect: An application to rodent brief-access taste aversion experiments.}, journal = {CPT: pharmacometrics & systems pharmacology}, volume = {5}, number = {8}, pages = {427-436}, pmid = {27472892}, issn = {2163-8306}, support = {MR/M008665/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Databases, Factual/*statistics & numerical data ; *Models, Biological ; *Poisson Distribution ; Quinine/pharmacology ; Random Allocation ; Rats ; Taste/drug effects/physiology ; Taste Perception/drug effects/*physiology ; }, abstract = {Pharmacodynamic (PD) count data can exhibit bimodality and nonequidispersion complicating the inclusion of drug effect. The purpose of this study was to explore four different mixture distribution models for bimodal count data by including both drug effect and distribution truncation. An example dataset, which exhibited bimodal pattern, was from rodent brief-access taste aversion (BATA) experiments to assess the bitterness of ascending concentrations of an aversive tasting drug. The two generalized Poisson mixture models performed the best and was flexible to explain both under and overdispersion. A sigmoid maximum effect (Emax) model with logistic transformation was introduced to link the drug effect to the data partition within each distribution. Predicted density-histogram plot is suggested as a model evaluation tool due to its capability to directly compare the model predicted density with the histogram from raw data. The modeling approach presented here could form a useful strategy for modeling similar count data types.}, } @article {pmid27468916, year = {2017}, author = {Sánchez-Catalán, MJ and Faivre, F and Yalcin, I and Muller, MA and Massotte, D and Majchrzak, M and Barrot, M}, title = {Response of the Tail of the Ventral Tegmental Area to Aversive Stimuli.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {42}, number = {3}, pages = {638-648}, pmid = {27468916}, issn = {1740-634X}, mesh = {Animals ; Antimanic Agents/administration & dosage/pharmacology ; Behavior, Animal/drug effects/*physiology ; Carbolines/administration & dosage/pharmacology ; Conditioning, Classical/drug effects/*physiology ; Disease Models, Animal ; Lipopolysaccharides/administration & dosage/pharmacology ; Lithium Chloride/pharmacology ; Male ; Morphine Dependence/*physiopathology ; Naloxone/administration & dosage/pharmacology ; Narcotic Antagonists/administration & dosage/pharmacology ; Neuralgia/physiopathology ; Neurotoxins/administration & dosage/pharmacology ; Olfactory Perception/drug effects/*physiology ; Pain/chemically induced/*physiopathology ; Proto-Oncogene Proteins c-fos/*drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu/*drug effects ; Substance Withdrawal Syndrome/*physiopathology ; Ventral Tegmental Area/drug effects/*physiology ; }, abstract = {The GABAergic tail of the ventral tegmental area (tVTA), also named rostromedial tegmental nucleus (RMTg), exerts an inhibitory control on dopamine neurons of the VTA and substantia nigra. The tVTA has been implicated in avoidance behaviors, response to drugs of abuse, reward prediction error, and motor functions. Stimulation of the lateral habenula (LHb) inputs to the tVTA, or of the tVTA itself, induces avoidance behaviors, which suggests a role of the tVTA in processing aversive information. Our aim was to test the impact of aversive stimuli on the molecular recruitment of the tVTA, and the behavioral consequences of tVTA lesions. In rats, we assessed Fos response to lithium chloride (LiCl), β-carboline, naloxone, lipopolysaccharide (LPS), inflammatory pain, neuropathic pain, foot-shock, restraint stress, forced swimming, predator odor, and opiate withdrawal. We also determined the effect of tVTA bilateral ablation on physical signs of opiate withdrawal, and on LPS- and LiCl-induced conditioned taste aversion (CTA). Naloxone-precipitated opiate withdrawal induced Fos in μ-opioid receptor-positive (15%) and -negative (85%) tVTA cells, suggesting the presence of both direct and indirect mechanisms in tVTA recruitment during withdrawal. However, tVTA lesion did not impact physical signs of opiate withdrawal. Fos induction was also present with repeated, but not single, foot-shock delivery. However, such induction was mostly absent with other aversive stimuli. Moreover, tVTA ablation had no impact on CTA. Although stimulation of the tVTA favors avoidance behaviors, present findings suggest that this structure may be important to the response to some, but not all, aversive stimuli.}, } @article {pmid27388762, year = {2016}, author = {Glover, EJ and McDougle, MJ and Siegel, GS and Jhou, TC and Chandler, LJ}, title = {Role for the Rostromedial Tegmental Nucleus in Signaling the Aversive Properties of Alcohol.}, journal = {Alcoholism, clinical and experimental research}, volume = {40}, number = {8}, pages = {1651-1661}, pmid = {27388762}, issn = {1530-0277}, support = {T32 AA007474/AA/NIAAA NIH HHS/United States ; F32 AA022836/AA/NIAAA NIH HHS/United States ; R29 AA010983/AA/NIAAA NIH HHS/United States ; P50 AA010761/AA/NIAAA NIH HHS/United States ; U01 AA019967/AA/NIAAA NIH HHS/United States ; K99 AA024208/AA/NIAAA NIH HHS/United States ; R01 AA022701/AA/NIAAA NIH HHS/United States ; R01 AA010983/AA/NIAAA NIH HHS/United States ; P50 DA016511/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Conditioning, Psychological/drug effects/*physiology ; Ethanol/*administration & dosage ; Female ; Habenula/drug effects/physiology ; Lithium Chloride/administration & dosage ; Male ; Rats ; Rats, Long-Evans ; Saccharin/administration & dosage ; Taste/drug effects/*physiology ; Tegmentum Mesencephali/drug effects/*physiology ; }, abstract = {BACKGROUND: While the rewarding effects of alcohol contribute significantly to its addictive potential, it is becoming increasingly appreciated that alcohol's aversive properties also play an important role in the propensity to drink. Despite this, the neurobiological mechanism for alcohol's aversive actions is not well understood. The rostromedial tegmental nucleus (RMTg) was recently characterized for its involvement in aversive signaling and has been shown to encode the aversive properties of cocaine, yet its involvement in alcohol's aversive actions have not been elucidated.

METHODS: Adult male and female Long-Evans rats underwent conditioned taste aversion (CTA) procedures where exposure to a novel saccharin solution was paired with intraperitoneal administration of saline, lithium chloride (LiCl), or ethanol (EtOH). Control rats underwent the same paradigm except that drug and saccharin exposure were explicitly unpaired. Saccharin consumption was measured on test day in the absence of drug administration, and rats were sacrificed 90 to 105 minutes following access to saccharin. Brains were subsequently harvested and processed for cFos immunohistochemistry. The number of cFos-labeled neurons was counted in the RMTg and the lateral habenula (LHb)-a region that sends prominent glutamatergic input to the RMTg.

RESULTS: In rats that received paired drug and saccharin exposure, EtOH and LiCl induced significant CTA compared to saline to a similar degree in males and females. Both EtOH- and LiCl-induced CTA significantly enhanced cFos expression in the RMTg and LHb but not the hippocampus. Similar to behavioral measures, no significant effect of sex on CTA-induced cFos expression was observed. cFos expression in both the RMTg and LHb was significantly correlated with CTA magnitude with greater cFos being associated with more pronounced CTA. In addition, cFos expression in the RMTg was positively correlated with LHb cFos.

CONCLUSIONS: These data suggest that the RMTg and LHb are involved in the expression of CTA and are consistent with previous work implicating the RMTg in aversive signaling. Furthermore, increased cFos expression in the RMTg following EtOH-induced CTA suggests that this region plays a role in signaling alcohol's aversive properties.}, } @article {pmid27316343, year = {2016}, author = {Tuerkmen, A and Bösche, K and Lückemann, L and Engler, H and Schedlowski, M and Hadamitzky, M}, title = {Rats taste-aversive learning with cyclosporine a is not affected by contextual changes.}, journal = {Behavioural brain research}, volume = {312}, number = {}, pages = {169-173}, doi = {10.1016/j.bbr.2016.06.025}, pmid = {27316343}, issn = {1872-7549}, mesh = {Animals ; Avoidance Learning/*drug effects ; Conditioning, Classical/*drug effects ; Cues ; Cyclosporine/*administration & dosage ; Extinction, Psychological/*drug effects ; *Immunosuppressive Agents ; Male ; Rats ; Saccharin/administration & dosage ; *Taste Perception ; }, abstract = {In conditioned taste aversion (CTA) rats associate a novel taste (conditioned stimulus; CS) with a treatment (unconditioned stimulus; US) that induces symptoms of malaise. During retrieval, animals learn that the CS no longer predicts the US, with the consequence that the behavior elicited by the CS extinguishes. Importantly, CTA data with lithium chloride (LiCl) as US indicate that extinction learning is affected by changing the physical context. However, if this is also the case in different taste-aversion paradigms employing compounds other than LiCL as US is unknown. Against this background the present study investigated in a CTA paradigm with saccharin as CS and the immunosuppressant cyclosporine A (CsA) as US the influence of contextual changes on CTA extinction. Our results show, that extinction of a learned CS-US association with CsA is not prone to contextual changes. Due to the direct effects of CsA on CNS functioning, CTA with this immunosuppressant apparently operates under different mechanisms compared to other drugs, such as LiCl. These data indicate that taste aversive learning and its extinction are not necessarily specific to the context in which it is learned but also depends, at least in part, on the physiological and neuropharmacological effects of the drug employed as US.}, } @article {pmid27311758, year = {2016}, author = {Hadamitzky, M and Orlowski, K and Schwitalla, JC and Bösche, K and Unteroberdörster, M and Bendix, I and Engler, H and Schedlowski, M}, title = {Transient inhibition of protein synthesis in the rat insular cortex delays extinction of conditioned taste aversion with cyclosporine A.}, journal = {Neurobiology of learning and memory}, volume = {133}, number = {}, pages = {129-135}, doi = {10.1016/j.nlm.2016.06.008}, pmid = {27311758}, issn = {1095-9564}, mesh = {Animals ; Anisomycin/administration & dosage/*pharmacology ; Behavior, Animal/*drug effects ; Cerebral Cortex/*drug effects ; Conditioning, Classical/*drug effects ; Cyclosporine/administration & dosage/*pharmacology ; Extinction, Psychological/*drug effects ; Immunosuppressive Agents/administration & dosage/*pharmacology ; Male ; Mental Recall/*drug effects ; Protein Biosynthesis/*drug effects ; Protein Synthesis Inhibitors/administration & dosage/*pharmacology ; Rats ; Time Factors ; }, abstract = {Conditioned responses gradually weaken and eventually disappear when subjects are repeatedly exposed to the conditioned stimulus (CS) in the absence of the unconditioned stimulus (US), a process called extinction. Studies have demonstrated that extinction of conditioned taste aversion (CTA) can be prevented by interfering with protein synthesis in the insular cortex (IC). However, it remained unknown whether it is possible to pharmacologically stabilize the taste aversive memory trace over longer periods of time. Thus, the present study aimed at investigating the time frame during which extinction of CTA can be efficiently prevented by blocking protein synthesis in the IC. Employing an established conditioning paradigm in rats with saccharin as CS, and the immunosuppressant cyclosporine A (CsA) as US, we show here that daily bilateral intra-insular injections of the protein synthesis inhibitor anisomycin (120μg/μl) immediately after retrieval significantly diminished CTA extinction over a period of five retrieval days and subsequently reached levels of saline-infused controls. These findings demonstrate that it is possible to efficiently delay but not to fully prevent CTA extinction during repeated retrieval trials by blocking protein translation with daily bilateral infusions of anisomycin in the IC. These data confirm and extent earlier reports indicating that the role of protein synthesis in CTA extinction learning is not limited to gastrointestinal malaise-inducing drugs such as lithium chloride (LiCl).}, } @article {pmid27301407, year = {2017}, author = {Lin, JY and Arthurs, J and Reilly, S}, title = {Conditioned taste aversions: From poisons to pain to drugs of abuse.}, journal = {Psychonomic bulletin & review}, volume = {24}, number = {2}, pages = {335-351}, pmid = {27301407}, issn = {1531-5320}, support = {R01 DC006456/DC/NIDCD NIH HHS/United States ; R56 DC006456/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Association Learning ; *Avoidance Learning ; Child ; *Conditioning, Classical ; Conditioning, Operant ; Cues ; Food Preferences ; Humans ; *Illicit Drugs ; Male ; Mental Recall ; Pain/*psychology ; *Poisons ; Quality of Life ; Smell ; *Taste ; Time Factors ; }, abstract = {Learning what to eat and what not to eat is fundamental to our well-being, quality of life, and survival. In particular, the acquisition of conditioned taste aversions (CTAs) protects all animals (including humans) against ingesting foods that contain poisons or toxins. Counterintuitively, CTAs can also develop in situations in which we know with absolute certainty that the food did not cause the subsequent aversive systemic effect. Recent nonhuman animal research, analyzing palatability shifts, has indicated that a wider range of stimuli than has been traditionally acknowledged can induce CTAs. This article integrates these new findings with a reappraisal of some known characteristics of CTA and presents a novel conceptual analysis that is broader and more comprehensive than previous accounts of CTA learning.}, } @article {pmid27293152, year = {2016}, author = {O'Tousa, DS and Grahame, NJ}, title = {Long-Term Alcohol Drinking Reduces the Efficacy of Forced Abstinence and Conditioned Taste Aversion in Crossed High-Alcohol-Preferring Mice.}, journal = {Alcoholism, clinical and experimental research}, volume = {40}, number = {7}, pages = {1577-1585}, pmid = {27293152}, issn = {1530-0277}, support = {P50 AA007611/AA/NIAAA NIH HHS/United States ; P60 AA007611/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Abstinence/*psychology ; Alcohol Drinking/*psychology ; Animals ; Aversive Agents/pharmacology ; Avoidance Learning/*drug effects ; Conditioning, Psychological ; Extinction, Psychological/drug effects ; Female ; Lithium Chloride/pharmacology ; Male ; Mice ; Mice, Inbred Strains ; Taste Perception ; Time Factors ; }, abstract = {BACKGROUND: Negative outcomes of alcoholism are progressively more severe as the duration of problem of alcohol use increases. Additionally, alcoholics demonstrate tendencies to neglect negative consequences associated with drinking and/or to choose to drink in the immediate presence of warning factors against drinking. The recently derived crossed high-alcohol-preferring (cHAP) mice, which volitionally drink to heavier intoxication (as assessed by blood ethanol [EtOH] concentration) than other alcohol-preferring populations, as well as spontaneously escalating their intake, may be a candidate to explore mechanisms underlying long-term excessive drinking. Here, we hypothesized that an extended drinking history would reduce the ability of 2 manipulations (forced abstinence [FA] and conditioned taste aversion [CTA]) to attenuate drinking.

METHODS: Experiment 1 examined differences between groups drinking for either 14 or 35 days, half of each subjected to 7 days of FA and half not, to characterize the potential changes in postabstinence drinking resulting from an extended drinking history. Experiment 2 used a CTA procedure to assess stimulus specificity of the ability of an aversive flavorant to decrease alcohol consumption. Experiment 3 used this taste aversion procedure to assess differences among groups drinking for 1, 14, or 35 days in their propensity to overcome this aversion when the flavorant was mixed with either EtOH or water.

RESULTS: Experiment 1 demonstrated that although FA decreased alcohol consumption in mice with a 14-day drinking history, it failed to do so in mice drinking alcohol for 35 days. Experiment 2 showed that the addition of a flavorant only suppressed alcohol drinking if an aversion to the flavorant was previously established. Experiment 3 demonstrated that an extended drinking history expedited extinction of suppressed alcohol intake caused by a conditioned aversive flavor.

CONCLUSIONS: These data show that a history of long-term drinking in cHAP mice attenuates the efficacy of interventions that normally reduce drinking. Analogous to alcoholics who may encounter difficulties in limiting their intake, cHAP mice with long drinking histories are relatively insensitive to both abstinence and signals of harmful consequences. We propose that the cHAP line may be a valid model for adaptations that occur following the extended heavy alcohol drinking.}, } @article {pmid27260351, year = {2016}, author = {Osorio-Gómez, D and Guzmán-Ramos, K and Bermúdez-Rattoni, F}, title = {Corrigendum to "Differential involvement of glutamatergic and catecholaminergic activity within the amygdala during taste aversion retrieval on memory expression and updating" [Behav. Brain Res. 307 (2016) 120-125].}, journal = {Behavioural brain research}, volume = {311}, number = {}, pages = {441}, doi = {10.1016/j.bbr.2016.05.053}, pmid = {27260351}, issn = {1872-7549}, } @article {pmid27227028, year = {2015}, author = {Rudd, JA and Nalivaiko, E and Matsuki, N and Wan, C and Andrews, PL}, title = {The involvement of TRPV1 in emesis and anti-emesis.}, journal = {Temperature (Austin, Tex.)}, volume = {2}, number = {2}, pages = {258-276}, pmid = {27227028}, issn = {2332-8940}, abstract = {Diverse transmitter systems (e.g. acetylcholine, dopamine, endocannabinoids, endorphins, glutamate, histamine, 5-hydroxytryptamine, substance P) have been implicated in the pathways by which nausea and vomiting are induced and are targets for anti-emetic drugs (e.g. 5-hydroxytryptamine3 and tachykinin NK1 antagonists). The involvement of TRPV1 in emesis was discovered in the early 1990s and may have been overlooked previously as TRPV1 pharmacology was studied in rodents (mice, rats) lacking an emetic reflex. Acute subcutaneous administration of resiniferatoxin in the ferret, dog and Suncus murinus revealed that it had "broad-spectrum" anti-emetic effects against stimuli acting via both central (vestibular system, area postrema) and peripheral (abdominal vagal afferents) inputs. One of several hypotheses discussed here is that the anti-emetic effect is due to acute depletion of substance P (or another peptide) at a critical site (e.g. nucleus tractus solitarius) in the central emetic pathway. Studies in Suncus murinus revealed a potential for a long lasting (one month) effect against the chemotherapeutic agent cisplatin. Subsequent studies using telemetry in the conscious ferret compared the anti-emetic, hypothermic and hypertensive effects of resiniferatoxin (pungent) and olvanil (non-pungent) and showed that the anti-emetic effect was present (but reduced) with olvanil which although inducing hypothermia it did not have the marked hypertensive effects of resiniferatoxin. The review concludes by discussing general insights into emetic pathways and their pharmacology revealed by these relatively overlooked studies with TRPV1 activators (pungent an non-pungent; high and low lipophilicity) and antagonists and the potential clinical utility of agents targeted at the TRPV1 system.}, } @article {pmid27167860, year = {2016}, author = {Manuelian, CL and Albanell, E and Rovai, M and Caja, G}, title = {How to Create Conditioned Taste Aversion for Grazing Ground Covers in Woody Crops with Small Ruminants.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {110}, pages = {}, pmid = {27167860}, issn = {1940-087X}, mesh = {Animal Husbandry/*methods ; Animals ; Avoidance Learning/*drug effects ; Conditioning, Classical/*drug effects ; Crops, Agricultural ; Feeding Behavior/*drug effects ; Goats ; Lithium Chloride/*administration & dosage ; Sheep ; Taste ; }, abstract = {Conditioned taste aversion (CTA) is a learning behavior process where animals are trained to reject certain feed after gastrointestinal discomfort has been produced. Lithium chloride (LiCl) is the preferred agent used in livestock to induce CTA because it specifically stimulates the vomit center. In addition, LiCl is commercially available, and easy to prepare and administer using a drenching gun. Nevertheless, some factors have to be considered to obtain an effective long-lasting CTA, which allows small ruminants to graze during the cropping season. A key aspect is to use animals with no previous contact with the target plant (the plant chosen to be avoided; new feed). Due to their native neophobic feeding behavior, small ruminants can easily associate the negative feedback effects with the new feed, resulting in a strong and persistent CTA. The recommended doses are 200 and 225 mg LiCl/kg body weight (BW) for goats and sheep, respectively. To induce CTA, 100 g of the target plant should be individually offered for at least 30 min, and LiCl administered thereafter if the intake is greater than 10 g. Each time the animal eats the target plant without negative consequences, the CTA becomes weaker. Consequently, to minimize the risk of target plant consumption, it is essential to have sufficient palatable ground cover available. The presence of an alternative feed (of quality and quantity) prevents the accidental consumption of the target plant. A close monitoring of the flock is recommended to remove and re-dose any animal consuming more than 4 bites or 10 g of the target plant. At the beginning of each grazing season, check the CTA status of each animal before moving them to the crop.}, } @article {pmid27144301, year = {2016}, author = {Choi, H and Conole, D and Atkinson, DJ and Laita, O and Jay-Smith, M and Pagano, MA and Ribaudo, G and Cavalli, M and Bova, S and Hopkins, B and Brimble, MA and Rennison, D}, title = {Fatty Acid-Derived Pro-Toxicants of the Rat Selective Toxicant Norbormide.}, journal = {Chemistry & biodiversity}, volume = {13}, number = {6}, pages = {762-775}, doi = {10.1002/cbdv.201500241}, pmid = {27144301}, issn = {1612-1880}, mesh = {Animals ; Male ; Molecular Structure ; Neovascularization, Pathologic/*chemically induced/pathology ; Norbornanes/chemical synthesis/*chemistry/*toxicity ; Prodrugs/*chemistry ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; }, abstract = {Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sublethal uptake and accompanying bait shyness. A series of NRB-derived pro-toxicants (3a - i, 4a - i, and 5a - i) were prepared in an effort to 'mask' this acute response and improve both palatability and efficacy. Their synthesis, in vitro biological evaluation (vasocontractile response in rat vasculature, stability in selected rat media) and palatability/efficacy in Sprague-Dawley, wild Norway, and wild ship rats is described. Most notably, pro-toxicant 3d was revealed to be free of all pre-cleavage vasoconstrictory activity in rat caudal artery and was subsequently demonstrated to release NRB in the presence of rat blood, liver, and pancreatic enzymes. Moreover, it consistently displayed a high level of acceptance by rats in a two-choice bait-palatability and efficacy trial, with accompanying high mortality. On this evidence, fatty acid ester prodrugs would appear to offer a promising platform for the further development of NRB-derived toxicants with enhanced palatability and efficacy profiles.}, } @article {pmid27114001, year = {2016}, author = {Herisson, FM and Waas, JR and Fredriksson, R and Schiöth, HB and Levine, AS and Olszewski, PK}, title = {Oxytocin Acting in the Nucleus Accumbens Core Decreases Food Intake.}, journal = {Journal of neuroendocrinology}, volume = {28}, number = {4}, pages = {}, doi = {10.1111/jne.12381}, pmid = {27114001}, issn = {1365-2826}, mesh = {Animals ; Appetite ; Camphanes/pharmacology ; Eating/*physiology ; Feeding Behavior/physiology ; Food Deprivation/physiology ; Male ; Microinjections ; Neurons/physiology ; Nucleus Accumbens/*physiology ; Oxytocin/administration & dosage/antagonists & inhibitors/biosynthesis/*physiology ; Paraventricular Hypothalamic Nucleus/physiology ; Piperazines/pharmacology ; Rats ; Social Behavior ; Supraoptic Nucleus/physiology ; }, abstract = {Central oxytocin (OT) promotes feeding termination in response to homeostatic challenges, such as excessive stomach distension, salt loading and toxicity. OT has also been proposed to affect feeding reward by decreasing the consumption of palatable carbohydrates and sweet tastants. Because the OT receptor (OTR) is expressed in the nucleus accumbens core (AcbC) and shell (AcbSh), a site regulating diverse aspects of eating behaviour, we investigated whether OT acts there to affect appetite in rats. First, we examined whether direct AcbC and AcbSh OT injections affect hunger- and palatability-driven consumption. We found that only AcbC OT infusions decrease deprivation-induced chow intake and reduce the consumption of palatable sucrose and saccharin solutions in nondeprived animals. These effects were abolished by pretreatment with an OTR antagonist, L-368,899, injected in the same site. AcbC OT at an anorexigenic dose did not induce a conditioned taste aversion, which indicates that AcbC OT-driven anorexia is not caused by sickness/malaise. The appetite-specific effect of AcbC OT is supported by the real-time polymerase chain reaction analysis of OTR mRNA in the AcbC, which revealed that food deprivation elevates OTR mRNA expression, whereas saccharin solution intake decreases OTR transcript levels. We also used c-Fos immunohistochemistry as a marker of neuronal activation and found that AcbC OT injection increases activation of the AcbC itself, as well as of two feeding-related sites: the hypothalamic paraventricular and supraoptic nuclei. Finally, considering the fact that OT plays a significant role in social behaviour, we examined whether offering animals a meal in a social setting would modify their hypophagic response to AcbC OT injections. We found that a social context abolishes the anorexigenic effects of AcbC OT. We conclude that OT acting via the AcbC decreases food intake driven by hunger and reward in rats offered a meal in a nonsocial setting.}, } @article {pmid27084929, year = {2016}, author = {Flores, VL and Moran, A and Bernstein, M and Katz, DB}, title = {Preexposure to salty and sour taste enhances conditioned taste aversion to novel sucrose.}, journal = {Learning & memory (Cold Spring Harbor, N.Y.)}, volume = {23}, number = {5}, pages = {221-228}, pmid = {27084929}, issn = {1549-5485}, support = {R01DC6666/DC/NIDCD NIH HHS/United States ; R01 DC006666/DC/NIDCD NIH HHS/United States ; R01 DC007703/DC/NIDCD NIH HHS/United States ; T32 GM084907/GM/NIGMS NIH HHS/United States ; R01DC7703/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Conditioning, Classical/*physiology ; Drinking Behavior/physiology ; Female ; Rats ; Rats, Long-Evans ; Sucrose/*administration & dosage ; Sweetening Agents/*administration & dosage ; Taste/*physiology ; Taste Perception/drug effects/*physiology ; Time Factors ; Water Deprivation/physiology ; }, abstract = {Conditioned taste aversion (CTA) is an intensively studied single-trial learning paradigm whereby animals are trained to avoid a taste that has been paired with malaise. Many factors influence the strength of aversion learning; prominently studied among these is taste novelty-the fact that preexposure to the taste conditioned stimulus (CS) reduces its associability. The effect of exposure to tastes other than the CS has, in contrast, received little investigation. Here, we exposed rats to sodium chloride (N) and citric acid (C), either before or within a conditioning session involving novel sucrose (S). Presentation of this taste array within the conditioning session weakened the resultant S aversion, as expected. The opposite effect, however, was observed when exposure to the taste array was provided in sessions that preceded conditioning: such experience enhanced the eventual S aversion-a result that was robust to differences in CS delivery method and number of tastes presented in conditioning sessions. This "non-CS preexposure effect" scaled with the number of tastes in the exposure array (experience with more stimuli was more effective than experience with fewer) and with the amount of exposure sessions (three preexposure sessions were more effective than two). Together, our results provide evidence that exposure and experience with the realm of tastes changes an animal's future handling of even novel tastes.}, } @article {pmid27083122, year = {2016}, author = {Twining, RC and Freet, CS and Wheeler, RA and Reich, CG and Tompers, DA and Wolpert, SE and Grigson, PS}, title = {The role of dose and restriction state on morphine-, cocaine-, and LiCl-induced suppression of saccharin intake: A comprehensive analysis.}, journal = {Physiology & behavior}, volume = {161}, number = {}, pages = {104-115}, pmid = {27083122}, issn = {1873-507X}, support = {R01 DA009815/DA/NIDA NIH HHS/United States ; R37 DA009815/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Antimanic Agents/*pharmacology ; Avoidance Learning/*drug effects ; Cocaine/*pharmacology ; Dose-Response Relationship, Drug ; Eating/drug effects ; Food Deprivation ; Food Preferences ; Lithium Chloride/*pharmacology ; Male ; Morphine/*pharmacology ; Narcotics/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Saccharin/*administration & dosage ; Vasoconstrictor Agents/*pharmacology ; Water Deprivation ; }, abstract = {Rats avoid intake of a taste cue when paired with a drug of abuse or with the illness-inducing agent, lithium chloride (LiCl). Although progress has been made, it is difficult to compare the suppressive effects of abused agents and LiCl on intake of a gustatory conditioned stimulus (CS) because of the cross-laboratory use of different CSs, different unconditioned stimuli (USs), and different doses of the drugs, different conditioning regimens, and different restriction states. Here we have attempted to unify these variables by comparing the suppressive effects of a range of doses of morphine, cocaine, and LiCl on intake of a saccharin CS using a common regimen in non-restricted, food restricted, or water restricted male Sprague-Dawley rats. The results showed that, while the putatively aversive agent, LiCl, was effective in suppressing intake of the taste cue across nearly all doses, regardless of restriction state, the suppressive effects of both morphine and cocaine were greatly reduced when evaluated in either food or water restricted rats. Greater sensitivity to drug was revealed, at very low doses, when testing occurred in the absence of need (i.e., when the rats were non-restricted). Together, these results provide the first uniform and comprehensive analysis of the suppressive effects of morphine, cocaine, and LiCl as a function of dose and restriction state. In the present case, the suppressive effects of morphine and cocaine are found to differ from those of LiCl and, in some respects, from one another as well.}, } @article {pmid27079998, year = {2016}, author = {Haus, DL and López-Velázquez, L and Gold, EM and Cunningham, KM and Perez, H and Anderson, AJ and Cummings, BJ}, title = {Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury.}, journal = {Experimental neurology}, volume = {281}, number = {}, pages = {1-16}, doi = {10.1016/j.expneurol.2016.04.008}, pmid = {27079998}, issn = {1090-2430}, mesh = {Animals ; Antigens, CD/metabolism ; Brain Injuries, Traumatic/*complications/pathology/surgery ; Cell Differentiation ; Cognition Disorders/*etiology/*surgery ; Conditioning, Classical ; Disease Models, Animal ; Escape Reaction/physiology ; Exploratory Behavior/physiology ; Hippocampus/pathology ; Humans ; Male ; Maze Learning/physiology ; Nerve Tissue Proteins/metabolism ; Neural Stem Cells/metabolism/*transplantation ; Neurogenesis ; Neurons/metabolism/pathology ; Rats ; Rats, Nude ; Recognition, Psychology/physiology ; Spatial Behavior ; }, abstract = {Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically <1month post-injury and cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2-3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9-25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18-38%), astrocytes (GFAP, 13-16%), and oligodendrocytes (Olig2, 11-13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal tissue volume. Instead, we have found an overall increase in host hippocampal neuron survival in hNSC transplanted animals and demonstrate that a correlation exists between hippocampal neuron survival and cognitive performance. Together, these findings support the use of immunodeficient rodents in models of TBI that involve the transplantation of human cells, and suggest that hNSC transplantation may be a viable, long-term therapy to restore cognition after brain injury.}, } @article {pmid27053000, year = {2016}, author = {Zheng, F and Kim, YJ and Moran, TH and Li, H and Bi, S}, title = {Central transthyretin acts to decrease food intake and body weight.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {24238}, pmid = {27053000}, issn = {2045-2322}, support = {R01 DK087888/DK/NIDDK NIH HHS/United States ; R01 DK104867/DK/NIDDK NIH HHS/United States ; DK104867/DK/NIDDK NIH HHS/United States ; DK087888/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Arcuate Nucleus of Hypothalamus/drug effects/metabolism ; Blotting, Western ; Body Weight/*drug effects ; Cells, Cultured ; Eating/*drug effects ; Gene Expression Profiling/methods ; Hyperphagia/metabolism/*prevention & control ; Hypothalamus/drug effects/metabolism ; Infusions, Intraventricular ; Male ; Neuropeptide Y/metabolism ; Obesity/metabolism/*prevention & control ; Oligonucleotide Array Sequence Analysis ; Prealbumin/administration & dosage/*pharmacology/physiology ; Rats, Inbred OLETF ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Transthyretin (TTR) is a blood and cerebrospinal fluid transporter of thyroxine and retinol. Gene expression profiling revealed an elevation of Ttr expression in the dorsomedial hypothalamus (DMH) of rats with exercise-induced anorexia, implying that central TTR may also play a functional role in modulating food intake and energy balance. To test this hypothesis, we have examined the effects of brain TTR on food intake and body weight and have further determined hypothalamic signaling that may underlie its feeding effect in rats. We found that intracerebroventricular (icv) administration of TTR in normal growing rats decreased food intake and body weight. This effect was not due to sickness as icv TTR did not cause a conditioned taste aversion. ICV TTR decreased neuropeptide Y (NPY) levels in the DMH and the paraventricular nucleus (P < 0.05). Chronic icv infusion of TTR in Otsuka Long-Evans Tokushima Fatty rats reversed hyperphagia and obesity and reduced DMH NPY levels. Overall, these results demonstrate a previously unknown anorectic action of central TTR in the control of energy balance, providing a potential novel target for treating obesity and its comorbidities.}, } @article {pmid27027859, year = {2016}, author = {Dannenhoffer, CA and Spear, LP}, title = {Age differences in conditioned place preferences and taste aversions to nicotine.}, journal = {Developmental psychobiology}, volume = {58}, number = {5}, pages = {660-666}, doi = {10.1002/dev.21400}, pmid = {27027859}, issn = {1098-2302}, support = {P50 AA017823/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Behavior, Animal/drug effects/*physiology ; Conditioning, Classical/*physiology ; Cotinine/blood ; Male ; Nicotine/administration & dosage/*pharmacology ; Nicotinic Agonists/administration & dosage/*pharmacology ; Rats ; Rats, Sprague-Dawley ; *Reward ; Taste/physiology ; }, abstract = {Adolescents and adults differ in their behavioral sensitivities to drugs of abuse, including nicotine. Studies have shown that both rewarding and aversive properties of drugs of abuse can exist concomitantly. The present study investigated the ontogeny of these opposing qualities across a range of doses using a combined conditioned taste aversion and place preference paradigm in pair-housed rats that were not deprived of food or water. Results indicated that adolescents were more sensitive to the rewarding properties of nicotine than adults. In contrast, although all doses produced a taste aversion at both ages in the same rats, the aversion was weaker at lower than high doses in adolescents whereas adults showed strong aversion at all doses, suggesting modest attenuation in nicotine's aversive properties among adolescents relative to adults. Thus, attenuated aversive and accented appetitive sensitivities of adolescents to nicotine can be experienced simultaneously in the same animals. © 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 660-666, 2016.}, } @article {pmid27018173, year = {2016}, author = {Osorio-Gómez, D and Guzmán-Ramos, K and Bermúdez-Rattoni, F}, title = {Differential involvement of glutamatergic and catecholaminergic activity within the amygdala during taste aversion retrieval on memory expression and updating.}, journal = {Behavioural brain research}, volume = {307}, number = {}, pages = {120-125}, doi = {10.1016/j.bbr.2016.03.038}, pmid = {27018173}, issn = {1872-7549}, mesh = {Amygdala/drug effects/*metabolism ; Animals ; Avoidance Learning/drug effects/*physiology ; Catecholamines/*metabolism ; Cobalt/pharmacology ; Conditioning, Psychological/drug effects ; Excitatory Amino Acid Agents/pharmacology ; Exploratory Behavior/drug effects ; Glutamic Acid/*metabolism ; Immobility Response, Tonic/drug effects ; Male ; Mental Recall/drug effects/*physiology ; Microdialysis ; N-Methylaspartate/pharmacology ; Nitric Oxide Synthase Type I/metabolism ; Rats ; Rats, Wistar ; Swimming/psychology ; Taste/drug effects/*physiology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology ; }, abstract = {During memory retrieval, consolidated memories are expressed and destabilized in order to maintain or update information through a memory reconsolidation process. Despite the key role of the amygdala during memory acquistion and consolidation, the participation of neurotransmitter signals in memory retrieval is poorly understood. Hence, we used conditioned taste aversion and in vivo microdialysis to evaluate changes in glutamate, norepinephrine and dopamine concentrations within the amygdala during memory retrieval. We observed that exposure to an aversive-conditioned stimulus induced an augmentation in glutamate, norepinephrine and dopamine levels within the amygdala, while exposure to a familiar and safe stimulus did not induce changes in these neurotransmitters levels. Also, we evaluated the amygdalar blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA), β-adrenergic and dopamine D1 receptors in memory retrieval and updating. Results showed that during retrieval, behavioural expression was impaired by intra-amygdalar blockade of AMPA and β-adrenergic receptors, whereas NMDA, D1 and β-adrenergic receptors blockade hindered memory updating. In summary, during conditioned taste aversion retrieval there was an increase in the extracellular levels of glutamate, norepinephrine and dopamine within the amygdala, and their receptors activity were differentially involved in the behavioural expression and memory updating during retrieval.}, } @article {pmid27014009, year = {2016}, author = {Villain, H and Benkahoul, A and Drougard, A and Lafragette, M and Muzotte, E and Pech, S and Bui, E and Brunet, A and Birmes, P and Roullet, P}, title = {Effects of Propranolol, a β-noradrenergic Antagonist, on Memory Consolidation and Reconsolidation in Mice.}, journal = {Frontiers in behavioral neuroscience}, volume = {10}, number = {}, pages = {49}, pmid = {27014009}, issn = {1662-5153}, abstract = {Memory reconsolidation impairment using the β-noradrenergic receptor blocker propranolol is a promising novel treatment avenue for patients suffering from pathogenic memories, such as post-traumatic stress disorder (PTSD). However, in order to better inform targeted treatment development, the effects of this compound on memory need to be better characterized via translational research. We examined the effects of systemic propranolol administration in mice undergoing a wide range of behavioral tests to determine more specifically which aspects of the memory consolidation and reconsolidation are impaired by propranolol. We found that propranolol (10 mg/kg) affected memory consolidation in non-aversive tasks (object recognition and object location) but not in moderately (Morris water maze (MWM) to highly (passive avoidance, conditioned taste aversion) aversive tasks. Further, propranolol impaired memory reconsolidation in the most and in the least aversive tasks, but not in the moderately aversive task, suggesting its amnesic effect was not related to task aversion. Moreover, in aquatic object recognition and location tasks in which animals were forced to behave (contrary to the classic versions of the tasks); propranolol did not impair memory reconsolidation. Taken together our results suggest that the memory impairment observed after propranolol administration may result from a modification of the emotional valence of the memory rather than a disruption of the contextual component of the memory trace. This is relevant to the use of propranolol to block memory reconsolidation in individuals with PTSD, as such a treatment would not erase the traumatic memory but only reduce the emotional valence associated with this event.}, } @article {pmid26992702, year = {2016}, author = {Dyr, W and Wyszogrodzka, E and Paterak, J and Siwińska-Ziółkowska, A and Małkowska, A and Polak, P}, title = {Ethanol-induced conditioned taste aversion in Warsaw Alcohol High-Preferring (WHP) and Warsaw Alcohol Low-Preferring (WLP) rats.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {51}, number = {}, pages = {63-69}, doi = {10.1016/j.alcohol.2015.11.011}, pmid = {26992702}, issn = {1873-6823}, mesh = {Alcohol Drinking/*genetics ; Alcoholism/genetics ; Animals ; Avoidance Learning/drug effects/*physiology ; Choice Behavior/drug effects/*physiology ; Conditioning, Classical/drug effects/*physiology ; Ethanol/*administration & dosage ; Male ; Rats ; Saccharin/administration & dosage ; Taste/*genetics ; }, abstract = {The aversive action of the pharmacological properties of ethanol was studied in selectively bred Warsaw Alcohol High-Preferring (WHP) and Warsaw Alcohol Low-Preferring (WLP) rats. For this study, a conditioned-taste aversion test was used. Male WHP and WLP rats were submitted to daily 20-min sessions for 5 days, in which a saccharin solution (1.0 g/L) was available (pre-conditioning phase). Next, this drinking was paired with the injection of ethanol (0, 0.5, 1.0 g/kg), intraperitoneally [i.p.] immediately after removal of the saccharin bottle (conditioning phase). Afterward, the choice between the saccharin solution and water was extended for 18 subsequent days for 20-min daily sessions (post-conditioning phase). Both doses of ethanol did not produce an aversion to saccharin in WLP and WHP rats in the conditioning phase. However, injection of the 1.0 g/kg dose of ethanol produced an aversion in WLP rats that was detected by a decrease in saccharin intake at days 1, 3, 7, and 10 of the post-conditioning phase, with a decrease in saccharin preference for 16 days of the post-conditioning phase. Conditioned taste aversion, measured as a decrease in saccharin intake and saccharin preference, was only visible in WHP rats at day 1 and day 3 of the post-conditioning phase. This difference between WLP and WHP rats was apparent despite similar blood ethanol levels in both rat lines following injection of 0.5 and 1.0 g/kg of ethanol. These results may suggest differing levels of aversion to the post-ingestional effects of ethanol between WLP and WHP rats. These differing levels of aversion may contribute to the selected line difference in ethanol preference in WHP and WLP rats.}, } @article {pmid26975440, year = {2016}, author = {Hurley, MM and Resch, JM and Maunze, B and Frenkel, MM and Baker, DA and Choi, S}, title = {N-acetylcysteine decreases binge eating in a rodent model.}, journal = {International journal of obesity (2005)}, volume = {40}, number = {7}, pages = {1183-1186}, pmid = {26975440}, issn = {1476-5497}, support = {R01 DK074734/DK/NIDDK NIH HHS/United States ; R21 DA035088/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Binge-Eating Disorder/*drug therapy ; Conditioning, Operant/drug effects ; Diet, High-Fat ; *Disease Models, Animal ; Feeding Behavior/*drug effects/*psychology ; Injections, Intraventricular ; Male ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Binge-eating behavior involves rapid consumption of highly palatable foods leading to increased weight gain. Feeding in binge disorders resembles other compulsive behaviors, many of which are responsive to N-acetylcysteine (NAC), which is a cysteine prodrug often used to promote non-vesicular glutamate release by a cystine-glutamate antiporter. To examine the potential for NAC to alter a form of compulsive eating, we examined the impact of NAC on binge eating in a rodent model. Specifically, we monitored consumption of standard chow and a high-fat, high carbohydrate western diet (WD) in a rodent limited-access binge paradigm. Before each session, rats received either a systemic or intraventricular injection of NAC. Both systemic and central administration of NAC resulted in significant reductions of binge eating the WD without decreasing standard chow consumption. The reduction in WD was not attributable to general malaise as NAC did not produce condition taste aversion. These results are consistent with the clinical evidence of NAC to reduce or reverse compulsive behaviors, such as, drug addiction, skin picking and hair pulling.}, } @article {pmid26961783, year = {2016}, author = {Kislal, S and Blizard, DA}, title = {Conditioned context aversion learning in the laboratory mouse.}, journal = {Learning & behavior}, volume = {44}, number = {4}, pages = {309-319}, pmid = {26961783}, issn = {1543-4508}, mesh = {Animals ; *Avoidance Learning ; *Conditioning, Classical ; Conditioning, Psychological ; Drinking ; Lithium Chloride ; Mice ; Rats ; Taste ; }, abstract = {It is well known that pairing of large contextual changes with illness can cause conditioned context aversion in laboratory rats. The aim of present study was to develop a paradigm to study this phenomenon in laboratory mice, a species widely employed in neurobehavioral studies. Genetically heterogeneous mice, drinking from plastic bottles in the colony room, learned to avoid glass bottles after a single conditioning trial when drinking from these was paired with injections of lithium chloride. The aversion was independent of any difference in the taste of water in plastic vs. glass bottles. When the variation in the visual stimulus was less distinct, development of a strong aversion required two conditioning trials and was not retained as well. The results also showed that conditioned context aversion, just like conditioned taste aversion, could also be developed across a 30-minute CS-UCS delay. The fact that taste was not a factor in distinguishing drinking from glass and plastic water bottles raises the possibility that, contextual stimuli, not taste, may have been the CS when rats (in Garcia's original experiments) avoided drinking from plastic bottles that had been paired with radiation. The development of contextual aversion conditioning protocols for mice will enable the molecular resources available for this species to be exploited. Furthermore, representation of the CS by discrete rather than the multimodal CSs typically used in most studies on contextual conditioning offers more focus when considering its neuroanatomical basis.}, } @article {pmid26885512, year = {2016}, author = {Albores-Garcia, D and Acosta-Saavedra, LC and Hernandez, AJ and Loera, MJ and Calderón-Aranda, ES}, title = {Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.}, journal = {BioMed research international}, volume = {2016}, number = {}, pages = {6532108}, pmid = {26885512}, issn = {2314-6141}, mesh = {Age Factors ; Animals ; Female ; Humans ; Learning/*drug effects/physiology ; Male ; Memory/*drug effects/physiology ; Methylmercury Compounds/*toxicity ; Pregnancy ; Rats ; }, abstract = {Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.}, } @article {pmid26857541, year = {2016}, author = {Blednov, YA and Black, M and Benavidez, JM and Stamatakis, EE and Harris, RA}, title = {PPAR Agonists: II. Fenofibrate and Tesaglitazar Alter Behaviors Related to Voluntary Alcohol Consumption.}, journal = {Alcoholism, clinical and experimental research}, volume = {40}, number = {3}, pages = {563-571}, pmid = {26857541}, issn = {1530-0277}, support = {AA013520/AA/NIAAA NIH HHS/United States ; R37 AA006399/AA/NIAAA NIH HHS/United States ; R01 AA006399/AA/NIAAA NIH HHS/United States ; U01 AA013520/AA/NIAAA NIH HHS/United States ; AA006399/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking/*drug therapy/psychology ; Alkanesulfonates/*pharmacology/therapeutic use ; Animals ; Avoidance Learning/drug effects/physiology ; Conditioning, Classical/drug effects/physiology ; Female ; Fenofibrate/*pharmacology/therapeutic use ; Locomotion/drug effects ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; PPAR alpha/*agonists/*physiology ; Phenylpropionates/*pharmacology/therapeutic use ; Reflex, Righting/drug effects/physiology ; Taste/drug effects/physiology ; }, abstract = {BACKGROUND: In the accompanying article, we showed that activation of peroxisome proliferator-activated receptor alpha (PPARα) signaling by fenofibrate and tesaglitazar decreases ethanol (EtOH) consumption in mice. In this study, we determined the role of these PPAR agonists in EtOH-related behaviors and other actions that may be important in regulating EtOH consumption.

METHODS: The effects of fenofibrate (150 mg/kg) and tesaglitazar (1.5 mg/kg) were examined on the following responses in male and female C57BL/6J (B6) and B6 × 129S4 mice: preference for saccharin, EtOH-induced conditioned place preference (CPP), conditioned taste aversion (CTA), loss of righting reflex, and withdrawal, acoustic startle reflex, response to novelty, and EtOH clearance. Because the B6 inbred strain usually displays weak EtOH-induced CPP and weak EtOH-induced acute withdrawal, B6 × 129S4 mice were also studied.

RESULTS: Fenofibrate and tesaglitazar decreased the novelty response and increased acute EtOH withdrawal severity, and fenofibrate increased EtOH-induced CTA. Two important factors for EtOH consumption (saccharin preference and EtOH-induced CPP) were not altered by fenofibrate or tesaglitazar. EtOH clearance was increased by both fenofibrate and tesaglitazar. Response to novelty, acute withdrawal, and EtOH clearance show sex differences and could contribute to the reduced EtOH consumption following fenofibrate administration.

CONCLUSIONS: These studies indicate the complexity of EtOH-dependent and EtOH-independent behaviors that are altered by PPAR agonists and provide evidence for novel behavioral actions of these drugs that may contribute to PPAR-mediated effects on alcohol drinking.}, } @article {pmid26854904, year = {2016}, author = {Rivera-Olvera, A and Rodríguez-Durán, LF and Escobar, ML}, title = {Conditioned taste aversion prevents the long-lasting BDNF-induced enhancement of synaptic transmission in the insular cortex: A metaplastic effect.}, journal = {Neurobiology of learning and memory}, volume = {130}, number = {}, pages = {71-76}, doi = {10.1016/j.nlm.2016.01.014}, pmid = {26854904}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*physiology ; Brain-Derived Neurotrophic Factor/*pharmacology ; Cerebral Cortex/*drug effects/physiology ; Conditioning, Classical/*physiology ; Male ; Neuronal Plasticity/*drug effects/physiology ; Rats ; Rats, Wistar ; Synaptic Transmission/*drug effects/physiology ; Taste/*physiology ; Taste Perception/physiology ; }, abstract = {Homeostatic plasticity mechanisms dynamically adjust synaptic strengths to promote stability that is crucial for memory storage. Metaplasticity is an example of these forms of plasticity that modify the capacity of synapses to experience subsequent Hebbian modifications. In particular, training in several behavioral tasks modifies the ability to induce long-term potentiation (LTP). Recently, we have reported that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP generated by high frequency stimulation in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC). One of the key molecular players that underlie long-term synaptic plasticity is brain-derived neurotrophic factor (BDNF). Previous studies from our group reported that acute microinfusion of BDNF in the IC induces a lasting potentiation of synaptic efficacy at the Bla-IC projection. Thus, the aim of the present study was to analyze whether CTA training modifies the ability to induce subsequent BDNF-induced potentiation of synaptic transmission in the Bla-IC projection in vivo. Accordingly, CTA trained rats received intracortical microinfusion of BDNF in order to induce lasting potentiation 48h after the aversion test. Our results show that CTA training prevents the induction of in vivo BDNF-LTP in the Bla-IC projection. The present results provide evidence that CTA modulates BDNF-dependent changes in IC synaptic strength.}, } @article {pmid26833633, year = {2016}, author = {Tracy, AL and Schurdak, JD and Chambers, JB and Benoit, SC}, title = {Aversion learning can reduce meal size without taste avoidance in rats.}, journal = {Obesity (Silver Spring, Md.)}, volume = {24}, number = {3}, pages = {606-614}, doi = {10.1002/oby.21379}, pmid = {26833633}, issn = {1930-739X}, mesh = {Adjuvants, Immunologic/administration & dosage/*toxicity ; Animals ; Avoidance Learning/*drug effects ; Behavior, Animal/drug effects ; Body Weight/drug effects ; Eating/*drug effects ; Lithium Chloride/*administration & dosage/toxicity ; Rats ; Taste/*drug effects ; }, abstract = {OBJECTIVE: Nausea and aversive food responses are commonly reported following bariatric surgery, along with post-surgical reduction in meal size. This study investigates whether a meal size limit can be conditioned by associating large meals with aversive outcomes.

METHODS: In rats, the intake of meals exceeding a pre-defined size threshold was paired with lithium chloride-induced gastric illness, and the effects on self-determined food intakes and body weight were measured.

RESULTS: Rats given LiCl contingent on the intake of a large meal learned to reliably reduce intake below this meal size threshold, while post-meal saline or LiCl before meals did not change meal size. It was further demonstrated that this is not a conditioned taste aversion and that this effect transferred to foods not explicitly trained. Finally, when rats received LiCl following all large meals, the number of small meals increased, but total food intake and body weight decreased.

CONCLUSIONS: While further work is needed, this is the first demonstration that meal size may be conditioned, using an aversion procedure, to remain under a target threshold and that this effect is distinct from taste avoidance. Corresponding reduction in food intake and body weight suggests that this phenomenon may have implications for developing weight loss strategies and understanding the efficacy of bariatric surgery.}, } @article {pmid26785229, year = {2016}, author = {Rosenberg, T and Elkobi, A and Dieterich, DC and Rosenblum, K}, title = {NMDAR-dependent proteasome activity in the gustatory cortex is necessary for conditioned taste aversion.}, journal = {Neurobiology of learning and memory}, volume = {130}, number = {}, pages = {7-16}, doi = {10.1016/j.nlm.2016.01.002}, pmid = {26785229}, issn = {1095-9564}, mesh = {Acetylcysteine/analogs & derivatives/pharmacology ; Animals ; Avoidance Learning/drug effects/*physiology ; Conditioning, Psychological/drug effects/physiology ; Cysteine Proteinase Inhibitors/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Male ; Proteasome Endopeptidase Complex/*metabolism ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*metabolism ; Somatosensory Cortex/drug effects/*metabolism ; Taste/drug effects/physiology ; Taste Perception/drug effects/*physiology ; Valine/analogs & derivatives/pharmacology ; }, abstract = {Taste information is processed in different brain structures in the mammalian brain, including the gustatory cortex (GC), which resides within the insular cortex. N-methyl-d-aspartate receptor (NMDAR) activity in the GC is necessary for the acquisition of conditioned taste aversion (CTA) but not positive novel taste learning. Previous studies have shown that taste memory consolidation requires intact protein synthesis in the GC. In addition, the direct involvement of translation initiation and elongation factors was documented in the GC during taste learning. However, protein expression is defined by protein synthesis, degradation, and localization. Protein degradation is critical for the consolidation and reconsolidation of other forms of learning, such as fear learning and addiction behavior, but its role in cortical-dependent learning is not clear. Here, we show for the first time that proteasome activity is specifically increased in the GC 4h following experiencing of a novel taste. This increase in proteasome activity was abolished by local administration to the GC of the NMDA antagonist, APV, as well as a CaMKII inhibitor, at the time of acquisition. In addition, local application of lactacystin, a proteasome inhibitor, resulted in impaired CTA, but not novel taste learning. These results suggest that NMDAR-dependent proteasome activity in the GC participates in the association process between novel taste experience and negative visceral sensation.}, } @article {pmid26783230, year = {2016}, author = {Feifel, D and Shilling, PD and Fazlinejad, AA and Melendez, G}, title = {Antipsychotic drug-like facilitation of latent inhibition by a brain-penetrating neurotensin-1 receptor agonist.}, journal = {Journal of psychopharmacology (Oxford, England)}, volume = {30}, number = {3}, pages = {312-317}, doi = {10.1177/0269881115625360}, pmid = {26783230}, issn = {1461-7285}, support = {R01MH080910/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Antipsychotic Agents/*pharmacology ; Avoidance Learning/drug effects ; Brain/*drug effects ; Conditioning, Classical/drug effects ; Conditioning, Psychological/drug effects ; Lithium Chloride/pharmacology ; Male ; Rats ; Rats, Brattleboro ; Receptors, Neurotensin/*agonists ; Schizophrenia/drug therapy ; }, abstract = {Latent inhibition (LI) is a measure of cognitive gating and refers to reduced conditioned learning when there is pre-exposure to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (US). Dysregulation of LI is associated with some neuropsychiatric disorders, including schizophrenia, and the ability to facilitate LI in rodents is a reasonably good predictive test for antipsychotic drugs. Converging evidence supports neurotensin-1 receptor (NTS1) agonists as novel drugs for schizophrenia. Therefore, we investigated the ability of a brain-penetrating, selective NTS1 agonist, PD149163, to facilitate LI in heterozygous Brattleboro rats, a strain that exhibits naturally low LI. Conditioned taste aversion to flavored water (FW; 0.1% saccharin) was induced by pairing it with malaise-inducing injections of lithium chloride (LiCl). Prior to LiCl-FW pairing, rats received subcutaneous injections of saline, or PD149163 (100 µg/kg or 200 µg/kg). Half the rats in each drug group had been allowed to drink FW the day before the LiCl-FW pairing (pre-exposed rats). Two days after pairing, the amount of FW each rat consumed was recorded. LI, defined as significantly greater FW drinking in the pre-exposed group compared with the non pre-exposed group, was exhibited only among rats that received 200 µg/kg of PD149163. These results further support NTS1 agonists as potentially novel drugs for the treatment of schizophrenia.}, } @article {pmid26774181, year = {2016}, author = {Saalfield, J and Spear, L}, title = {The ontogeny of ethanol aversion.}, journal = {Physiology & behavior}, volume = {156}, number = {}, pages = {164-170}, pmid = {26774181}, issn = {1873-507X}, support = {P50 AA017823/AA/NIAAA NIH HHS/United States ; P50AA017823/AA/NIAAA NIH HHS/United States ; }, mesh = {Age Factors ; Animals ; Avoidance Learning/*drug effects ; Conditioning, Classical/drug effects ; Ethanol/*pharmacology ; Female ; Male ; Rats ; Rats, Sprague-Dawley ; Saccharin/pharmacology ; *Taste ; }, abstract = {Recent work has suggested separate developmental periods within the broader framework of adolescence, with data suggesting distinct alterations and vulnerabilities within these intervals. While previous research has suggested reduced sensitivity to the aversive effects of alcohol in adolescence relative to adults, a more detailed ontogeny of this effect has yet to be conducted. The adolescent brain undergoes significant transitions throughout adolescence, including in regions linked with drug reward and aversion. The current study aimed to determine the ontogeny of ethanol aversion by utilizing a conditioned taste aversion procedure at six different ages to test the hypothesis that the transitions into, through, and out of adolescence are associated with ontogenetic alterations in sensitivity to the aversive properties of ethanol. Non-deprived animals given Boost® as the conditioned stimulus (CS) were used in Experiment 1, whereas Experiment 2 used water-restricted animals provided with a saccharin/sucrose solution as the CS. In both experiments, an attenuated sensitivity to the aversive properties of ethanol was evident in adolescents compared to adults, although more age differences were apparent in water deprived animals than when a highly palatable CS was given to ad libitum animals. Overall, the data suggest an attenuated sensitivity to the aversive properties of ethanol that is most pronounced during pre- and early adolescence, declining thereafter to reach the enhanced aversive sensitivity of adults.}, } @article {pmid26752235, year = {2016}, author = {Kwok, DW and Sun, Q and Boakes, RA}, title = {Mediated overshadowing and potentiation of long-delay taste aversion learning: Two versus six cue-taste pairings.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {42}, number = {1}, pages = {106-115}, doi = {10.1037/xan0000088}, pmid = {26752235}, issn = {2329-8464}, mesh = {Animals ; *Avoidance Learning ; Conditioning, Classical ; Cues ; Lithium Chloride ; Male ; Rats ; Rats, Wistar ; Sucrose ; *Taste Perception ; Time Factors ; }, abstract = {Mediated overshadowing occurs when an evoked representation of one stimulus interferes with the formation of an association between two other stimuli. This study tested whether such an effect can be found in long-delay taste aversion learning. The general methodology was to pair a cue with a sour taste (hydrochloric acid [HCl]) and then introduce the cue during the delay between the target taste, sucrose, and injection with lithium chloride (LiCl). Either 2 or 6 cue-HCl pairings were given. In Experiment 1, introduction of the cue, an almond flavor, produced overshadowing of the sucrose aversion in the group given 2 cue-HCl pairings (Paired-2), relative to an unpaired control, but potentiation of the sucrose aversion in the group given 6 cue-HCl pairings (Paired-6). This confirms that few pairings can be better than many in determining whether representation-mediated effects occur (Holland, 1990). A possible explanation for the Paired-6 results is that almond evoked an aversive response rather than memory of the sour HCl and that this added to the aversion produced by the sucrose-lithium pairing. Experiment 2 obtained similar results when a context was used as the cue intended to evoke an HCl representation.}, } @article {pmid26740565, year = {2016}, author = {Ward-Fear, G and Pearson, DJ and Brown, GP and Rangers, B and Shine, R}, title = {Ecological immunization: in situ training of free-ranging predatory lizards reduces their vulnerability to invasive toxic prey.}, journal = {Biology letters}, volume = {12}, number = {1}, pages = {20150863}, pmid = {26740565}, issn = {1744-957X}, mesh = {Animals ; Avoidance Learning ; *Bufo marinus ; Introduced Species ; Lizards/*physiology ; *Predatory Behavior ; Toxins, Biological/toxicity ; Western Australia ; }, abstract = {In Australia, large native predators are fatally poisoned when they ingest invasive cane toads (Rhinella marina). As a result, the spread of cane toads has caused catastrophic population declines in these predators. Immediately prior to the arrival of toads at a floodplain in the Kimberley region, we induced conditioned taste aversion in free-ranging varanid lizards (Varanus panoptes), by offering them small cane toads. By the end of the 18-month study, only one of 31 untrained lizards had survived longer than 110 days, compared to more than half (nine of 16) of trained lizards; the maximum known survival of a trained lizard in the presence of toads was 482 days. In situ aversion training (releasing small toads in advance of the main invasion front) offers a logistically simple and feasible way to buffer the impact of invasive toads on apex predators.}, } @article {pmid26731530, year = {2016}, author = {Kim, HJ and Koh, HY}, title = {Impaired Reality Testing in Mice Lacking Phospholipase Cβ1: Observed by Persistent Representation-Mediated Taste Aversion.}, journal = {PloS one}, volume = {11}, number = {1}, pages = {e0146376}, pmid = {26731530}, issn = {1932-6203}, mesh = {Animals ; Avoidance Learning/*physiology ; Disease Models, Animal ; Mice ; Mice, Knockout ; Phospholipase C beta/genetics/*metabolism ; *Reality Testing ; Schizophrenia/physiopathology ; Taste/*physiology ; Taste Perception/*physiology ; }, abstract = {Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized by impaired reality testing. Representation-mediated taste aversion (RMTA) has been proposed as a potential behavioral assessment of reality testing and has been applied to a neurodevelopmental rat model of schizophrenia. However, the theory underlying this approach has not been generalized yet with any demonstration of impaired reality testing in other animal models of schizophrenia, such as genetically-modified mice. We devised a RMTA procedure for mice that combines a Pavlovian association protocol pairing odor conditioned stimulus (CS) with sugar reward unconditioned stimulus (US), and a conditioned taste aversion (CTA) method. In this RMTA paradigm, we compared performances of wild-type (PLCβ1+/+) mice and phospholipase C β1 knock-out (PLCβ1-/-) mice which are known as one of the genetic models for schizophrenia. With a minimal amount of initial odor-sugar associative training, both PLCβ1+/+ and PLCβ1-/- mice were able to form an aversion to the sugar reward when the odor CS predicting sugar was paired with nausea. With an extended initial training, however, only PLCβ1-/- mice could form a RMTA. This persistent RMTA displayed by PLCβ1-/- mice shows their inability to distinguish real sugar from the CS-evoked representation of sugar at a stage in associative learning where wild-type mice normally could differentiate the two. These results demonstrate an impaired reality testing first observed in a genetic mouse model of schizophrenia, and suggest that RMTA paradigm may, with general applicability, allow diverse biological approaches to impaired reality testing.}, } @article {pmid26708104, year = {2016}, author = {Cocorocchio, M and Ives, R and Clapham, D and Andrews, PL and Williams, RS}, title = {Bitter tastant responses in the amoeba Dictyostelium correlate with rat and human taste assays.}, journal = {ALTEX}, volume = {33}, number = {3}, pages = {225-236}, doi = {10.14573/altex.1509011}, pmid = {26708104}, issn = {1868-8551}, support = {NC/S01201/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, mesh = {Animal Testing Alternatives ; Animals ; Chemotaxis ; Dictyostelium/*drug effects/*physiology ; Humans ; Movement ; Rats ; *Taste ; Time ; }, abstract = {Treatment compliance is reduced when pharmaceutical compounds have a bitter taste and this is particularly marked for paediatric medications. Identification of bitter taste liability during drug discovery utilises the rat in vivo brief access taste aversion (BATA) test which apart from animal use is time consuming with limited throughput. We investigated the suitability of using a simple, non-animal model, the amoeba Dictyostelium discoideum to investigate taste-related responses and particularly identification of compounds with a bitter taste liability. The effect of taste-related compounds on Dictyostelium behaviour following acute exposure (15 minutes) was monitored. Dictyostelium did not respond to salty, sour, umami or sweet tasting compounds, however, cells rapidly responded to bitter tastants. Using time-lapse photography and computer-generated quantification to monitor changes in cell membrane movement, we developed an assay to assess the response of Dictyostelium to a wide range of structurally diverse known bitter compounds and blinded compounds. Dictyostelium showed varying responses to the bitter tastants, with IC50 values providing a rank order of potency. Comparison of Dictyostelium IC50 values to those observed in response to a similar range of compounds in the rat in vivo brief access taste aversion test showed a significant (p = 0.0172) positive correlation between the two models, and additionally a similar response to that provided by a human sensory panel assessment test. These experiments demonstrate that Dictyostelium may provide a suitable model for early prediction of bitterness for novel tastants and drugs. Interestingly, a response to bitter tastants appears conserved from single-celled amoebae to humans.}, } @article {pmid26651338, year = {2015}, author = {Xu, LH and Tang, GR and Yang, JJ and Liu, HX and Li, JC and Jiang, ZL}, title = {AVP modulation of the vestibular nucleus via V1b receptors potentially contributes to the development of motion sickness in rat.}, journal = {Molecular brain}, volume = {8}, number = {}, pages = {86}, pmid = {26651338}, issn = {1756-6606}, mesh = {Afferent Pathways/physiopathology ; Animals ; Antidiuretic Hormone Receptor Antagonists/therapeutic use ; Arginine Vasopressin/biosynthesis/genetics/*physiology/toxicity ; Axonal Transport ; Calcium Channels, L-Type/physiology ; Calcium Signaling ; Cells, Cultured ; Conditioning, Classical ; Disease Models, Animal ; Dysgeusia/chemically induced/physiopathology ; Female ; Indoles/pharmacology/therapeutic use ; Male ; Microinjections ; Motion Sickness/genetics/*physiopathology/prevention & control ; Nerve Endings/chemistry ; Paraventricular Hypothalamic Nucleus/metabolism/*physiopathology ; Polymorphism, Single Nucleotide ; Pyrrolidines/pharmacology/therapeutic use ; RNA, Messenger/biosynthesis/genetics ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/physiology ; Receptors, Vasopressin/biosynthesis/genetics/*physiology ; Rotation ; Saccharin ; Synaptophysin/analysis ; Vestibular Nuclei/cytology/metabolism/*physiopathology ; }, abstract = {BACKGROUND: Arginine vasopressin (AVP) is considered to be an etiologic hormone in motion sickness (MS). The present study was designed to investigate whether individual differences in AVP expression in the paraventricular nucleus (PVN) and in modulation on the vestibular nucleus (VN) are involved in MS. Systemic application or microinjection of AVP into rat VN and rotatory stimulus were used to induce conditioned taste aversion (CTA) to 0.15 % saccharin sodium solution as a model of MS.

RESULTS: Intra-VN use of SSR149415, an antagonist of V1b receptors (V1bRs), blunted CTA. AVP inhibited Ca(2+) influxes through L-type Ca(2+) channels and NMDA receptor channels in cultured VN neurones, but antagonised by SSR149415. More AVP and V1bRs were expressed respectively in the PVN and VN after rotatory stimulus, especially in rats susceptible to MS. In the VN, AVP content was low, the AVP mRNA was less expressed, a few AVP-positive fibres were sparsely distributed, and fewer AVP/synaptophysin-positive terminals were identified. Almost no fluoro-ruby-labelled AVP-positive neurones in the PVN were found with retrograde tracing from the VN. SNP analysis of the reported 9 sites of the AVP gene showed significant difference between the groups susceptible and insusceptible to MS at the site rs105235842 in the allele frequencies and genotypes. However, there was not any difference between these two groups in the SNP of the reported 38 sites of V1bR gene.

CONCLUSIONS: AVP, through its modulatory, possibly humoral action on the VN neurones via the mediation of V1bR, may contribute to the development of motion sickness in rats; AVP gene polymorphisms may contribute to the individual difference in the responsive expression of AVP in the PVN; and higher expressions of AVP in the PVN and V1bRs in the VN may contribute to the development of motion sickness in rats after vestibular stimulation.}, } @article {pmid26650928, year = {2016}, author = {Daniel, C}, title = {Economic constraints on taste formation and the true cost of healthy eating.}, journal = {Social science & medicine (1982)}, volume = {148}, number = {}, pages = {34-41}, pmid = {26650928}, issn = {1873-5347}, support = {UL1 TR001102/TR/NCATS NIH HHS/United States ; 8UL1TR000170-05/TR/NCATS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Boston ; Child ; Child, Preschool ; Choice Behavior ; Diet/*economics/*psychology ; *Feeding Behavior ; Female ; Food Preferences ; *Health Behavior ; Health Status Disparities ; Humans ; Male ; Middle Aged ; Parents/psychology ; Qualitative Research ; Socioeconomic Factors ; *Taste ; Young Adult ; }, abstract = {This article shows how an interaction between economic constraints and children's taste preferences shapes low-income families' food decisions. According to studies of eating behavior, children often refuse unfamiliar foods 8 to 15 times before accepting them. Using 80 interviews and 41 grocery-shopping observations with 73 primary caregivers in the Boston area in 2013-2015, I find that many low-income respondents minimize the risk of food waste by purchasing what their children like--often calorie-dense, nutrient-poor foods. High-income study participants, who have greater resources to withstand the cost of uneaten food, are more likely to repeatedly introduce foods that their children initially refuse. Several conditions moderate the relationship between children's taste aversion and respondents' risk aversion, including household-level food preferences, respondents' conceptions of adult authority, and children's experiences outside of the home. Low-income participants' risk aversion may affect children's taste acquisition and eating habits, with implications for socioeconomic disparities in diet quality. This article proposes that the cost of providing children a healthy diet may include the possible cost of foods that children waste as they acquire new tastes.}, } @article {pmid26615907, year = {2016}, author = {Itoga, CA and Berridge, KC and Aldridge, JW}, title = {Ventral pallidal coding of a learned taste aversion.}, journal = {Behavioural brain research}, volume = {300}, number = {}, pages = {175-183}, pmid = {26615907}, issn = {1872-7549}, support = {R01 MH063649/MH/NIMH NIH HHS/United States ; R01 DA015188/DA/NIDA NIH HHS/United States ; EY017878/EY/NEI NIH HHS/United States ; DA017752/DA/NIDA NIH HHS/United States ; T32 DA007281/DA/NIDA NIH HHS/United States ; R01 DA017752/DA/NIDA NIH HHS/United States ; DA007281/DA/NIDA NIH HHS/United States ; T32 NS076401/NS/NINDS NIH HHS/United States ; MH63649/MH/NIMH NIH HHS/United States ; T32 EY017878/EY/NEI NIH HHS/United States ; DA015188/DA/NIDA NIH HHS/United States ; }, mesh = {Action Potentials/physiology ; Animals ; Association Learning/*physiology ; Avoidance Learning/*physiology ; Basal Forebrain/*physiology ; Catheters, Indwelling ; Conditioning, Classical/*physiology ; Dietary Sucrose/administration & dosage ; Electrodes, Implanted ; Glucans/administration & dosage ; Lithium Chloride ; Male ; Motor Activity ; Nausea ; Neurons/*physiology ; Rats, Sprague-Dawley ; Reward ; Saccharin/administration & dosage ; Taste Perception/*physiology ; }, abstract = {The hedonic value of a sweet food reward, or how much a taste is 'liked', has been suggested to be encoded by neuronal firing in the posterior ventral pallidum (VP). Hedonic impact can be altered by psychological manipulations, such as taste aversion conditioning, which can make an initially pleasant sweet taste become perceived as disgusting. Pairing nausea-inducing LiCl injection as a Pavlovian unconditioned stimulus (UCS) with a novel taste that is normally palatable as the predictive conditioned stimulus (CS+) suffices to induce a learned taste aversion that changes orofacial 'liking' responses to that sweet taste (e.g., lateral tongue protrusions) to 'disgust' reactions (e.g., gapes) in rats. We used two different sweet tastes of similar initial palatability (a sucrose solution and a polycose/saccharin solution, CS ± assignment was counterbalanced across groups) to produce a discriminative conditioned aversion. Only one of those tastes (arbitrarily assigned and designated as CS+) was associatively paired with LiCl injections as UCS to form a conditioned aversion. The other taste (CS-) was paired with mere vehicle injections to remain relatively palatable as a control sweet taste. We recorded the neural activity in VP in response to each taste, before and after aversion training. We found that the safe and positively hedonic taste always elicited excitatory increases in firing rate of VP neurons. By contrast, aversion learning reversed the VP response to the 'disgusting' CS+ taste from initial excitation into a conditioned decrease in neuronal firing rate after training. Such neuronal coding of hedonic impact by VP circuitry may contribute both to normal pleasure and disgust, and disruptions of VP coding could result in affective disorders, addictions and eating disorders.}, } @article {pmid26599914, year = {2015}, author = {Bales, MB and Schier, LA and Blonde, GD and Spector, AC}, title = {Extensive Gustatory Cortex Lesions Significantly Impair Taste Sensitivity to KCl and Quinine but Not to Sucrose in Rats.}, journal = {PloS one}, volume = {10}, number = {11}, pages = {e0143419}, pmid = {26599914}, issn = {1932-6203}, support = {R01 DC009821/DC/NIDCD NIH HHS/United States ; T32 DC000044/DC/NIDCD NIH HHS/United States ; }, mesh = {Analysis of Variance ; Anatomic Landmarks ; Anatomy, Artistic ; Animals ; Atlases as Topic ; Behavior, Animal ; Cerebral Cortex/drug effects/*pathology/surgery ; Conditioning, Classical ; Male ; Potassium Chloride/*pharmacology ; Quinine/*pharmacology ; Rats, Sprague-Dawley ; Sodium Chloride/pharmacology ; Sucrose/*pharmacology ; Taste/drug effects/*physiology ; }, abstract = {Recently, we reported that large bilateral gustatory cortex (GC) lesions significantly impair taste sensitivity to salts in rats. Here we extended the tastants examined to include sucrose and quinine in rats with ibotenic acid-induced lesions in GC (GCX) and in sham-operated controls (SHAM). Presurgically, immediately after drinking NaCl, rats received a LiCl or saline injection (i.p.), but postsurgical tests indicated a weak conditioned taste aversion (CTA) even in controls. The rats were then trained and tested in gustometers to discriminate a tastant from water in a two-response operant taste detection task. Psychometric functions were derived for sucrose, KCl, and quinine. Our mapping system was used to determine placement, size, and symmetry of the lesions (~91% GC damage on average). For KCl, there was a significant rightward shift (ΔEC50 = 0.57 log10 units; p<0.001) in the GCX psychometric function relative to SHAM, replicating our prior work. There was also a significant lesion-induced impairment (ΔEC50 = 0.41 log10 units; p = 0.006) in quinine sensitivity. Surprisingly, taste sensitivity to sucrose was unaffected by the extensive lesions and was comparable between GCX and SHAM rats. The fact that such large bilateral GC lesions did not shift sucrose psychometric functions relative to SHAM, but did significantly compromise quinine and KCl sensitivity suggests that the neural circuits responsible for the detection of specific taste stimuli are partially dissociable. Lesion-induced impairments were observed in expression of a postsurgical CTA to a maltodextrin solution as assessed in a taste-oriented brief-access test, but were not reflected in a longer term 46-h two-bottle test. Thus, deficits observed in rats after extensive damage to the GC are also dependent on the test used to assess taste function. In conclusion, the degree to which the GC is necessary for the maintenance of normal taste detectability apparently depends on the chemical and/or perceptual features of the stimulus.}, } @article {pmid26524511, year = {2016}, author = {Rebecca Glatt, A and St John, SJ and Lu, L and Boughter, JD}, title = {Temporal and qualitative dynamics of conditioned taste aversions in C57BL/6J and DBA/2J mice self-administering LiCl.}, journal = {Physiology & behavior}, volume = {153}, number = {}, pages = {97-108}, doi = {10.1016/j.physbeh.2015.10.033}, pmid = {26524511}, issn = {1873-507X}, support = {DC000353/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Conditioning, Psychological/*drug effects/physiology ; Dose-Response Relationship, Drug ; Drinking Behavior/*drug effects/physiology ; Extinction, Psychological ; Female ; Generalization, Psychological ; Lithium Chloride/*administration & dosage/*pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Self Administration ; Sodium Chloride/pharmacology ; Taste/*drug effects/physiology ; Time Factors ; }, abstract = {Self-administration of LiCl solution has been shown to result in the formation of a conditioned taste aversion (CTA) that generalizes to NaCl in rats. This paradigm may have considerable ecological validity as it models CTA learning in natural settings, and also allows for the investigation of drinking microstructure as an assay of potential shifts in stimulus palatability. We used this paradigm to examine possible mouse strain differences in CTA acquisition, generalization, and extinction. In the first experiment, C57BL/6J (B6) and DBA/2J (D2) mice self-administered LiCl (or control NaCl) over a 20-minute free access acquisition period and were tested on the following day with a panel of taste solutions available in brief (5-s) trials delivered in random order. In the second experiment, mice again self-administered LiCl or NaCl (at low, 0.12 M, or high, 0.24 M concentrations) in a 20-minute session, and on the following day received a 20-minute free access period to equimolar NaCl. Strain differences were found for aspects of ingestive behavior, with B6 mice showing greater consumption of all stimuli, including water, while D2 mice lick faster, in less frequent but longer bursts. We did not, however, find evidence of a robust strain difference in taste aversion learning. Both strains demonstrated profound alterations in licking microstructure in the generalization session relative to controls. We suggest that a decrease in "lick efficiency" (the percentage of inter-lick intervals within a burst of short duration vs. longer duration) reflects avoidance behavior, and signals a shift in palatability of a stimulus following CTA.}, } @article {pmid26524411, year = {2015}, author = {Jahng, JW and Lee, JH}, title = {Activation of the hypothalamic-pituitary-adrenal axis in lithium-induced conditioned taste aversion learning.}, journal = {European journal of pharmacology}, volume = {768}, number = {}, pages = {182-188}, doi = {10.1016/j.ejphar.2015.10.052}, pmid = {26524411}, issn = {1879-0712}, mesh = {Adrenal Glands/*drug effects/metabolism/physiology ; Animals ; Avoidance Learning/*drug effects/physiology ; Conditioning, Psychological/*drug effects ; Hypothalamo-Hypophyseal System/*drug effects/metabolism/physiology ; Lithium/*pharmacology ; Taste/*physiology ; }, abstract = {Intraperitoneal injections (ip) of lithium chloride at large doses induce c-Fos expression in the brain regions implicated in conditioned taste aversion (CTA) learning, and also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase the plasma corticosterone levels in rats. A pharmacologic treatment blunting the lithium-induced c-Fos expression in the brain regions, but not the HPA axis activation, induced CTA formation. Synthetic glucocorticoids at conditioning, but not glucocorticoid antagonist, attenuated the lithium-induced CTA acquisition. The CTA acquisition by ip lithium was not affected by adrenalectomy regardless of basal corticosterone supplement, but the extinction was delayed in the absence of basal corticosterone. Glucocorticoids overloading delayed the extinction memory formation of lithium-induced CTA. ip lithium consistently induced the brain c-Fos expression, the HPA activation and CTA formation regardless of the circadian activation of the HPA axis. Intracerebroventricular (icv) injections of lithium at day time also increased the brain c-Fos expression, activated the HPA axis and induced CTA acquisition. However, icv lithium at night, when the HPA axis shows its circadian activation, did not induce CTA acquisition nor activate the HPA axis, although it increased the brain c-Fos expression. These results suggest that the circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA learning in rats, and the HPA axis activation may be necessary for the central effect of lithium in CTA formation. Also, glucocorticoids may be required for a better extinction; however, increased glucocorticoids hinder both the acquisition and the extinction of lithium-induced CTA.}, } @article {pmid26497913, year = {2015}, author = {Lemay, F and Doré, FY and Beaulieu, JM}, title = {Increased ethanol consumption despite taste aversion in mice with a human tryptophan hydroxylase 2 loss of function mutation.}, journal = {Neuroscience letters}, volume = {609}, number = {}, pages = {194-197}, doi = {10.1016/j.neulet.2015.10.045}, pmid = {26497913}, issn = {1872-7972}, mesh = {Alcohol Drinking/genetics/*psychology ; Animals ; Avoidance Learning ; Ethanol/administration & dosage ; Humans ; Mice, Mutant Strains ; Motivation ; Mutation ; Self Administration ; *Taste ; Tryptophan ; Tryptophan Hydroxylase/*genetics ; }, abstract = {Polymorphisms in the gene encoding the brain serotonin synthesis enzyme Tph2 have been identified in mental illnesses, with co-morbidity of substance use disorder. However, little is known about the impact of Tph2 gene variants on addiction. Mice expressing a human Tph2 loss of function variant were used to investigate consequences of aversive conditions on ethanol intake. Mice were familiarized either with ethanol or a solution containing both ethanol and the bittering agent quinine. Effect of familiarization to ethanol or an ethanol-quinine solution was then evaluated using a two-bottles preference test in Tph2-KI and control littermates. Mice from both genotypes displayed similar levels of ethanol consumption and quinine avoidance when habituated to ethanol alone. In contrast, addition of quinine to ethanol during the familiarization period resulted in a reduction of avoidance for the quinine-ethanol solution only in mutant mice. These results indicate that loss of function mutation in Tph2 results in greater motivation for ethanol consumption under aversive conditions and may confer enhanced sensitivity to alcohol use disorder.}, } @article {pmid26496996, year = {2016}, author = {Aranda-Fernandez, PE and Gaztañaga, M and Arias, C and Chotro, MG}, title = {Conditioned inhibition in preweanling rats.}, journal = {Developmental psychobiology}, volume = {58}, number = {1}, pages = {98-106}, doi = {10.1002/dev.21359}, pmid = {26496996}, issn = {1098-2302}, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Conditioning, Psychological/drug effects/*physiology ; Extinction, Psychological/drug effects/physiology ; Female ; Male ; *Odorants ; Rats ; Rats, Sprague-Dawley ; Saccharin/*pharmacology ; Taste/drug effects/physiology ; }, abstract = {Inhibitory conditioning is a very well established phenomenon in associative learning that has been demonstrated in both humans and adult animals. But in spite of the fact that this topic has generated much empirical and theoretical work, there are no published studies assessing inhibitory learning during the early ontogeny of the rat. In this study we test the possibility of finding conditioned inhibition in infant rats (Day 10) using a conditioned taste aversion procedure. We tested whether the consumption of saccharin (A) was reduced when paired with a LiCl injection compared to the presentation of saccharin in compound with a lemon odor (AX) without any aversive consequence. After training, retardation, and summation tests were conducted in order to evaluate the inhibitory properties of the lemon odor (X). The results of this study showed that in male pups, after conditioned inhibition training, stimulus X passed both retardation and summation tests. These results indicate that conditioned inhibition can be established in the early development of the rat, suggesting that animals at this stage of ontogeny have the capacity to acquire and to express inhibitory conditioning, although this effect appears to be sex-dependent.}, } @article {pmid26493441, year = {2015}, author = {Gonzalez, MC and Villar, ME and Igaz, LM and Viola, H and Medina, JH}, title = {Dorsal medial prefrontal cortex contributes to conditioned taste aversion memory consolidation and retrieval.}, journal = {Neurobiology of learning and memory}, volume = {126}, number = {}, pages = {1-6}, doi = {10.1016/j.nlm.2015.10.007}, pmid = {26493441}, issn = {1095-9564}, mesh = {Animals ; Benzylamines/administration & dosage ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/physiology ; Conditioning, Psychological/drug effects/physiology ; Emetine/administration & dosage ; GABA-A Receptor Agonists/administration & dosage ; Male ; Memory Consolidation/drug effects/*physiology ; Mental Recall/drug effects/*physiology ; Muscimol/administration & dosage ; Prefrontal Cortex/drug effects/metabolism/*physiology ; Protein Synthesis Inhibitors/administration & dosage ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/physiology ; Signal Transduction/drug effects ; Sulfonamides/administration & dosage ; Taste Perception/drug effects/*physiology ; Valine/administration & dosage/analogs & derivatives ; }, abstract = {The medial prefrontal cortex (mPFC) is known for its role in decision making and memory processing, including the participation in the formation of extinction memories. However, little is known regarding its contribution to aversive memory consolidation. Here we demonstrate that neural activity and protein synthesis are required in the dorsal mPFC for memory formation of a conditioned taste aversion (CTA) task and that this region is involved in the retrieval of recent and remote long-term CTA memory. In addition, both NMDA receptor and CaMKII activity in dorsal mPFC are needed for CTA memory consolidation, highlighting the complexity of mPFC functions.}, } @article {pmid26462569, year = {2016}, author = {Valenza, M and DiLeo, A and Steardo, L and Cottone, P and Sabino, V}, title = {Ethanol-related behaviors in mice lacking the sigma-1 receptor.}, journal = {Behavioural brain research}, volume = {297}, number = {}, pages = {196-203}, pmid = {26462569}, issn = {1872-7549}, support = {R01 DA030425/DA/NIDA NIH HHS/United States ; DA023680/DA/NIDA NIH HHS/United States ; R00 DA023680/DA/NIDA NIH HHS/United States ; K99 AA016731/AA/NIAAA NIH HHS/United States ; AA016731/AA/NIAAA NIH HHS/United States ; R01 MH091945/MH/NIMH NIH HHS/United States ; R00 AA016731/AA/NIAAA NIH HHS/United States ; DA030425/DA/NIDA NIH HHS/United States ; MH093650/MH/NIMH NIH HHS/United States ; MH091945/MH/NIMH NIH HHS/United States ; K99 DA023680/DA/NIDA NIH HHS/United States ; R01 MH093650/MH/NIMH NIH HHS/United States ; }, mesh = {Alcohol Drinking/*metabolism ; Alcohol-Related Disorders/*metabolism ; Animals ; Ataxia/chemically induced/metabolism ; Avoidance Learning/drug effects/physiology ; Body Temperature/drug effects/physiology ; Central Nervous System Depressants/*pharmacology ; Choice Behavior/drug effects/physiology ; Disease Models, Animal ; Ethanol/*pharmacology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity/drug effects/physiology ; Receptors, sigma/genetics/*metabolism ; Taste/drug effects/physiology ; Taste Perception/drug effects/physiology ; }, abstract = {RATIONALE: The Sigma-1 receptor (Sig-1R) is a chaperone protein that has been implicated in drug abuse and addiction. Multiple studies have characterized the role the Sig-1R plays in psychostimulant addiction; however, fewer studies have specifically investigated its role in alcohol addiction. We have previously shown that antagonism of the Sig-1R reduces excessive drinking and motivation to drink, whereas agonism induces binge-like drinking in rodents.

OBJECTIVES: The objectives of these studies were to investigate the impact of Sig-1R gene deletion in C57Bl/6J mice on ethanol drinking and other ethanol-related behaviors.

METHODS: We used an extensive panel of behavioral tests to examine ethanol actions in male, adult mice lacking Oprs1, the gene encoding the Sig-1R. To compare ethanol drinking behavior, Sig-1 knockout (KO) and wild type (WT) mice were subject to a two-bottle choice, continuous access paradigm with different concentrations of ethanol (3-20% v/v) vs. water. Consumption of sweet and bitter solutions was also assessed in Sig-1R KO and WT mice. Finally, motor stimulant sensitivity, taste aversion and ataxic effects of ethanol were assessed.

RESULTS: Sig-1R KO mice displayed higher ethanol intake compared to WT mice; the two genotypes did not differ in their sweet or bitter taste perception. Sig-1R KO mice showed lower sensitivity to ethanol stimulant effects, but greater sensitivity to its taste aversive effects. Ethanol-induced sedation was instead unaltered in the mutants.

CONCLUSIONS: Our results prove that the deletion of the Sig-1R increases ethanol consumption, likely by decreasing its rewarding effects, and therefore indicating that the Sig-1R is involved in modulation of the reinforcing effects of alcohol.}, } @article {pmid26454025, year = {2015}, author = {Vishnoi, S and Raisuddin, S and Parvez, S}, title = {Modulatory effects of an NMDAR partial agonist in MK-801-induced memory impairment.}, journal = {Neuroscience}, volume = {311}, number = {}, pages = {22-33}, doi = {10.1016/j.neuroscience.2015.10.008}, pmid = {26454025}, issn = {1873-7544}, mesh = {Acetylcholinesterase/metabolism ; Animals ; Avoidance Learning/drug effects/physiology ; Conditioning, Psychological/drug effects/physiology ; Cycloserine/*pharmacology ; Disease Models, Animal ; Dizocilpine Maleate ; Dopamine/metabolism ; Exploratory Behavior/drug effects/physiology ; Female ; Memory Disorders/*drug therapy/metabolism ; Monoamine Oxidase/metabolism ; Nootropic Agents/*pharmacology ; Prefrontal Cortex/drug effects/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/*agonists/metabolism ; Recognition, Psychology/drug effects/physiology ; Taste Perception/drug effects/physiology ; }, abstract = {RATIONALE: Acute administration of the N-methyl-d-aspartate (NMDA) non-competitive antagonist, MK-801, impairs novel object recognition (NOR), locomotor activity in open field (OF) and conditioned taste aversion (CTA) in rodents. NMDAR partial agonist d-cycloserine (DCS) reverses these effects in NOR and CTA via modulation of glutamatergic, cholinergic and dopaminergic systems.

OBJECTIVES AND METHODS: To test this hypothesis, we investigated the effects of DCS, a partial NMDAR agonist, on NOR memory, locomotor activity, and CTA memory in Wistar rats on NMDA-glutamate receptor antagonism by MK-801. The potential involvement of dopaminergic and cholinergic systems in improving cognitive functions was explored. MK-801-induced cognitive deficits were assessed using NOR, OF and CTA paradigms. MK-801-induced dopamine release increase in acetylcholinesterase (AChE), mono amine oxidase (MAO) activity and increase in c-fos expression were also investigated.

RESULTS: The effects caused by MK-801 (0.2 mg/kg) were inhibited by administration of the NMDA receptor agonist DCS (15 mg/kg). NOR and CTA paradigms inhibited by MK-801 were attenuated by DCS administration. Moreover, DCS also blocked the MK-801-induced abnormal increase in dopamine content, AChE activity and MAO activity. However, c-fos overexpression was controlled to some extent only.

CONCLUSIONS: Based on the NMDAR hypo function hypothesis in some neuropsychiatric disorders, our finding suggests that improving NMDAR hypo function by agonist DCS may play a significant role.}, } @article {pmid26452094, year = {2015}, author = {Adaikkan, C and Rosenblum, K}, title = {A molecular mechanism underlying gustatory memory trace for an association in the insular cortex.}, journal = {eLife}, volume = {4}, number = {}, pages = {e07582}, pmid = {26452094}, issn = {2050-084X}, mesh = {Animals ; *Avoidance Learning ; Cerebral Cortex/*physiology ; Conditioning, Classical ; *Memory ; Rats ; *Taste ; }, abstract = {Events separated in time are associatively learned in trace conditioning, recruiting more neuronal circuits and molecular mechanisms than in delay conditioning. However, it remains unknown whether a given sensory memory trace is being maintained as a unitary item to associate. Here, we used conditioned taste aversion learning in the rat model, wherein animals associate a novel taste with visceral nausea, and demonstrate that there are two parallel memory traces of a novel taste: a short-duration robust trace, lasting approximately 3 hr, and a parallel long-duration weak one, lasting up to 8 hr, and dependent on the strong trace for its formation. Moreover, only the early robust trace is maintained by a NMDAR-dependent CaMKII- AMPAR pathway in the insular cortex. These findings suggest that a memory trace undergoes rapid modifications, and that the mechanisms underlying trace associative learning differ when items in the memory are experienced at different time points.}, } @article {pmid26433146, year = {2016}, author = {Martínez-Moreno, A and Rodríguez-Durán, LF and Escobar, ML}, title = {Brain-derived neurotrophic factor into adult neocortex strengthens a taste aversion memory.}, journal = {Behavioural brain research}, volume = {297}, number = {}, pages = {1-4}, doi = {10.1016/j.bbr.2015.09.034}, pmid = {26433146}, issn = {1872-7549}, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Brain-Derived Neurotrophic Factor/*pharmacology ; Catheters, Indwelling ; Conditioning, Psychological/drug effects/physiology ; Lithium Chloride ; Male ; Memory/*drug effects/physiology ; Microinjections ; Neocortex/*drug effects/physiology ; Nootropic Agents/*pharmacology ; Rats, Wistar ; Taste Perception/*drug effects/physiology ; Water Deprivation ; }, abstract = {Nowadays, it is known that brain derived neurotrophic-factor (BDNF) is a protein critically involved in regulating long-term memory related mechanisms. Previous studies from our group in the insular cortex (IC), a brain structure of the temporal lobe implicated in acquisition, consolidation and retention of conditioned taste aversion (CTA), demonstrated that BDNF is essential for CTA consolidation. Recent studies show that BDNF-TrkB signaling is able to mediate the enhancement of memory. However, whether BDNF into neocortex is able to enhance aversive memories remains unexplored. In the present work, we administrated BDNF in a concentration capable of inducing in vivo neocortical LTP, into the IC immediately after CTA acquisition in two different conditions: a "strong-CTA" induced by 0.2M lithium chloride i.p. as unconditioned stimulus, and a "weak-CTA" induced by 0.1M lithium chloride i.p. Our results show that infusion of BDNF into the IC converts a weak CTA into a strong one, in a TrkB receptor-dependent manner. The present data suggest that BDNF into the adult insular cortex is sufficient to increase an aversive memory-trace.}, } @article {pmid26403065, year = {2015}, author = {Bernal-Gamboa, R and Nieto, J and Rosas, JM}, title = {Context specificity of taste aversion is boosted by pre-exposure and conditioning with a different taste.}, journal = {Behavioural processes}, volume = {120}, number = {}, pages = {111-115}, doi = {10.1016/j.beproc.2015.09.008}, pmid = {26403065}, issn = {1872-8308}, mesh = {Animals ; Avoidance Learning/*drug effects ; Conditioning, Classical/drug effects ; Cues ; Extinction, Psychological ; Male ; Rats ; Rats, Wistar ; Sodium Chloride/*pharmacology ; Sucrose/*pharmacology ; Taste/*physiology ; Taste Perception/physiology ; }, abstract = {Recent reports in the literature show that an extinction treatment makes subsequently learned information context-specific. An experiment in conditioned taste aversion evaluated whether pre-exposure and conditioning with a given flavor would make conditioning of a different flavor context specific as well. Rats received conditioning with taste Y in context A, before being tested in extinction either in context A or in a different but equally familiar context (context B). Half of the animals received a pre-exposure and conditioning treatment with a different flavor (X), while the other half only received conditioning. The context change at testing led to higher consumption of Y in the animals that had received previous pre-exposure and conditioning with X. The implications of these results for the mechanisms underlying context-switch effects are discussed.}, } @article {pmid26393333, year = {2015}, author = {Wang, S and Zhuang, L and Yang, X and Li, Q and Xue, Q and Luo, Y and Zhang, F and Yu, B}, title = {Impaired acquisition of conditioned taste aversion memory induced by isoflurane is accompanied with calcineurin activation and Egr-1 down-regulation in amygdala in rats.}, journal = {Neuroscience letters}, volume = {607}, number = {}, pages = {114-119}, doi = {10.1016/j.neulet.2015.09.022}, pmid = {26393333}, issn = {1872-7972}, mesh = {Amygdala/*drug effects/metabolism ; Anesthetics, Inhalation/*adverse effects ; Animals ; Avoidance Learning/*drug effects ; Calcineurin/*metabolism ; Conditioning, Psychological ; Down-Regulation ; Early Growth Response Protein 1/*metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Isoflurane/*adverse effects ; Male ; Memory/*drug effects ; Phosphorylation ; Rats, Sprague-Dawley ; Taste/*drug effects ; }, abstract = {Compared to neutral memory, emotional memory is extremely strong and persistent immediately after acquisition, therefore it may recruit specific mechanisms during acquisition. The calcineurin-dependent mechanisms engaging early growth response 1 (Egr-1) have been proved to determine the strength of emotional memory during establishment. Isoflurane, a widely used inhalation anesthetic, can interfere with the acquisition of emotional memory. We hypothesized that isoflurane impairs the acquisition of conditioned taste aversion (CTA) memory in rats and the Egr-1 expression regulation via calcineurin (CaN) and ERK signaling pathway is involved in isoflurane-induced repression of CTA memory. To examine this, we investigated the influence of isoflurane on CTA memory and the expression and activity of CaN, the phosphorylation level of ERK and the expression of Egr-1 in amygdala in response to CTA training in rats. The results showed that isoflurane exposure (1.5%, 2h) before training impaired the acquisition of CTA memory in rats. Isoflurane exposure increased the CaN activity and decreased the p-ERK and Egr-1 in amygdala in rats. These findings suggest that isoflurane can disrupt the establishment of aversion memory, and CaN activation associating with p-ERK and Egr-1 down-regulation may contribute to the isoflurane induced impairment of aversion memory acquisition.}, } @article {pmid26386321, year = {2016}, author = {Hadamitzky, M and Bösche, K and Wirth, T and Buck, B and Beetz, O and Christians, U and Schniedewind, B and Lückemann, L and Güntürkün, O and Engler, H and Schedlowski, M}, title = {Memory-updating abrogates extinction of learned immunosuppression.}, journal = {Brain, behavior, and immunity}, volume = {52}, number = {}, pages = {40-48}, doi = {10.1016/j.bbi.2015.09.009}, pmid = {26386321}, issn = {1090-2139}, mesh = {Amygdala/immunology/physiology ; Animals ; Avoidance Learning/drug effects/*physiology ; Conditioning, Classical/physiology ; Cyclosporine/pharmacology ; Extinction, Psychological/drug effects/*physiology ; Fear/physiology ; Immune Tolerance/physiology ; Immunosuppressive Agents/pharmacology ; Interferon-gamma/immunology ; Interleukin-2/immunology ; Male ; Mental Recall/drug effects/*physiology ; Rats ; Rats, Inbred Strains ; Taste/physiology ; }, abstract = {When memories are recalled, they enter a transient labile phase in which they can be impaired or enhanced followed by a new stabilization process termed reconsolidation. It is unknown, however, whether reconsolidation is restricted to neurocognitive processes such as fear memories or can be extended to peripheral physiological functions as well. Here, we show in a paradigm of behaviorally conditioned taste aversion in rats memory-updating in learned immunosuppression. The administration of sub-therapeutic doses of the immunosuppressant cyclosporin A together with the conditioned stimulus (CS/saccharin) during retrieval blocked extinction of conditioned taste aversion and learned suppression of T cell cytokine (interleukin-2; interferon-γ) production. This conditioned immunosuppression is of clinical relevance since it significantly prolonged the survival time of heterotopically transplanted heart allografts in rats. Collectively, these findings demonstrate that memories can be updated on both neural and behavioral levels as well as on the level of peripheral physiological systems such as immune functioning.}, } @article {pmid26374758, year = {2016}, author = {Pennell, CG and Popay, AJ and Rolston, MP and Townsend, RJ and Lloyd-West, CM and Card, SD}, title = {Avanex Unique Endophyte Technology: Reduced Insect Food Source at Airports.}, journal = {Environmental entomology}, volume = {45}, number = {1}, pages = {101-108}, doi = {10.1093/ee/nvv145}, pmid = {26374758}, issn = {1938-2936}, mesh = {Airports ; Animals ; *Endophytes ; Epichloe/*physiology ; Insecta/*microbiology ; New Zealand ; *Pest Control, Biological ; Poaceae/*microbiology ; }, abstract = {Birds and other forms of wildlife are a major issue for airport authorities worldwide, as they can create hazards to operating aircraft. Wildlife "strikes," the majority caused by birds, can cause damage to operating aircraft and in severe cases lead to a loss of human life. Many airfields contain large areas of ground cover herbage alongside their runways that consist of mixtures of grasses, legumes, and weeds that can harbor many invertebrates. Many airfields use insecticides to control insect populations; however, mounting pressure from regional councils and water boards aim to reduce this practice due to ground water runoff and contamination concerns. Avanex Unique Endophyte Technology, a product specifically developed to reduce the attractiveness of airports and surrounding areas to birds, is based on a novel association between a selected strain of Epichloë endophyte and a turf-type tall fescue cultivar. This grass-endophyte association acts through a direct mechanism whereby a negative response in birds is created through taste aversion and postingestion feedback as well as an indirect mechanism by deterring many invertebrates, a food source of many bird species.}, } @article {pmid26365026, year = {2016}, author = {Lueckemann, L and Bösche, K and Engler, H and Schwitalla, JC and Hadamitzky, M and Schedlowski, M}, title = {Pre-exposure to the unconditioned or conditioned stimulus does not affect learned immunosuppression in rats.}, journal = {Brain, behavior, and immunity}, volume = {51}, number = {}, pages = {252-257}, doi = {10.1016/j.bbi.2015.09.005}, pmid = {26365026}, issn = {1090-2139}, mesh = {Animals ; Avoidance Learning/drug effects/*physiology ; Conditioning, Psychological/*drug effects ; Cyclosporine/*administration & dosage ; *Immunosuppression Therapy ; Immunosuppressive Agents/*administration & dosage ; Male ; Rats ; Taste/physiology ; }, abstract = {In order to analyze the effects of pre-exposure to either the unconditioned (US) or conditioned stimulus (CS) on learned immunosuppression, we employed an established conditioned taste aversion (CTA) paradigm in rats. In our model, a sweet-tasting drinking solution (saccharin) serves as CS and injection of the immunosuppressive drug cyclosporine A (CsA) is used as US. The conditioned response is reflected by a pronounced CTA and diminished cytokine production by anti-CD3 stimulated splenic T cells. In the present study, experimental animals were exposed either to the US or the CS three times prior to the acquisition phase. On the behavioral level, we found a significantly diminished CTA when animals were pre-exposed to the US or the CS before acquisition. In contrast, US or CS pre-exposure did not affect the behaviorally conditioned suppression of interleukin (IL)-2 production. From the clinical perspective, our data may suggest that conditioning paradigms could be systemically integrated as supportive therapeutic interventions in patients that are already on immunosuppressive therapy or have had previous contact to the gustatory stimulus. Such supportive therapies to pharmacological regimens could not only help to reduce the amount of medication needed and, thus, unwanted toxic side effects, but may also maximize the therapeutic outcome.}, } @article {pmid26302696, year = {2016}, author = {Braquet, P and Mercier, G and Reynes, J and Jeandel, C and Pinzani, V and Guilpain, P and Rivière, S and Le Quellec, A}, title = {[Diagnostic value of selective anorexia in pathological weight loss].}, journal = {La Revue de medecine interne}, volume = {37}, number = {2}, pages = {84-90}, doi = {10.1016/j.revmed.2015.07.007}, pmid = {26302696}, issn = {1768-3122}, mesh = {Aged ; Aged, 80 and over ; Anorexia/classification/*etiology ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Surveys and Questionnaires ; *Symptom Assessment ; *Taste ; *Weight Loss ; }, abstract = {PURPOSE: The diagnostic value of selective anorexia is debated. Some authors have suggested an association between meat aversion and cancer, but most do not use it as a diagnostic tool. We aimed to characterize anorexia of different diseases to search for an association between selective aversions and diagnostic groups.

METHODS: All the patients admitted to three departments of a teaching hospital were included consecutively for 22months if they had more than 10 % weight loss in less than one year. Patients were excluded if history taking was not reliable, or if they suffered from anorexia nervosa. We compiled diagnoses at discharge and validated them six months later. We used logistic regression to identify independent factors associated with selective anorexia.

RESULTS: Inclusion criteria were met in 106patients (female 44 %, median age 65years). Most frequent diagnoses were: cancer (36 %), infection (35 %), digestive diseases (19 %), non organic diseases (21 %). Recent selective anorexia was found in 46 % of the cases. It was significantly associated with female gender (P=0.002), marginally with young age (P=0.069) and long duration of weight loss (P=0.079). Opioid use at admission was negatively associated with selective anorexia (P=0.001). No specific diagnostic category was found to be associated.

CONCLUSION: Selective anorexia does not appear to be a useful symptom to investigate pathological weight loss. It behaves more like a non-specific reactivation by current disease of earlier latent personal food aversions.}, } @article {pmid26298172, year = {2015}, author = {Lin, SF and Tsai, YF and Tai, MY and Yeh, KY}, title = {Estradiol enhances the acquisition of lithium chloride-induced conditioned taste aversion in castrated male rats.}, journal = {Die Naturwissenschaften}, volume = {102}, number = {9-10}, pages = {52}, pmid = {26298172}, issn = {1432-1904}, mesh = {Animals ; Drug Combinations ; Estradiol/*analogs & derivatives/pharmacology ; Estrogens/pharmacology ; Lithium Chloride/*toxicity ; Male ; Orchiectomy ; Progesterone/*pharmacology ; Random Allocation ; Rats ; Taste/*drug effects ; }, abstract = {The present study examined the effects of short-term treatment with ovarian hormones on the acquisition of conditioned taste aversion (CTA). Adult male rats were castrated and randomly divided into LiCl- and saline-treated groups. Nineteen days after castration, all of the animals were subjected to 23.5-h daily water deprivation for seven successive days (day 1 to day 7). On the conditioning day (day 8), the rats received either a 4 ml/kg of 0.15 M LiCl or the same dose of saline injection immediately after administration of a 2 % sucrose solution during the 30-min water session. Starting from day 6, rats in both groups received one of the following treatments: daily subcutaneous injection of (1) estradiol alone (30 μg/kg; estradiol benzoate (E) group), (2) estradiol plus progesterone (500 μg; E + progesterone (P) group), or (3) olive oil. From day 9 to day 11, all of the rats were given daily two-bottle preference tests during the 30-min fluid session. The estradiol and estradiol plus progesterone treatments in the LiCl groups resulted in significantly lower preference scores for the sucrose solution compared with the olive oil treatment groups, but no difference in preference score was seen between these two groups. These results indicate that both the estradiol and estradiol plus progesterone treatments in the LiCl groups enhanced the acquisition of CTA learning and suggest that estradiol affects the acquisition of CTA mediated by an activational effect in male rats, whereas progesterone treatment does not influence the effects of estradiol on the acquisition of CTA.}, } @article {pmid26291688, year = {2015}, author = {Molero-Chamizo, A and Morón, I}, title = {Latent inhibition of conditioned taste aversion in rats with excitotoxic dorsal hippocampal lesions.}, journal = {Journal of neuroscience research}, volume = {93}, number = {11}, pages = {1740-1747}, doi = {10.1002/jnr.23633}, pmid = {26291688}, issn = {1097-4547}, mesh = {Animals ; Association Learning/*physiology ; Conditioning, Classical ; Disease Models, Animal ; Hippocampus/*injuries/*physiopathology ; Male ; Neural Inhibition/*physiology ; Rats ; Rats, Wistar ; Taste ; }, abstract = {The hippocampus plays crucial roles for the acquisition of latent inhibition in different associative learning procedures, such as fear conditioning. However, the involvement of the hippocampus in the latent inhibition of conditioned taste aversion (CTA) is uncertain. Because different subregions of the hippocampus are associated with distinct functions, it is possible that specific regions of this structure are selectively involved in this learning. To explore the relationship between the dorsal hippocampal region and the latent inhibition of CTA, we analyzed the behavioral effects of excitotoxic lesions of the dorsal hippocampus vs. sham lesions in this paradigm. The results provide no evidence that the latent inhibition of CTA is compromised in rats with excitotoxic dorsal hippocampal lesions. The differential involvement of specific hippocampal regions in the latent inhibition of other associative learning paradigms is briefly discussed.}, } @article {pmid26290239, year = {2015}, author = {Gisquet-Verrier, P and Lynch, JF and Cutolo, P and Toledano, D and Ulmen, A and Jasnow, AM and Riccio, DC}, title = {Integration of New Information with Active Memory Accounts for Retrograde Amnesia: A Challenge to the Consolidation/Reconsolidation Hypothesis?.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {35}, number = {33}, pages = {11623-11633}, pmid = {26290239}, issn = {1529-2401}, mesh = {Amnesia, Retrograde/*physiopathology ; Animals ; Brain/*physiopathology ; *Cognition ; Male ; *Memory ; Nerve Tissue Proteins/*metabolism ; Rats ; Rats, Long-Evans ; Rats, Sprague-Dawley ; *Retention, Psychology ; }, abstract = {UNLABELLED: Active (new and reactivated) memories are considered to be labile and sensitive to treatments disrupting the time-dependent consolidation/reconsolidation processes required for their stabilization. Active memories also allow the integration of new information for updating memories. Here, we investigate the possibility that, when active, the internal state provided by amnesic treatments is represented and integrated within the initial memory and that amnesia results from the absence of this state at testing. We showed in rats that the amnesia resulting from systemic, intracerebroventricular and intrahippocampal injections of the protein synthesis inhibitor cycloheximide, administered after inhibitory avoidance training or reactivation, can be reversed by a reminder, including re-administration of the same drug. Similar results were obtained with lithium chloride (LiCl), which does not affect protein synthesis, when delivered systemically after training or reactivation. However, LiCl can induce memory given that a conditioned taste aversion was obtained for a novel taste, presented just before conditioning or reactivation. These results indicate that memories can be established and maintained without de novo protein synthesis and that experimental amnesia may not result from a disruption of memory consolidation/reconsolidation. The findings more likely support the integration hypothesis: posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval. This integration concept includes most of the previous explanations of memory recovery after retrograde amnesia and critically challenges the traditional memory consolidation/reconsolidation hypothesis, providing a more dynamic and flexible view of memory.

SIGNIFICANCE STATEMENT: This study provides evidence challenging the traditional consolidation/reconsolidation hypotheses that have dominated the literature over the past 50 years. Based on amnesia studies, that hypothesis states that active (i.e., new and reactivated) memories are similarly labile and (re)established in a time-dependent manner within the brain through processes that require de novo protein synthesis. Our data show that new/reactivated memories can be formed without protein synthesis and that amnesia can be induced by drugs that do not affect protein synthesis. We propose that amnesia results from memory integration of the internal state produced by the drug that is subsequently necessary for retrieval of the memory. This interpretation gives a dynamic view of memory, rapidly stored and easily updated when active.}, } @article {pmid26253212, year = {2015}, author = {Bortolatto, CF and Heck, SO and Zborowski, VA and Gai, BM and Neto, JS and Nogueira, CW}, title = {Evidence for the contribution of multiple mechanisms in the feeding pattern of rats exposed to p-chloro-diphenyl diselenide-supplemented diets.}, journal = {Physiology & behavior}, volume = {151}, number = {}, pages = {298-307}, doi = {10.1016/j.physbeh.2015.07.029}, pmid = {26253212}, issn = {1873-507X}, mesh = {Adipose Tissue ; Animals ; Avoidance Learning ; Body Weight ; Choice Behavior ; Conditioning, Psychological ; *Diet ; *Dietary Supplements ; *Feeding Behavior/physiology ; Male ; Motor Activity ; Organoselenium Compounds/*administration & dosage ; Rats, Wistar ; Satiation/physiology ; Taste Perception ; Time Factors ; }, abstract = {Preliminary findings suggest that food intake reduction induced by p-chloro-diphenyl diselenide [(p-ClPhSe)2] in rats is mediated by a satiating action; however, additional experiments are necessary to clarify its actions. The purpose of this study was to investigate the effects of diets supplemented with (p-ClPhSe)2 on feeding behavior of rats as well as the (p-ClPhSe)2 effectiveness in producing aversive reactions or specific flavor. The results demonstrated that behavioral satiety sequence (BSS) was preserved in animals exposed to (p-ClPhSe)2-supplemented diets (0.01 and 0.1%) and associated with a shift of the onset of resting to the left indicating a satiating action at the first contact. In addition, the frequency, the mean duration and the mean size of meals were decreased in rats exposed to a 0.1% (p-ClPhSe)2 diet. Alternatively, a second contact with a 0.01% (p-ClPhSe)2 diet caused disruption of BSS and pronounced changes in the meal pattern, suggesting that it produces aversiveness. In fact, rats developed a significant taste aversion to the saccharin solution after receiving the administration of (p-ClPhSe)2 (1 and 10mg/kg; i.p.). Lastly, a diet containing 0.1% of (p-ClPhSe)2 seems to alter the palatability of food given that rats had a preference for the control diet. The findings of the present study suggest that (p-ClPhSe)2 reduced the food intake of rats by inducing a satiating action at the first contact, but it also produced aversive reactions when rats were re-exposed to it. A specific flavor seems also to contribute to (p-ClPhSe)2 suppressant effects on feeding.}, } @article {pmid26233474, year = {2015}, author = {Kojima, S and Sunada, H and Mita, K and Sakakibara, M and Lukowiak, K and Ito, E}, title = {Function of insulin in snail brain in associative learning.}, journal = {Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology}, volume = {201}, number = {10}, pages = {969-981}, pmid = {26233474}, issn = {1432-1351}, support = {MOP 64339//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Association Learning/*physiology ; Brain/*metabolism ; Insulins/*metabolism ; Snails/*physiology ; }, abstract = {Insulin is well known as a hormone regulating glucose homeostasis across phyla. Although there are insulin-independent mechanisms for glucose uptake in the mammalian brain, which had contributed to a perception of the brain as an insulin-insensitive organ for decades, the finding of insulin and its receptors in the brain revolutionized the concept of insulin signaling in the brain. However, insulin's role in brain functions, such as cognition, attention, and memory, remains unknown. Studies using invertebrates with their open blood-vascular system have the promise of promoting a better understanding of the role played by insulin in mediating/modulating cognitive functions. In this review, the relationship between insulin and its impact on long-term memory (LTM) is discussed particularly in snails. The pond snail Lymnaea stagnalis has the ability to undergo conditioned taste aversion (CTA), that is, it associatively learns and forms LTM not to respond with a feeding response to a food that normally elicits a robust feeding response. We show that molluscan insulin-related peptides are up-regulated in snails exhibiting CTA-LTM and play a key role in the causal neural basis of CTA-LTM. We also survey the relevant literature of the roles played by insulin in learning and memory in other phyla.}, } @article {pmid26192710, year = {2015}, author = {Huang, AC and Wang, CC and Wang, S}, title = {Examinations of the reward comparison hypothesis: The modulation of gender and footshock.}, journal = {Physiology & behavior}, volume = {151}, number = {}, pages = {129-138}, doi = {10.1016/j.physbeh.2015.07.022}, pmid = {26192710}, issn = {1873-507X}, mesh = {Animals ; Central Nervous System Stimulants/pharmacology ; Conditioning, Psychological/*drug effects/physiology ; *Electroshock ; Female ; Foot ; Illicit Drugs/*pharmacology ; Lithium Chloride/pharmacology ; Male ; Methamphetamine/pharmacology ; *Models, Psychological ; Morphine/pharmacology ; Motor Activity/drug effects/physiology ; Narcotics/pharmacology ; Psychotropic Drugs/pharmacology ; Random Allocation ; Rats, Wistar ; *Reward ; Saccharin ; *Sex Characteristics ; }, abstract = {The reward comparison hypothesis suggests that drugs of abuse-induced conditioned saccharin suppression intake is due to the reward value of drugs of abuse that outweighs that of a saccharin solution dissociating from the aversive LiCl-induced conditioned taste aversion (CTA). Huang and Hsiao (2008) provided some conflict data to challenge the reward comparison hypothesis. Whether the rewarding drugs of abuse-induced conditioned suppression and the aversive LiCl-induced CTA resulted from aversion or reward should be addressed. The present study investigated how gender and footshock affect aversive LiCl- and rewarding morphine- and methamphetamine (MAMPH)-induced conditioned suppression to re-examine the reward comparison hypothesis. The results indicated that gender and footshock did not directly influence the aversive LiCl-induced CTA or rewarding morphine- and MAMPH-induced conditioned suppression. The gender effect interacted with the drug effect in the aversive LiCl- and rewarding MAMPH-induced conditioned suppression but did not interact with the drug effect in the rewarding morphine-induced conditioned suppression. Footshock interacted with the drug effect in rewarding morphine- and MAMPH-induced conditioned suppression, but footshock did not interact with the drug effect in the aversive LiCl-induced CTA. Therefore, the gender and footshock effects might play a modulatory (but not a mediating) role with the drug effect. The present data indicated that footshock modulates drugs of abuse-induced conditioned suppression, which is consistent with the reward comparison hypothesis, but our findings with regard to the modulatory role of the gender effect and the drug effect do not support this hypothesis. The reward comparison hypothesis should be discussed and possibly reconsidered.}, } @article {pmid26165136, year = {2015}, author = {Dines, M and Grinberg, S and Vassiliev, M and Ram, A and Tamir, T and Lamprecht, R}, title = {The roles of Eph receptors in contextual fear conditioning memory formation.}, journal = {Neurobiology of learning and memory}, volume = {124}, number = {}, pages = {62-70}, doi = {10.1016/j.nlm.2015.07.003}, pmid = {26165136}, issn = {1095-9564}, mesh = {Animals ; Conditioning, Classical/*physiology ; Fear/*physiology ; Memory, Long-Term/*physiology ; Mice ; Mice, Knockout ; Prosencephalon/*physiology ; Receptor, EphA4/genetics/*physiology ; Receptor, EphB2/genetics/*physiology ; Signal Transduction ; }, abstract = {Eph receptors regulate glutamate receptors functions, neuronal morphology and synaptic plasticity, cellular events believed to be involved in memory formation. In this study we aim to explore the roles of Eph receptors in learning and memory. Toward that end, we examined the roles of EphB2 and EphA4 receptors, key regulators of synaptic functions, in fear conditioning memory formation. We show that mice lacking EphB2 (EphB2(-/-)) are impaired in short- and long-term contextual fear conditioning memory. Mice that express a carboxy-terminally truncated form of EphB2 that lacks forward signaling, instead of the full EphB2, are impaired in long-term, but not short-term, contextual fear conditioning memory. Long-term contextual fear conditioning memory is attenuated in CaMKII-cre;EphA4(lx/-) mice where EphA4 is removed from all pyramidal neurons of the forebrain. Mutant mice with targeted kinase-dead EphA4 (EphA4(KD)) exhibit intact long-term contextual fear conditioning memory showing that EphA4 kinase-mediated forward signaling is not needed for contextual fear memory formation. The ability to form long-term conditioned taste aversion (CTA) memory is not impaired in the EphB2(-/-) and CaMKII-cre;EphA4(lx/-) mice. We conclude that EphB2 forward signaling is required for long-term contextual fear conditioning memory formation. In contrast, EphB2 mediates short-term contextual fear conditioning memory formation in a forward signaling-independent manner. EphA4 mediates long-term contextual fear conditioning memory formation in a kinase-independent manner.}, } @article {pmid26157056, year = {2015}, author = {Sasaki, T and Kinoshita, Y and Matsui, S and Kakuta, S and Yokota-Hashimoto, H and Kinoshita, K and Iwasaki, Y and Kinoshita, T and Yada, T and Amano, N and Kitamura, T}, title = {N-methyl-d-aspartate receptor coagonist d-serine suppresses intake of high-preference food.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {309}, number = {5}, pages = {R561-75}, doi = {10.1152/ajpregu.00083.2015}, pmid = {26157056}, issn = {1522-1490}, mesh = {Agouti-Related Protein/metabolism ; Animals ; Appetite Depressants/*pharmacology ; Choice Behavior ; Conditioning, Psychological ; Diet, High-Fat ; Down-Regulation ; Eating/*drug effects ; Excitatory Amino Acid Agonists/*pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Feeding Behavior/*drug effects ; Food Preferences/*drug effects ; Hypothalamus/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Neuropeptide Y/metabolism ; Receptors, N-Methyl-D-Aspartate/*agonists/metabolism ; Sensory System Agents ; Serine/*pharmacology ; Time Factors ; }, abstract = {d-Serine is abundant in the forebrain and physiologically important for modulating excitatory glutamatergic neurotransmission as a coagonist of synaptic N-methyl-d-aspartate (NMDA) receptor. NMDA signaling has been implicated in the control of food intake. However, the role of d-serine on appetite regulation is unknown. To clarify the effects of d-serine on appetite, we investigated the effect of oral d-serine ingestion on food intake in three different feeding paradigms (one-food access, two-food choice, and refeeding after 24-h fasting) using three different strains of male mice (C57Bl/6J, BKS, and ICR). The effect of d-serine was also tested in leptin signaling-deficient db/db mice and sensory-deafferented (capsaicin-treated) mice. The expression of orexigenic neuropeptides [neuropeptide Y (Npy) and agouti-related protein (Agrp)] in the hypothalamus was compared in fast/refed experiments. Conditioned taste aversion for high-fat diet (HFD) was tested in the d-serine-treated mice. Under the one-food-access paradigm, some of the d-serine-treated mice showed starvation, but not when fed normal chow. HFD feeding with d-serine ingestion did not cause aversion. Under the two-food-choice paradigm, d-serine suppressed the intake of high-preference food but not normal chow. d-Serine also effectively suppressed HFD intake but not normal chow in db/db mice and sensory-deafferented mice. In addition, d-serine suppressed normal chow intake after 24-h fasting despite higher orexigenic gene expression in the hypothalamus. d-Serine failed to suppress HFD intake in the presence of L-701,324, the selective and full antagonist at the glycine-binding site of the NMDA receptor. Therefore, d-serine suppresses the intake of high-preference food through coagonism toward NMDA receptors.}, } @article {pmid26141191, year = {2015}, author = {Ripley, TL and Sanchez-Roige, S and Bullmore, ET and Mugnaini, M and Maltby, K and Miller, SR and Wille, DR and Nathan, P and Stephens, DN}, title = {The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.}, journal = {Psychopharmacology}, volume = {232}, number = {18}, pages = {3431-3441}, pmid = {26141191}, issn = {1432-2072}, mesh = {Alcohol Drinking ; Alcoholism/drug therapy ; Animals ; Autoradiography ; Behavior, Animal/*drug effects ; Central Nervous System Depressants/*administration & dosage ; Cross-Over Studies ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- ; Ethanol/*administration & dosage ; Indans/*pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Naltrexone/*pharmacology ; Narcotic Antagonists/*pharmacology ; Radiopharmaceuticals ; Receptors, Opioid, mu/*antagonists & inhibitors ; Self Administration ; Triazoles/*pharmacology ; Tritium ; }, abstract = {RATIONALE: Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice.

OBJECTIVE: We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy.

METHODS: Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding.

RESULTS: Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75% receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection.

CONCLUSIONS: Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone.}, } @article {pmid26136115, year = {2015}, author = {May, CE and Haun, HL and Griffin, WC}, title = {Sensitization and Tolerance Following Repeated Exposure to Caffeine and Alcohol in Mice.}, journal = {Alcoholism, clinical and experimental research}, volume = {39}, number = {8}, pages = {1443-1452}, pmid = {26136115}, issn = {1530-0277}, support = {P50 AA010761/AA/NIAAA NIH HHS/United States ; R01 AA018036/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Ataxia/chemically induced/prevention & control ; Caffeine/*administration & dosage/toxicity ; *Drug Tolerance/physiology ; Ethanol/*administration & dosage/toxicity ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity/*drug effects/physiology ; }, abstract = {BACKGROUND: Energy drinks are popular mixers with alcohol. While energy drinks contain many ingredients, caffeine is an important pharmacologically active component and is generally present in larger amounts than in other caffeinated beverages. In these studies, we investigated the hypothesis that caffeine would influence the effects of alcohol (ethanol [EtOH]) on conditioned taste aversion (CTA), ataxia, and locomotor activity (LA) after repeated exposure.

METHODS: Four groups of mice were exposed by oral gavage twice daily to vehicle, EtOH (4 g/kg), caffeine (15 mg/kg), or the EtOH/caffeine combination. CTA to saccharin and ataxia in the parallel rod task was evaluated after 8 or 16 gavages, respectively, using EtOH (1 to 3 g/kg) or EtOH/caffeine (3 mg/kg + 2 g/kg) challenges. In addition, LA was evaluated initially and after repeated exposure to oral gavage of these drugs and doses.

RESULTS: Repeated oral gavage of EtOH produced significant locomotor sensitization, with those mice increasing total distance traveled by 2-fold. The locomotor response to caffeine, while significantly greater than vehicle gavage, did not change with repeated exposure. On the other hand, repeated gavage of caffeine/EtOH combination produced a substantial increase in total distance traveled after repeated exposure (~4-fold increase). After repeated EtOH exposure, there was significant tolerance to EtOH in the CTA and parallel rod tests. However, neither a history of caffeine exposure nor including caffeine influenced EtOH-induced CTA. Interestingly, a history of caffeine exposure increased the ataxic response to the caffeine/EtOH combination and appeared to reduce the ataxic response to high doses of EtOH.

CONCLUSIONS: The data support the general hypothesis that repeated exposure to caffeine influences the response to EtOH. Together with previously published work, these data indicate that caffeine influences some EtOH-related behaviors, notably locomotion and ataxia, but appears not to influence the expression of conditioned behaviors.}, } @article {pmid26126924, year = {2015}, author = {Hadamitzky, M and Bösche, K and Engler, A and Schedlowski, M and Engler, H}, title = {Extinction of conditioned taste aversion is related to the aversion strength and associated with c-fos expression in the insular cortex.}, journal = {Neuroscience}, volume = {303}, number = {}, pages = {34-41}, doi = {10.1016/j.neuroscience.2015.06.040}, pmid = {26126924}, issn = {1873-7544}, mesh = {Amygdala/metabolism ; Animals ; Avoidance Learning/*physiology ; Cerebral Cortex/*metabolism ; Conditioning, Classical ; Cyclosporine ; Extinction, Psychological/*physiology ; Male ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Saccharin ; Taste Perception/*physiology ; }, abstract = {Taste aversion learning is a type of conditioning where animals learn to associate a novel taste (conditioned stimulus; CS) with a stimulus inducing symptoms of poisoning or illness (unconditioned stimulus; US). As a consequence animals later avoid this taste, a reaction known as conditioned taste aversion (CTA). An established CTA extinguishes over time when the CS is repeatedly presented in the absence of the US. However, inter-individual differences in CTA extinction do exist. Using a model of behavioral conditioning with saccharin as CS and the immunosuppressant cyclosporine A as US, the present study aimed at further elucidating the factors underlying individual differences in extinction learning by investigating whether extinction of an established CTA is related to the strength of the initially acquired CS-US association. In addition, we analyzed the expression of the neuronal activation marker c-fos in brain structures relevant for acquisition and retrieval of the CTA, such as the insular cortex and the amygdala. We here show that animals, displaying a strong CS-US association during acquisition, maintained a strong CTA during unreinforced CS re-exposures, in contrast to animals with moderate CS-US association. Moreover, the latter animals showed increased c-fos mRNA expression in the insular cortex. Our data indicate that CTA extinction apparently depends on the strength of the initially learned CS-US association. In addition, these findings provide further evidence that the memory for the initial excitatory conditioning and its subsequent extinction is probably stored in those structures that participate in the processing of the CS and the US.}, } @article {pmid26097499, year = {2015}, author = {Pittman, DW and Hansen, DR and Gilbertson, TA}, title = {High-Fat Diet Alters the Orosensory Sensitivity to Fatty Acids in Obesity-Resistant but not Obesity-Prone Rats.}, journal = {Journal of molecular and genetic medicine : an international journal of biomedical research}, volume = {9}, number = {2}, pages = {}, pmid = {26097499}, issn = {1747-0862}, support = {R01 DC013318/DC/NIDCD NIH HHS/United States ; R01 DK059611/DK/NIDDK NIH HHS/United States ; R56 DK059611/DK/NIDDK NIH HHS/United States ; }, abstract = {Gene-environment interactions play a role in the development of obesity but specific effects of diet on the orosensory detection of fatty acids have yet to be clarified. The objective of this study is to characterize the effect of prolonged (5-week) exposure to a high-fat (60%) diet on the behavioral sensitivity to the fatty acid linoleate following a conditioned taste aversion in obesity-prone and obesity-resistant rats. Exposure to the high-fat diet significantly enhanced the sensitivity of obesity-resistant (S5B/Pl) rats to linoleate while producing no effect on the fatty acid sensitivity for obesity-prone rats. Specifically, high-fat diet fed S5B/Pl rats showed stronger initial avoidance of linoleate and slower extinction rates than their normal diet cohorts. Our study suggests that prolonged dietary fat consumption may alter the behavioral sensitivity to fatty acids particularly in obesity-resistant animals.}, } @article {pmid26067784, year = {2015}, author = {Kwok, DW and Boakes, RA}, title = {Proximal, but not distal, pre-exposure reduces serial overshadowing in one-trial taste aversion learning.}, journal = {Behavioural processes}, volume = {118}, number = {}, pages = {111-114}, doi = {10.1016/j.beproc.2015.06.006}, pmid = {26067784}, issn = {1872-8308}, mesh = {Animals ; Avoidance Learning/*drug effects ; Conditioning, Operant/*drug effects ; Hydrochloric Acid/pharmacology ; Inhibition, Psychological ; Lithium Compounds/pharmacology ; Male ; Rats ; Rats, Wistar ; Sucrose/pharmacology ; Taste/*drug effects ; }, abstract = {This experiment tested whether pre-exposing a taste would reduce its ability to overshadow conditioning to a target taste and whether this effect would depend on the delay between pre-exposure and conditioning. Two groups of rats were pre-exposed to an interfering taste (HCl) either a week before conditioning (Group Distal) or the day preceding conditioning (Group Proximal). In the single conditioning trial, rats were given the target taste (sucrose) and 65min later were injected with lithium. The groups differed as to what they were given to drink 50min after sucrose: The Distal, Proximal and Novel groups were given HCl, while the Control group was given water. Pre-exposure to HCl reduced overshadowing of the sucrose aversion by HCl in Group Proximal but not in Group Distal. Possible explanations for the latter result include extinction of the context-HCl association and loss of context control over an HCl-no outcome association.}, } @article {pmid26053891, year = {2016}, author = {Schier, LA and Blonde, GD and Spector, AC}, title = {Bilateral lesions in a specific subregion of posterior insular cortex impair conditioned taste aversion expression in rats.}, journal = {The Journal of comparative neurology}, volume = {524}, number = {1}, pages = {54-73}, pmid = {26053891}, issn = {1096-9861}, support = {F32 DC013494/DC/NIDCD NIH HHS/United States ; R01 DC009821/DC/NIDCD NIH HHS/United States ; T32 DC000044/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*physiology ; Cerebral Cortex/drug effects/pathology/*physiology/physiopathology ; Choice Behavior/physiology ; Conditioning, Psychological/*physiology ; Dietary Sucrose ; Food Preferences/*physiology ; Ibotenic Acid/toxicity ; Male ; Neuropsychological Tests ; Rats, Sprague-Dawley ; Sodium Chloride, Dietary ; Taste Perception/*physiology ; }, abstract = {The gustatory cortex (GC) is widely regarded for its integral role in the acquisition and retention of conditioned taste aversions (CTAs) in rodents, but large lesions in this area do not always result in CTA impairment. Recently, using a new lesion mapping system, we found that severe CTA expression deficits were associated with damage to a critical zone that included the posterior half of GC in addition to the insular cortex (IC) that is just dorsal and caudal to this region (visceral cortex). Lesions in anterior GC were without effect. Here, neurotoxic bilateral lesions were placed in the anterior half of this critical damage zone, at the confluence of the posterior GC and the anterior visceral cortex (termed IC2), the posterior half of this critical damage zone that contains just VC (termed IC3), or both of these subregions (IC2 + IC3). Then, pre- and postsurgically acquired CTAs (to 0.1 M NaCl and 0.1 M sucrose, respectively) were assessed postsurgically in 15-minute one-bottle and 96-hour two-bottle tests. Li-injected rats with histologically confirmed bilateral lesions in IC2 exhibited the most severe CTA deficits, whereas those with bilateral lesions in IC3 were relatively normal, exhibiting transient disruptions in the one-bottle sessions. Groupwise lesion maps showed that CTA-impaired rats had more extensive damage to IC2 than did unimpaired rats. Some individual differences in CTA expression among rats with similar lesion profiles were observed, suggesting idiosyncrasies in the topographic representation of information in the IC. Nevertheless, this study implicates IC2 as the critical zone of the IC for normal CTA expression.}, } @article {pmid26003276, year = {2015}, author = {Kim, YS and Yoo, SB and Ryu, V and Kim, KN and Kim, BT and Lee, JH and Jahng, JW}, title = {Circadian activation of the hypothalamic-pituitary-adrenal axis may affect central, but not peripheral, effect of lithium in conditioned taste aversion learning in rats.}, journal = {European journal of pharmacology}, volume = {762}, number = {}, pages = {11-17}, doi = {10.1016/j.ejphar.2015.05.029}, pmid = {26003276}, issn = {1879-0712}, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Circadian Rhythm/*drug effects ; Conditioning, Psychological/*drug effects ; Cyclic AMP Response Element Modulator/metabolism ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Hypothalamo-Hypophyseal System/*drug effects/*physiology ; Lithium Chloride/*pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Taste Perception/drug effects/*physiology ; }, abstract = {Activation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in conditioned taste aversion (CTA) learning induced by lithium chloride. This study investigated if circadian activation of the HPA axis affects the lithium-induced CTA formation. The pairing of conditioned stimulus (sucrose) and unconditioned stimulus (lithium chloride) was performed at night (shortly after light-off) when the HPA activity shows its circadian increase. Intraperitoenal injection of lithium chloride (0.15M, 3ml/kg or 12ml/kg) at night induced CTA formation and the HPA axis activation and increased c-Fos expression in both the parabrachial nucleus (PBN) and the nucleus tractus of solitarius (NTS) in a dose dependent manner. However, intracerebroventricular lithium (0.6M, 5µl) at night failed to induce CTA or the HPA axis activation, although it increased c-Fos expression in the PBN and NTS. Results suggest that circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA formation, and the lithium-induced c-Fos expression in brain regions may not be effective to induce CTA unless it is coupled with the HPA axis activation. It is concluded that the HPA axis activation may play an important role mediating not only peripheral but also central effect of lithium in CTA formation.}, } @article {pmid25972577, year = {2015}, author = {Kalyanasundar, B and Perez, CI and Luna, A and Solorio, J and Moreno, MG and Elias, D and Simon, SA and Gutierrez, R}, title = {D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell.}, journal = {Journal of neurophysiology}, volume = {114}, number = {1}, pages = {585-607}, pmid = {25972577}, issn = {1522-1598}, mesh = {Action Potentials/drug effects/physiology ; Animals ; Appetite Depressants/adverse effects/*pharmacology ; Benzazepines/pharmacology ; Bupropion/adverse effects/pharmacology ; Diethylpropion/adverse effects/pharmacology ; Dopamine D2 Receptor Antagonists/*pharmacology ; Drug Interactions ; Eating/drug effects/physiology ; Locomotion/drug effects/physiology ; Male ; Nucleus Accumbens/*drug effects/physiology ; Phentermine/adverse effects/pharmacology ; Raclopride/pharmacology ; Random Allocation ; Rats, Sprague-Dawley ; Receptors, Dopamine D1/*antagonists & inhibitors/metabolism ; Receptors, Dopamine D2/metabolism ; Sleep Initiation and Maintenance Disorders/chemically induced ; Stereotyped Behavior/drug effects/physiology ; Weight Loss/drug effects/physiology ; }, abstract = {Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds.}, } @article {pmid25950618, year = {2016}, author = {Boutros, N and Semenova, S and Markou, A}, title = {Adolescent alcohol exposure decreased sensitivity to nicotine in adult Wistar rats.}, journal = {Addiction biology}, volume = {21}, number = {4}, pages = {826-834}, pmid = {25950618}, issn = {1369-1600}, support = {U01 AA019970/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking ; Animals ; Central Nervous System Depressants/*pharmacology ; Conditioning, Classical/drug effects ; Disease Models, Animal ; Ethanol/*pharmacology ; Male ; Nicotine/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {Many adolescents engage in heavy alcohol use. Limited research in humans indicates that adolescent alcohol use predicts adult tobacco use. The present study investigated whether adolescent intermittent ethanol (AIE) exposure alters nicotine sensitivity in adulthood. Adolescent male Wistar rats (postnatal day 28-53) were exposed to AIE exposure that consisted of 5 g/kg of 25 percent ethanol three times per day in a 2 days on/2 days off regimen. Control rats received water with the same exposure regimen. In adulthood, separate groups of rats were tested for nicotine intravenous self-administration (IVSA), drug discrimination and conditioned taste aversion (CTA). The dose-response function for nicotine IVSA under a fixed-ratio schedule of reinforcement was similar in AIE-exposed and control rats. However, AIE-exposed rats self-administered less nicotine at the lowest dose, suggesting that low-dose nicotine was less reinforcing in AIE-exposed, compared with control rats. AIE-exposed rats self-administered less nicotine under a progressive-ratio schedule, suggesting decreased motivation for nicotine after AIE exposure. The discriminative stimulus effects of nicotine were diminished in AIE-exposed rats compared with control rats. No group differences in nicotine CTA were observed, suggesting that AIE exposure had no effect on the aversive properties of nicotine. Altogether, these results demonstrate that AIE exposure decreases sensitivity to the reinforcing, motivational and discriminative properties of nicotine while leaving the aversive properties of nicotine unaltered in adult rats. These findings suggest that drinking during adolescence may result in decreased sensitivity to nicotine in adult humans, which may in turn contribute to the higher rates of tobacco smoking.}, } @article {pmid25907741, year = {2016}, author = {Miranda-Morales, RS and Pautassi, RM}, title = {Pharmacological characterization of the nociceptin/orphanin FQ receptor on ethanol-mediated motivational effects in infant and adolescent rats.}, journal = {Behavioural brain research}, volume = {298}, number = {Pt A}, pages = {88-96}, doi = {10.1016/j.bbr.2015.04.016}, pmid = {25907741}, issn = {1872-7549}, mesh = {Aging/*drug effects/metabolism/psychology ; Alcohol Drinking/physiopathology ; Animals ; Anxiety/drug therapy/physiopathology ; Choice Behavior/drug effects/physiology ; Conditioning, Psychological/drug effects/physiology ; Ethanol/*pharmacology ; Female ; Imidazoles/pharmacology ; Male ; Motivation/*drug effects/physiology ; Motor Activity/drug effects/physiology ; Neuropsychological Tests ; Opioid Peptides/pharmacology ; Psychotropic Drugs/*pharmacology ; Rats, Wistar ; Receptors, Opioid/agonists/*metabolism ; Saccharin ; Spiro Compounds/pharmacology ; Taste Perception/drug effects/physiology ; }, abstract = {Activation of nociceptin/orphanin FQ (NOP) receptors attenuates ethanol drinking and prevents relapse in adult rodents. In younger rodents (i.e., infant rats), activation of NOP receptors blocks ethanol-induced locomotor activation but does not attenuate ethanol intake. The aim of the present study was to extend the analysis of NOP modulation of ethanol's effects during early ontogeny. Aversive and anxiolytic effects of ethanol were measured in infant and adolescent rats via conditioned taste aversion and the light-dark box test; whereas ethanol-induced locomotor activity and ethanol intake was measured in adolescents only. Before these tests, infant rats were treated with the natural ligand of NOP receptors, nociceptin (0.0, 0.5 or 1.0 μg) and adolescent rats were treated with the specific agonist Ro 64-6198 (0.0, 0.1 or 0.3 mg/kg). The activation of NOP receptors attenuated ethanol-induced anxiolysis in adolescents only, and had no effect on ethanol's aversive effects. Administration of Ro 64-6198 blocked ethanol-induced locomotor activation but did not modify ethanol intake patterns. The attenuation of ethanol stimulating and anxiolytic effect by activation of NOP receptors indicates a modulatory role of this receptor on ethanol effects, which is expressed early in ontogeny.}, } @article {pmid25883377, year = {2015}, author = {Ito, E and Yamagishi, M and Hatakeyama, D and Watanabe, T and Fujito, Y and Dyakonova, V and Lukowiak, K}, title = {Memory block: a consequence of conflict resolution.}, journal = {The Journal of experimental biology}, volume = {218}, number = {Pt 11}, pages = {1699-1704}, doi = {10.1242/jeb.120329}, pmid = {25883377}, issn = {1477-9145}, support = {MOP 64339//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Avoidance Learning ; Conditioning, Classical ; Food Deprivation ; Lymnaea/*physiology ; Memory, Long-Term ; Taste/physiology ; }, abstract = {Food deprivation for 1 day in the pond snail Lymnaea stagnalis before aversive classical conditioning results in optimal conditioned taste aversion (CTA) and long-term memory (LTM) formation, whereas 5-day food deprivation before training does not. We hypothesize that snails do in fact learn and form LTM when trained after prolonged food deprivation, but that severe food deprivation blocks their ability to express memory. We trained 5-day food-deprived snails under various conditions, and found that memory was indeed formed but is overpowered by severe food deprivation. Moreover, CTA-LTM was context dependent and was observed only when the snails were in a context similar to that in which the training occurred.}, } @article {pmid25878268, year = {2015}, author = {Kirkhart, C and Scott, K}, title = {Gustatory learning and processing in the Drosophila mushroom bodies.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {35}, number = {15}, pages = {5950-5958}, pmid = {25878268}, issn = {1529-2401}, support = {R01 DC013280/DC/NIDCD NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; }, mesh = {Afferent Pathways/*physiology ; Animals ; Animals, Genetically Modified ; Calcium/metabolism ; Conditioning, Classical/*physiology ; Drosophila ; Drosophila Proteins/genetics/metabolism ; Female ; Functional Laterality ; Ion Channels ; Memory, Short-Term/*physiology ; Mushroom Bodies/*physiology ; Nerve Tissue Proteins/metabolism ; Receptors, Odorant/genetics/metabolism ; Sensory Receptor Cells/*physiology ; TRPA1 Cation Channel ; TRPC Cation Channels/genetics/metabolism ; Taste/*physiology ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {The Drosophila mushroom bodies are critical association areas whose role in olfactory associative learning has been well characterized. Recent behavioral studies using a taste association paradigm revealed that gustatory conditioning also requires the mushroom bodies (Masek and Scott, 2010; Keene and Masek, 2012). Here, we examine the representations of tastes and the neural sites for taste associations in the mushroom bodies. Using molecular genetic approaches to target different neuronal populations, we find that the gamma lobes of the mushroom bodies and a subset of dopaminergic input neurons are required for taste associative learning. Monitoring responses to taste compounds in the mushroom body calyx with calcium imaging reveals sparse, taste-specific and organ-specific activation in the Kenyon cell dendrites of the main calyx and the dorsal accessory calyx. Our work provides insight into gustatory representations in the mushroom bodies, revealing the essential role of gustatory inputs not only as rewards and punishments but also as adaptive cues.}, } @article {pmid25839897, year = {2015}, author = {Blednov, YA and Benavidez, JM and Black, M and Mayfield, J and Harris, RA}, title = {Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines.}, journal = {Neuropharmacology}, volume = {95}, number = {}, pages = {309-320}, pmid = {25839897}, issn = {1873-7064}, support = {AA013520/AA/NIAAA NIH HHS/United States ; R37 AA006399/AA/NIAAA NIH HHS/United States ; R01 AA006399/AA/NIAAA NIH HHS/United States ; U01 AA013520/AA/NIAAA NIH HHS/United States ; AA006399/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking/metabolism ; Animals ; Avoidance Learning/drug effects/physiology ; Behavior, Animal/*drug effects/physiology ; Benzodiazepines/*pharmacology ; Ethanol/*pharmacology ; Female ; Flurazepam/pharmacology ; Hypnotics and Sedatives/*pharmacology ; Interleukin 1 Receptor Antagonist Protein/genetics/*metabolism/pharmacology ; Ketamine/pharmacology ; Male ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity/drug effects/physiology ; Pentobarbital/pharmacology ; Receptors, Interleukin-1 Type I/genetics/*metabolism ; Severity of Illness Index ; Substance Withdrawal Syndrome/metabolism ; Taste Perception/drug effects/physiology ; }, abstract = {Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway.}, } @article {pmid25820205, year = {2015}, author = {Saites, LN and Goldsmith, Z and Densky, J and Guedes, VA and Boughter, JD}, title = {Mice perceive synergistic umami mixtures as tasting sweet.}, journal = {Chemical senses}, volume = {40}, number = {5}, pages = {295-303}, pmid = {25820205}, issn = {1464-3553}, support = {DC000353/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Female ; *Glutamic Acid/administration & dosage ; *Inositol Phosphates/administration & dosage ; Male ; Mice ; Mice, Inbred C57BL ; Sucrose/administration & dosage ; Taste/*physiology ; }, abstract = {Previous electrophysiological investigation shows that combinations of compounds classified by humans as umami-tasting, such as glutamate salts and 5'-ribonucleotides, elicit synergistic responses in neurons throughout the rodent taste system and produce a pattern that resembles responses to sweet compounds. The current study tested the hypothesis that a synergistic mixture of monopotassium glutamate (MPG) and inositol monophosphate (IMP) possesses perceptual similarity to sucrose in mice. We estimated behavioral similarity among these tastants and the individual umami compounds using a series of conditioned taste aversion (CTA) tests, a procedure that measures whether a CTA formed to one stimulus generalizes to another. Our primary finding was that a CTA to a synergistic mixture of MPG + IMP generalizes to sucrose, and vice-versa. This indicates umami synergistic mixtures are perceived as having a sweet, or at least sucrose-like, taste to mice. Considering other recent studies, our data argue strongly in favor of multiple receptor mechanisms for umami detection, and complexity in taste perception models for rodents.}, } @article {pmid25788675, year = {2015}, author = {Carter, ME and Han, S and Palmiter, RD}, title = {Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {35}, number = {11}, pages = {4582-4586}, pmid = {25788675}, issn = {1529-2401}, support = {P30 DK017047/DK/NIDDK NIH HHS/United States ; R01 DA024908/DA/NIDA NIH HHS/United States ; DA024908/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*physiology ; Calcitonin Gene-Related Peptide/*physiology ; Conditioning, Psychological/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Parabrachial Nucleus/*physiology ; Taste/*physiology ; }, abstract = {Conditioned taste aversion (CTA) is a phenomenon in which an individual forms an association between a novel tastant and toxin-induced gastrointestinal malaise. Previous studies showed that the parabrachial nucleus (PBN) contains neurons that are necessary for the acquisition of CTA, but the specific neuronal populations involved are unknown. Previously, we identified calcitonin gene-related peptide (CGRP)-expressing neurons in the external lateral subdivision of the PBN (PBel) as being sufficient to suppress appetite and necessary for the anorexigenic effects of appetite-suppressing substances including lithium chloride (LiCl), a compound often used to induce CTA. Here, we test the hypothesis that PBel CGRP neurons are sufficient and necessary for CTA acquisition in mice. We show that optogenetic activation of these neurons is sufficient to induce CTA in the absence of anorexigenic substances, whereas genetically induced silencing of these neurons attenuates acquisition of CTA upon exposure to LiCl. Together, these results demonstrate that PBel CGRP neurons mediate a gastrointestinal distress signal required to establish CTA.}, } @article {pmid25778639, year = {2015}, author = {Tiunova, AA and Bezryadnov, DV and Anokhin, KV}, title = {Involvement of protein kinase Mζ in the maintenance of long-term memory for taste aversion learning in young chicks.}, journal = {Bulletin of experimental biology and medicine}, volume = {158}, number = {5}, pages = {592-594}, doi = {10.1007/s10517-015-2813-0}, pmid = {25778639}, issn = {1573-8221}, mesh = {Animals ; Avoidance Learning/drug effects ; Chickens ; Memory, Long-Term/drug effects ; Peptides/pharmacology ; Protein Kinase C/antagonists & inhibitors/*metabolism ; Taste/physiology ; }, abstract = {The effects of an inhibitor of protein kinase Mζ on long-term memory were studied using the model of taste aversion in newborn chicks. Memory was impaired by intracerebral injection of 10 or 20 nmol of ζ-inhibiting peptide 24 h after training. Memory impairment was found 2 h after peptide administration, and repeated examination 24 h after treatment showed no recovery. Memory impairment was not observed 24 h after inhibitor administration if the testing 2 h after treatment was not performed. The results indicate the contribution of protein kinase Mζ in the maintenance of long-term memory in the avian brain. These data confirm the hypothesis of several authors that inhibition of protein kinase Mζ does not abolish memory, but rather interacts with processes of memory retrieval and/or reconsolidation.}, } @article {pmid25761841, year = {2015}, author = {Malcolm, E and Carroll, FI and Blough, B and Damaj, MI and Shoaib, M}, title = {Examination of the metabolite hydroxybupropion in the reinforcing and aversive stimulus effects of nicotine in rats.}, journal = {Psychopharmacology}, volume = {232}, number = {15}, pages = {2763-2771}, pmid = {25761841}, issn = {1432-2072}, mesh = {Animals ; Antidepressive Agents/therapeutic use ; Avoidance Learning/drug effects ; Bupropion/*analogs & derivatives/pharmacology ; Male ; Nicotine/*administration & dosage ; Rats ; Receptors, Nicotinic/*physiology ; *Reward ; Self Administration ; *Smoking Cessation ; Tobacco Use Disorder ; }, abstract = {BACKGROUND: Preclinical studies with bupropion in rodent models of nicotine dependence have generated equivocal findings with regard to translating the clinical efficacy of the antidepressant as a smoking cessation agent.

OBJECTIVE: Given that rats are poor metabolizers of bupropion, the present experiments examined (2S,3S)-hydroxybupropion, the major active metabolite, on the positive reinforcing and aversive stimulus properties of nicotine in rats.

METHODS: In male hooded Lister rats, (2S,3S)-hydroxybupropion (1.0-10.0 mg/kg IP) was tested on intravenous nicotine (0.03 mg/kg/inf) self-administration behaviour for three sessions (n = 8), and in another experiment, the same doses of (2S,3S)-hydroxybupropion were tested in a conditioned taste aversion procedure to assess the aversive stimulus properties of nicotine, a function implicated in the regulation of nicotine intake.

RESULTS: (2S,3S)-hydroxybupropion attenuated nicotine intake in a manner similar to that produced by mecamylamine pretreatment (1.0 mg/kg SC). This effect on nicotine-taking was specific since these doses had no effect on responding maintained by sucrose presented orally (200 μl of 5 % w/v). (2S,3S)-hydroxybupropion (1, 3 and 10 mg/kg IP) pretreatment failed to modify the aversive effects produced by a small dose of nicotine (0.1 mg/kg SC).

CONCLUSIONS: These results demonstrate this metabolite to specifically modify the positive reinforcing effects of nicotine without affecting its aversive motivational effects. We propose that the clinical efficacy of bupropion may be due to a combination of effects produced by bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine and noradrenaline in reward centres of the brain and the noncompetitive antagonism of neuronal nicotinic receptors.}, } @article {pmid25740289, year = {2015}, author = {Harkness, JH and Shi, X and Janowsky, A and Phillips, TJ}, title = {Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {40}, number = {9}, pages = {2175-2184}, pmid = {25740289}, issn = {1740-634X}, support = {T32 DA007262/DA/NIDA NIH HHS/United States ; P50 DA018165/DA/NIDA NIH HHS/United States ; I01 BX002758/BX/BLRD VA/United States ; I01 BX002106/BX/BLRD VA/United States ; P60 AA010760/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/drug effects ; Body Temperature/drug effects/genetics ; Central Nervous System Stimulants/*administration & dosage ; Choice Behavior/*drug effects ; Conditioning, Operant/*drug effects ; Cyclic AMP/metabolism ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Methamphetamine/administration & dosage/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Transgenic ; Models, Molecular ; Mutation/genetics ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Taste/drug effects/genetics ; Transfection ; }, abstract = {Continued methamphetamine (MA) use is dependent on a positive MA experience and is likely attenuated by sensitivity to the aversive effects of MA. Bidirectional selective breeding of mice for high (MAHDR) or low (MALDR) voluntary consumption of MA demonstrates a genetic influence on MA intake. Quantitative trait locus (QTL) mapping identified a QTL on mouse chromosome 10 that accounts for greater than 50% of the genetically-determined differences in MA intake in the MAHDR and MALDR lines. The trace amine-associated receptor 1 gene (Taar1) is within the confidence interval of the QTL and encodes a receptor (TAAR1) that modulates monoamine neurotransmission and at which MA serves as an agonist. We demonstrate the existence of a non-functional allele of Taar1 in the DBA/2J mouse strain, one of the founder strains of the selected lines, and show that this non-functional allele co-segregates with high MA drinking and with reduced sensitivity to MA-induced conditioned taste aversion (CTA) and hypothermia. The functional Taar1 allele, derived from the other founder strain, C57BL/6J, segregates with low MA drinking and heightened sensitivity to MA-induced CTA and hypothermia. A role for TAAR1 in these phenotypes is corroborated in Taar1 transgenic mice: Taar1 knockout mice consume more MA and exhibit insensitivity to MA-induced CTA and hypothermia, compared with Taar1 wild-type mice. These are the first data to show that voluntary MA consumption is, in part, regulated by TAAR1 function. Behavioral and physiological studies indicate that TAAR1 function increases sensitivity to aversive effects of MA, and may thereby protect against MA use.}, } @article {pmid25703200, year = {2015}, author = {Swick, JC and Alhadeff, AL and Grill, HJ and Urrea, P and Lee, SM and Roh, H and Baird, JP}, title = {Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {40}, number = {8}, pages = {2001-2014}, pmid = {25703200}, issn = {1740-634X}, support = {R01 DK021397/DK/NIDDK NIH HHS/United States ; R15 DC007389/DC/NIDCD NIH HHS/United States ; 52006280//Howard Hughes Medical Institute/United States ; DC07389/DC/NIDCD NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Antimanic Agents/pharmacology ; Appetitive Behavior/drug effects ; Brain Injuries/chemically induced/*pathology ; Eating/drug effects ; Excitatory Amino Acid Agonists/toxicity ; Exenatide ; Feeding and Eating Disorders/*chemically induced ; Glucagon-Like Peptide-1 Receptor/agonists/metabolism ; Hypoglycemic Agents/*toxicity ; Ibotenic Acid/toxicity ; Lithium Chloride/administration & dosage ; Male ; Parabrachial Nucleus/drug effects/*pathology ; Peptides/*toxicity ; Rats ; Rats, Sprague-Dawley ; Sucrose/administration & dosage ; Taste/drug effects ; Venoms/*toxicity ; Water Deprivation ; }, abstract = {Exendin-4 (Ex4), a glucagon-like peptide-1 receptor (GLP-1R) agonist approved to treat type 2 diabetes mellitus, is well known to induce hypophagia in human and animal models. We evaluated the contributions of the hindbrain parabrachial nucleus (PBN) to systemic Ex4-induced hypophagia, as the PBN receives gustatory and visceral afferent relays and descending input from several brain nuclei associated with feeding. Rats with ibotenic-acid lesions targeted to the lateral PBN (PBNx) and sham controls received Ex4 (1 μg/kg) before 24 h home cage chow or 90 min 0.3 M sucrose access tests, and licking microstructure was analyzed to identify components of feeding behavior affected by Ex4. PBN lesion efficacy was confirmed using conditioned taste aversion (CTA) tests. As expected, sham control but not PBNx rats developed a CTA. In sham-lesioned rats, Ex4 reduced chow intake within 4 h of injection and sucrose intake within 90 min. PBNx rats did not show reduced chow or sucrose intake after Ex4 treatment, indicating that the PBN is necessary for Ex4 effects under the conditions tested. In sham-treated rats, Ex4 affected licking microstructure measures associated with hedonic taste evaluation, appetitive behavior, oromotor coordination, and inhibitory postingestive feedback. Licking microstructure responses in PBNx rats after Ex4 treatment were similar to sham-treated rats with the exception of inhibitory postingestive feedback measures. Together, the results suggest that the PBN critically contributes to the hypophagic effects of systemically delivered GLP-1R agonists by enhancing visceral feedback.}, } @article {pmid25698309, year = {2015}, author = {Saalfield, J and Spear, L}, title = {Consequences of repeated ethanol exposure during early or late adolescence on conditioned taste aversions in rats.}, journal = {Developmental cognitive neuroscience}, volume = {16}, number = {}, pages = {174-182}, pmid = {25698309}, issn = {1878-9307}, support = {R01 AA018026/AA/NIAAA NIH HHS/United States ; U01 AA019972/AA/NIAAA NIH HHS/United States ; R01-AA018026/AA/NIAAA NIH HHS/United States ; UO1-AA019972-01/AA/NIAAA NIH HHS/United States ; }, mesh = {Aging/psychology ; Animals ; Avoidance Learning/drug effects ; Central Nervous System Depressants/administration & dosage/*pharmacology ; Conditioning, Operant/*drug effects ; Cues ; Dose-Response Relationship, Drug ; Ethanol/administration & dosage/*pharmacology ; Injections, Intraperitoneal ; Rats ; Rats, Sprague-Dawley ; Taste/*drug effects ; }, abstract = {Alcohol use is prevalent during adolescence, yet little is known about possible long-lasting consequences. Recent evidence suggests that adolescents are less sensitive than adults to ethanol's aversive effects, an insensitivity that may be retained into adulthood after repeated adolescent ethanol exposure. This study assessed whether intermittent ethanol exposure during early or late adolescence (early-AIE or late-AIE, respectively) would affect ethanol conditioned taste aversions 2 days (CTA1) and >3 weeks (CTA2) post-exposure using supersaccharin and saline as conditioning stimuli (CS), respectively. Pair-housed male Sprague-Dawley rats received 4g/kg i.g. ethanol (25%) or water every 48 h from postnatal day (P) 25-45 (early AIE) or P45-65 (late AIE), or were left non-manipulated (NM). During conditioning, 30 min home cage access to the CS was followed by 0, 1, 1.5, 2 or 2.5g/kg ethanol i.p., with testing 2 days later. Attenuated CTA relative to controls was seen among early and late AIE animals at both CTA1 and CTA2, an effect particularly pronounced at CTA1 after late AIE. Thus, adolescent exposure to ethanol was found to induce an insensitivity to ethanol CTA seen soon after exposure and lasting into adulthood, and evident with ethanol exposures not only early but also later in adolescence.}, } @article {pmid25678534, year = {2015}, author = {Blednov, YA and Benavidez, JM and Black, M and Leiter, CR and Osterndorff-Kahanek, E and Harris, RA}, title = {Glycine receptors containing α2 or α3 subunits regulate specific ethanol-mediated behaviors.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {353}, number = {1}, pages = {181-191}, pmid = {25678534}, issn = {1521-0103}, support = {R01 AA006399/AA/NIAAA NIH HHS/United States ; U01 AA013520/AA/NIAAA NIH HHS/United States ; R01-AA006399/AA/NIAAA NIH HHS/United States ; R01-AA013520/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/drug effects ; Behavior, Animal/*drug effects ; Brain/metabolism ; Drinking Behavior/drug effects ; Ethanol/*pharmacology ; Food Preferences/drug effects ; Mice, Knockout ; Motor Activity/drug effects ; Mutation ; RNA, Messenger/metabolism ; Receptors, Glycine/genetics/*metabolism ; Reflex, Startle/drug effects ; }, abstract = {Glycine receptors (GlyRs) are broadly expressed in the central nervous system. Ethanol enhances the function of brain GlyRs, and the GlyRα1 subunit is associated with some of the behavioral actions of ethanol, such as loss of righting reflex. The in vivo role of GlyRα2 and α3 subunits in alcohol responses has not been characterized despite high expression levels in the nucleus accumbens and amygdala, areas that are important for the rewarding properties of drugs of abuse. We used an extensive panel of behavioral tests to examine ethanol actions in mice lacking Glra2 (the gene encoding the glycine receptor alpha 2 subunit) or Glra3 (the gene encoding the glycine receptor alpha 3 subunit). Deletion of Glra2 or Glra3 alters specific ethanol-induced behaviors. Glra2 knockout mice demonstrate reduced ethanol intake and preference in the 24-hour two-bottle choice test and increased initial aversive responses to ethanol and lithium chloride. In contrast, Glra3 knockout mice show increased ethanol intake and preference in the 24-hour intermittent access test and increased development of conditioned taste aversion to ethanol. Mutants and wild-type mice consumed similar amounts of ethanol in the limited access drinking in the dark test. Other ethanol effects, such as anxiolysis, motor incoordination, loss of righting reflex, and acoustic startle response, were not altered in the mutants. The behavioral changes in mice lacking GlyRα2 or α3 subunits were distinct from effects previously observed in mice with knock-in mutations in the α1 subunit. We provide evidence that GlyRα2 and α3 subunits may regulate ethanol consumption and the aversive response to ethanol.}, } @article {pmid25658323, year = {2015}, author = {Blonde, GD and Bales, MB and Spector, AC}, title = {Extensive lesions in rat insular cortex significantly disrupt taste sensitivity to NaCl and KCl and slow salt discrimination learning.}, journal = {PloS one}, volume = {10}, number = {2}, pages = {e0117515}, pmid = {25658323}, issn = {1932-6203}, support = {R01 DC009821/DC/NIDCD NIH HHS/United States ; T32 DC000044/DC/NIDCD NIH HHS/United States ; R01-DC-DC009821/DC/NIDCD NIH HHS/United States ; T32-DC-000044/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/drug effects/physiology ; Cerebral Cortex/drug effects/*physiopathology ; Discrimination Learning/drug effects/*physiology ; Ibotenic Acid/toxicity ; Male ; Potassium Chloride/*administration & dosage ; Rats ; Rats, Sprague-Dawley ; Sodium Chloride/*administration & dosage ; Taste/drug effects/*physiology ; Taste Perception/drug effects/*physiology ; }, abstract = {While studies of the gustatory cortex (GC) mostly focus on its role in taste aversion learning and memory, the necessity of GC for other fundamental taste-guided behaviors remains largely untested. Here, rats with either excitotoxic lesions targeting GC (n = 26) or sham lesions (n = 14) were assessed for postsurgical retention of a presurgically LiCl-induced conditioned taste aversion (CTA) to 0.1M sucrose using a brief-access taste generalization test in a gustometer. The same animals were then trained in a two-response operant taste detection task and psychophysically tested for their salt (NaCl or KCl) sensitivity. Next, the rats were trained and tested in a NaCl vs. KCl taste discrimination task with concentrations varied. Rats meeting our histological inclusion criterion had large lesions (resulting in a group averaging 80% damage to GC and involving surrounding regions) and showed impaired postsurgical expression of the presurgical CTA (LiCl-injected, n = 9), demonstrated rightward shifts in the NaCl (0.54 log10 shift) and KCl (0.35 log10 shift) psychometric functions, and displayed retarded salt discrimination acquisition (n = 18), but eventually learned and performed the discrimination comparable to sham-operated animals. Interestingly, the degree of deficit between tasks correlated only modestly, if at all, suggesting that idiosyncratic differences in insular cortex lesion topography were the root of the individual differences in the behavioral effects demonstrated here. This latter finding hints at some degree of interanimal variation in the functional topography of insular cortex. Overall, GC appears to be necessary to maintain normal taste sensitivity to NaCl and KCl and for salt discrimination learning. However, higher salt concentrations can be detected and discriminated by rats with extensive damage to GC suggesting that the other resources of the gustatory system are sufficient to maintain partial competence in these tasks, supporting the view that such basic sensory-discriminative taste functions involve distributed processes among central gustatory structures.}, } @article {pmid25629943, year = {2015}, author = {Niikura, R and Nozawa, T and Yamada, K and Kato, K and Ichitani, Y}, title = {Latent inhibition in rats neonatally treated chronically with MK-801: differential effects on conditioned taste aversion and conditioned emotional response.}, journal = {Behavioural brain research}, volume = {283}, number = {}, pages = {102-107}, doi = {10.1016/j.bbr.2015.01.029}, pmid = {25629943}, issn = {1872-7549}, mesh = {Animals ; Animals, Newborn ; Auditory Perception/drug effects/physiology ; Avoidance Learning/drug effects/physiology ; Conditioning, Classical/*drug effects/physiology ; Dietary Sucrose/administration & dosage ; Dizocilpine Maleate/*pharmacology ; Electroshock ; Emotions/drug effects/physiology ; Excitatory Amino Acid Antagonists/*pharmacology ; Foot ; *Inhibition, Psychological ; Lithium Chloride/administration & dosage ; Male ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Taste Perception/drug effects/physiology ; }, abstract = {Chronic neonatal blockade of N-methyl-d-aspartate (NMDA) receptors produces various abnormal behaviors in adulthood animals. This study investigated the effects of neonatal treatment chronically with MK-801 in rats on the preexposure-induced retardation of CS-US association, i.e. latent inhibition (LI), of two aversive classical conditioning tasks in adulthood. In conditioned taste aversion (CTA) using sucrose taste and LiCl, neonatal chronic MK-801 (0.4 mg/kg twice/day) treatment attenuated the inhibitory effect of sucrose preexposure on the aversive conditioning, although the treatment did not affect CTA conditioning itself. On the other hand, in conditioned emotional response (CER) using tone and electrical foot shock, rats neonatally treated with MK-801 showed the same degree of inhibitory effect of tone preexposure on the aversive conditioning compared with neonatally vehicle-treated rats, and also showed the same level of CER conditioning itself. Thus, the effect of chronic neonatal blockade of NMDA receptors on the LI of classical conditioning in adulthood was differentiated by the task employed. Results suggest that LI of CTA paradigm compared with that of CER is more sensitive to abnormal development after chronic neonatal blockade of NMDA receptors as an index of cognitive/attentional deficits caused by the treatment.}, } @article {pmid25619919, year = {2015}, author = {Soto, J and Sheng, Y and Standing, JF and Orlu Gul, M and Tuleu, C}, title = {Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {91}, number = {}, pages = {47-51}, doi = {10.1016/j.ejpb.2015.01.016}, pmid = {25619919}, issn = {1873-3441}, support = {MR/M008665/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Algorithms ; Animals ; Behavior, Animal/*drug effects ; *Drug Evaluation, Preclinical ; Drugs, Investigational/*adverse effects ; Flavoring Agents/toxicity ; Male ; *Models, Statistical ; Monitoring, Ambulatory ; Osmolar Concentration ; Quinine/toxicity ; Rats, Sprague-Dawley ; Taste ; Taste Buds/*drug effects ; *Tongue Habits ; }, abstract = {The rodent brief-access taste aversion (BATA) model is an efficient in vivo screening tool for taste assessment. A new E(max) (maximum effect attributable to the drug) model was developed and further investigated in comparison with three previously published models for analysing the rodent BATA data; the robustness of all the models was discussed. The rodent BATA data were obtained from a series of experiments conducted with a bitter reference compound, quinine hydrochloride dihydrate (QHD). A new E(max) model that could be applied to both "lick numbers" and "lick ratios" was built and three published models that used lick ratios were employed for analysing the BATA data. IC50, the concentration that inhibits 50% of the maximum lick numbers, quantified the oral aversiveness of QHD. One thousand bootstrap datasets were generated from the original data. All models were applied to estimate the confidence intervals of the IC50s without symmetric assumption. The IC50 value obtained from the new E(max) model was 0.0496 mM (95% CI 0.0297-0.0857) using the lick numbers for analysis, while an IC50 of 0.0502 mM (95% CI 0.0267-0.0859) was acquired with the lick ratios. Except one published model, the IC50 values have a similar range for the 95% CI. The new E(max) model enabled the analysis of both "lick numbers" and "lick ratios" whereas other models could only handle data presented as "lick ratios". IC50s obtained with these two types of datasets showed similarity among all models thereby justified the robustness of the new E(max) model.}, } @article {pmid25617666, year = {2015}, author = {Lin, JY and Arthurs, J and Reilly, S}, title = {Gustatory insular cortex, aversive taste memory and taste neophobia.}, journal = {Neurobiology of learning and memory}, volume = {119}, number = {}, pages = {77-84}, pmid = {25617666}, issn = {1095-9564}, support = {R01 DC006456/DC/NIDCD NIH HHS/United States ; R56 DC006456/DC/NIDCD NIH HHS/United States ; DC06456/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*physiology ; Cerebral Cortex/*physiology ; Conditioning, Psychological ; Male ; Memory/*physiology ; Rats ; Rats, Sprague-Dawley ; Taste/*physiology ; Taste Perception/*physiology ; }, abstract = {Prior research indicates a role for the gustatory insular cortex (GC) in taste neophobia. Rats with lesions of the GC show much weaker avoidance to a novel and potentially dangerous taste than do neurologically intact animals. The current study used the retention of conditioned taste aversion (CTA) as a tool to determine whether the GC modulates neophobia by processing taste novelty or taste danger. The results show that GC lesions attenuate CTA retention (Experiment 1) and impair taste neophobia (Experiment 2). Given that normal CTA retention does not involve the processing of taste novelty, the pattern of results suggests that the GC is involved in taste neophobia via its function in processing the danger conveyed by a taste stimulus.}, } @article {pmid25604941, year = {2015}, author = {Delay, ER and Kondoh, T}, title = {Dried bonito dashi: taste qualities evaluated using conditioned taste aversion methods in wild-type and T1R1 knockout mice.}, journal = {Chemical senses}, volume = {40}, number = {2}, pages = {125-140}, doi = {10.1093/chemse/bju067}, pmid = {25604941}, issn = {1464-3553}, mesh = {Amiloride/pharmacology ; Amino Acids/*pharmacology ; Animals ; Avoidance Learning ; Citric Acid/pharmacology ; Conditioning, Classical ; Cooking ; Dose-Response Relationship, Drug ; *Food ; Glutamic Acid/pharmacology ; Hydrogen-Ion Concentration ; Inosine Monophosphate/*pharmacology ; Lactic Acid/pharmacology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Quinine/pharmacology ; Receptors, G-Protein-Coupled/*genetics/metabolism ; Sodium Glutamate/pharmacology ; Sucrose/pharmacology ; Taste Perception/drug effects/*physiology ; }, abstract = {The primary taste of dried bonito dashi is thought to be umami, elicited by inosine 5'-monphosphate (IMP) and L-amino acids. The present study compared the taste qualities of 25% dashi with 5 basic tastes and amino acids using conditioned taste aversion methods. Although wild-type C57BL/6J mice with compromised olfactory systems generalized an aversion of dashi to all 5 basic tastes, generalization was greater to sucrose (sweet), citric acid (sour), and quinine (bitter) than to NaCl (salty) or monosodium L-glutamate (umami) with amiloride. At neutral pH (6.5-6.9), the aversion generalized to l-histidine, L-alanine, L-proline, glycine, L-aspartic acid, L-serine, and monosodium L-glutamate, all mixed with IMP. Lowering pH of the test solutions to 5.7-5.8 (matching dashi) with HCl decreased generalization to some amino acids. However, adding lactic acid to test solutions with the same pH increased generalization to 5'-inosine monophosphate, L-leucine, L-phenylalanine, L-valine, L-arginine, and taurine but eliminated generalization to L-histidine. T1R1 knockout mice readily learned the aversion to dashi and generalized the aversion to sucrose, citric acid, and quinine but not to NaCl, glutamate, or any amino acid. These results suggest that dashi elicits a complex taste in mice that is more than umami, and deleting T1R1 receptor altered but did not eliminate their ability to taste dashi. In addition, lactic acid may alter or modulate taste transduction or cell-to-cell signaling.}, } @article {pmid25592442, year = {2015}, author = {Huang, AC and Wang, S and Wu, JJ and Wang, CC}, title = {Footshock facilitates methamphetamine-induced conditioned suppression through HPA axis, not dopamine.}, journal = {Physiology & behavior}, volume = {141}, number = {}, pages = {78-84}, doi = {10.1016/j.physbeh.2015.01.013}, pmid = {25592442}, issn = {1873-507X}, mesh = {Animals ; Conditioning, Classical/*drug effects/physiology ; Corticosterone/blood ; Dexamethasone/pharmacology ; Dopamine/*metabolism ; Dopamine Antagonists/pharmacology ; Dopamine Uptake Inhibitors/*pharmacology ; Electroshock ; Female ; Glucocorticoids/pharmacology ; Haloperidol/pharmacology ; Hypothalamo-Hypophyseal System/*drug effects/metabolism ; Methamphetamine/*pharmacology ; Pituitary-Adrenal System/*drug effects/metabolism ; Rats ; Rats, Wistar ; }, abstract = {The present study examined whether footshock can enhance methamphetamine (MAMPH)-induced conditioned suppression and whether this effect involves the dopamine (DA) reward system or hypothalamic-pituitary-adrenal (HPA) axis. We also examined whether the footshock-induced enhancements of MAMPH-induced conditioned suppression are attributable to MAMPH's rewarding or aversive properties. During the footshock phase, all female rats received 0.1mg/kg haloperidol (HAL) and its vehicle (2% tartaric acid solution), or low and high doses of dexamethasone (DEX; 0.5 and 1.0mg/kg) and its vehicle before each footshock (1mA, 2s), or no footshock, in seven trials once per day. The control group did not receive any drugs or footshocks. All of the rats were then allowed 15min access to a 0.1% saccharin solution and then received 2mg/kg MAMPH in five trials once per day. Footshock exhibited an increase in MAMPH-induced taste suppression. The low- and high-dose DEX groups but not the HAL group exhibited a blocking effect of the footshock enhancements of MAMPH-induced taste suppression. The low- and high-dose DEX groups exhibited a significant decrease in corticosterone levels during the footshock treatment phase but not during the testing phase. Altogether, the HPA stress system and not the DA reward system, particularly D2 receptors, appear to mediate the footshock-induced enhancements of MAMPH-induced conditioned taste suppression, which may result from the aversive and not the rewarding properties of MAMPH. The present findings may provide some clinical implications for alternating aversively classical conditioning for psychiatric disorders.}, } @article {pmid25557105, year = {2015}, author = {Seraydar, KR and Kaufman, PE}, title = {Does behaviour play a role in house fly resistance to imidacloprid-containing baits?.}, journal = {Medical and veterinary entomology}, volume = {29}, number = {1}, pages = {60-67}, doi = {10.1111/mve.12095}, pmid = {25557105}, issn = {1365-2915}, mesh = {Animals ; Biological Evolution ; Feeding Behavior/drug effects ; Female ; Houseflies/drug effects/genetics/*physiology ; Imidazoles/*pharmacology ; Insect Control/methods ; *Insecticide Resistance ; Insecticides/*pharmacology ; Male ; Neonicotinoids ; Nitro Compounds/*pharmacology ; Selection, Genetic/*drug effects ; }, abstract = {The objective of this research was to examine the role and type of behavioural mechanisms that function in house fly, Musca domestica L. (Diptera: Muscidae), resistance to an imidacloprid-containing commercial fly bait, QuickBayt(®) , using an insecticide-susceptible and an imidacloprid-resistant strain. Mortality and feeding behaviour were observed through choice bioassays of three post-imidacloprid selected house fly generations to determine whether flies would consume the bait in the presence of an alternative food source. Mortality rates in choice containers progressively decreased in post-selection flies as QuickBayt(®) no-choice selections proceeded. There were no differences between the proportions of flies observed contacting QuickBayt(®) and sugar, respectively, a finding that eliminates repellency as a mechanism of stimulus-dependent behavioural resistance. However, differences in QuickBayt(®) consumption and subsequent mortality between choice and no-choice containers provided strong support for the evolution of consumption irritancy- or taste aversion-related behavioural resistance. The results of this study support the responsible rotation of insecticide bait formulations for house fly control.}, } @article {pmid25548209, year = {2015}, author = {Manuelian, CL and Albanell, E and Rovai, M and Caja, G and Guitart, R}, title = {Kinetics of lithium as a lithium chloride dose suitable for conditioned taste aversion in lactating goats and dry sheep.}, journal = {Journal of animal science}, volume = {93}, number = {2}, pages = {562-569}, doi = {10.2527/jas.2014-8223}, pmid = {25548209}, issn = {1525-3163}, mesh = {Animals ; Cattle ; Feces/chemistry ; Female ; Food Preferences/*drug effects ; Goats ; Kinetics ; Lactation/metabolism ; Lithium/blood/metabolism/urine ; Lithium Chloride/administration & dosage/*pharmacokinetics/pharmacology ; Milk/chemistry ; Ruminants/*metabolism ; Sheep, Domestic ; Spectrophotometry, Atomic ; Taste/*drug effects ; Time Factors ; }, abstract = {Lithium chloride (LiCl) is widely used for inducing conditioned taste aversion (CTA) so that livestock will reduce or avoid ingestion of toxic plants and graze groundcover mingled with valuable crops. However, pharmacokinetic studies of LiCl at effective CTA doses are lacking. With this aim, 6 Murciano-Grandina dairy does during late lactation and 6 dry Manchega dairy ewes were orally dosed with 200 and 225 mg LiCl/kg BW, respectively. Does were placed in metabolism cages whereas ewes were group fed in pens. Lithium was measured over 168 (does) and 192 h (ewes) at predefined intervals in plasma, urine, feces, and milk using flame atomic absorption spectroscopy. Plasma Li concentrations reached a maximum at 4 h in does (13.4 ± 1.35 mg Li/L) and 12 h in ewes (17.7 ± 0.8 mg Li/L). The calculated plasma half-lives were 40.3 ± 3.8 and 30.9 ± 2.1 h for does and ewes, respectively. In goats, all Li administered was recovered at 96 h (92 ± 4% in urine, 6.5 ± 1.3% in feces, and 2.8 ± 0.4% in milk); however, the estimated clearance time in feces was 11 and 9 d for does and ewes, respectively. Additionally, maximum Li excretion in doe milk was 15.6 ± 0.5 mg/L, which was approximately half of the calculated effective dose for a 5-kg BW sucking kid. In conclusion, Li kinetics in goats and sheep were similar to cattle and elimination took longer than in monogastric species. The low concentration of Li in feces, urine, and milk, as well as the complete elimination of Li from the body after 1.5 wk allows us to conclude that LiCl is safe and suitable for inducing CTA in ruminants.}, } @article {pmid25546096, year = {2014}, author = {Boakes, RA and Costa, DS}, title = {Temporal contiguity in associative learning: Interference and decay from an historical perspective.}, journal = {Journal of experimental psychology. Animal learning and cognition}, volume = {40}, number = {4}, pages = {381-400}, doi = {10.1037/xan0000040}, pmid = {25546096}, issn = {2329-8464}, mesh = {Animals ; *Association Learning ; Behavior, Animal/*physiology ; Humans ; *Reinforcement, Psychology ; *Time ; }, abstract = {The greater the separation in time between 2 events, A followed by B, the less likely they are to become associated. The dominant explanation of this temporal contiguity effect has been trace decay: During the interval between A and B, the trace left by A becomes too weak by the time B occurs for an association to be formed between them. Pavlov adopted this idea in the context of classical conditioning and Hull used it to account for the deleterious effect of delaying reinforcement on the acquisition of instrumental responses. By 1960 various studies supported the conclusion that animals could not learn to associate 2 events separated by more than around 45 s. Research on human skill acquisition with delayed feedback and later studies using causal or predictive judgment tasks indicated that explicit cognitive processing is generally involved when humans associate events separated by more than a few seconds. The discovery of long-delay taste aversion learning prompted Revusky's (1971) alternative analysis of contiguity effects in terms of interference: The greater the separation between A and B, the more likely that extraneous events compete for association with A and B. Although the analysis of overshadowing provided by associative learning theories provides a context for this account, none of these theories provide a satisfactory account of evidence on temporal contiguity from a wide range of animal studies. Alternative timing theories are arguably also unsatisfactory.}, } @article {pmid25540931, year = {2015}, author = {Grigson, PS and Colechio, EM and Power, ML and Schulkin, J and Norgren, R}, title = {Parabrachial lesions in rats disrupt sodium appetite induced by furosemide but not by calcium deprivation.}, journal = {Physiology & behavior}, volume = {140}, number = {}, pages = {172-179}, pmid = {25540931}, issn = {1873-507X}, support = {R01 DC000240/DC/NIDCD NIH HHS/United States ; DC05435/DC/NIDCD NIH HHS/United States ; R01 DC005435/DC/NIDCD NIH HHS/United States ; DC00240/DC/NIDCD NIH HHS/United States ; R01 DA012473/DA/NIDA NIH HHS/United States ; DA012473/DA/NIDA NIH HHS/United States ; R37 DA009815/DA/NIDA NIH HHS/United States ; DA009815/DA/NIDA NIH HHS/United States ; R01 DA009815/DA/NIDA NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Appetite/*drug effects ; Calcium/*deficiency ; Calcium Chloride/administration & dosage ; Conditioning, Psychological/drug effects ; Desoxycorticosterone Acetate/pharmacology ; Disease Models, Animal ; Diuretics/*pharmacology ; Excitatory Amino Acid Agonists/toxicity ; Furosemide/*pharmacology ; Ibotenic Acid/toxicity ; Parabrachial Nucleus/*injuries/physiology ; Polyethylene Glycols ; Rats ; Rats, Sprague-Dawley ; Sodium Chloride/*administration & dosage ; }, abstract = {An appetite for CaCl2 and NaCl occurs in young rats after they are fed a diet lacking Ca or Na, respectively. Bilateral lesions of the parabrachial nuclei (PBN) disrupt normal taste aversion learning and essentially eliminate the expression of sodium appetite. Here we tested whether similar lesions of the PBN would disrupt the calcium-deprivation-induced appetite for CaCl2 or NaCl. Controls and rats with PBN lesions failed to exhibit a calcium-deprivation-induced appetite for CaCl2. Nevertheless, both groups did exhibit a significant calcium-deprivation-induced appetite for 0.5M NaCl. Thus, while damage to the second central gustatory relay in the PBN disrupts the appetite for 0.5M NaCl induced by furosemide, deoxycorticosterone acetate, and polyethylene glycol, the sodium appetite induced by dietary CaCl2 depletion remains intact.}, } @article {pmid25524986, year = {2015}, author = {Ito, E and Yamagishi, M and Takigami, S and Sakakibara, M and Fujito, Y and Lukowiak, K}, title = {The Yerkes-Dodson law and appropriate stimuli for conditioned taste aversion in Lymnaea.}, journal = {The Journal of experimental biology}, volume = {218}, number = {Pt 3}, pages = {336-339}, doi = {10.1242/jeb.113266}, pmid = {25524986}, issn = {1477-9145}, mesh = {Animals ; Avoidance Learning ; Conditioning, Classical ; Electric Stimulation ; Lymnaea/*physiology ; Memory/physiology ; Sucrose ; Taste ; }, abstract = {The pond snail Lymnaea stagnalis can learn conditioned taste aversion and then consolidate it into long-term memory (LTM). A high-voltage electric shock was used as the unconditioned stimulus, where we have previously used KCl. We varied the strength of both the conditioned and unconditioned stimuli to determine whether the so-called Yerkes-Dodson law prevailed. This is an empirical relationship between the state of arousal and LTM formation, showing that there is an optimal level of arousal leading to memory formation. However, too little or too much arousal results in poorer LTM. We found here that the most appropriate stimuli to use in taste aversion training in Lymnaea were a 10 mmol l(-1) sucrose solution as the conditioned stimulus and a 3 s electric shock as the unconditioned stimulus.}, } @article {pmid25506318, year = {2014}, author = {Gonzalez, MC and Kramar, CP and Tomaiuolo, M and Katche, C and Weisstaub, N and Cammarota, M and Medina, JH}, title = {Medial prefrontal cortex dopamine controls the persistent storage of aversive memories.}, journal = {Frontiers in behavioral neuroscience}, volume = {8}, number = {}, pages = {408}, pmid = {25506318}, issn = {1662-5153}, abstract = {Medial prefrontal cortex (mPFC) is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-term aversive memories requires dopamine D1/D5 receptors activation in mPFC immediately after training and, depending on the task, between 6 and 12 h later. Our results indicate that besides its well-known participation in retrieval and early consolidation, mPFC also modulates the endurance of long-lasting aversive memories regardless of whether formation of the aversive mnemonic trace requires the participation of the hippocampus.}, } @article {pmid25489006, year = {2015}, author = {Ancel, D and Bernard, A and Subramaniam, S and Hirasawa, A and Tsujimoto, G and Hashimoto, T and Passilly-Degrace, P and Khan, NA and Besnard, P}, title = {The oral lipid sensor GPR120 is not indispensable for the orosensory detection of dietary lipids in mice.}, journal = {Journal of lipid research}, volume = {56}, number = {2}, pages = {369-378}, pmid = {25489006}, issn = {1539-7262}, mesh = {Animals ; Calcium/metabolism ; Dietary Fats/*metabolism ; Food Preferences/drug effects/physiology ; Immunohistochemistry ; Male ; Mice ; Receptors, G-Protein-Coupled/agonists/*metabolism ; Taste Buds/cytology/drug effects/*metabolism ; }, abstract = {Implication of the long-chain fatty acid (LCFA) receptor GPR120, also termed free fatty acid receptor 4, in the taste-guided preference for lipids is a matter of debate. To further unravel the role of GPR120 in the "taste of fat", the present study was conducted on GPR120-null mice and their wild-type littermates. Using a combination of morphological [i.e., immunohistochemical staining of circumvallate papillae (CVP)], behavioral (i.e., two-bottle preference tests, licking tests and conditioned taste aversion) and functional studies [i.e., calcium imaging in freshly isolated taste bud cells (TBCs)], we show that absence of GPR120 in the oral cavity was not associated with changes in i) gross anatomy of CVP, ii) LCFA-mediated increases in intracellular calcium levels ([Ca(2+)]i), iii) preference for oily and LCFA solutions and iv) conditioned avoidance of LCFA solutions. In contrast, the rise in [Ca(2+)]i triggered by grifolic acid, a specific GPR120 agonist, was dramatically curtailed when the GPR120 gene was lacking. Taken together, these data demonstrate that activation of lingual GPR120 and preference for fat are not connected, suggesting that GPR120 expressed in TBCs is not absolutely required for oral fat detection in mice.}, } @article {pmid25454591, year = {2014}, author = {Sano, Y and Shobe, JL and Zhou, M and Huang, S and Shuman, T and Cai, DJ and Golshani, P and Kamata, M and Silva, AJ}, title = {CREB regulates memory allocation in the insular cortex.}, journal = {Current biology : CB}, volume = {24}, number = {23}, pages = {2833-2837}, pmid = {25454591}, issn = {1879-0445}, support = {R01 AG013622/AG/NIA NIH HHS/United States ; R37 AG013622/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/physiology ; Cerebral Cortex/*physiology ; Conditioning, Classical/physiology ; Cyclic AMP Response Element-Binding Protein/*physiology ; Gene Silencing ; Humans ; In Situ Hybridization, Fluorescence ; Lithium Chloride/pharmacology ; Memory/*physiology ; Mice, Inbred C57BL ; Neurons/physiology ; Taste ; }, abstract = {The molecular and cellular mechanisms of memory storage have attracted a great deal of attention. By comparison, little is known about memory allocation, the process that determines which specific neurons in a neural network will store a given memory. Previous studies demonstrated that memory allocation is not random in the amygdala; these studies showed that amygdala neurons with higher levels of the cyclic-AMP-response-element-binding protein (CREB) are more likely to be recruited into encoding and storing fear memory. To determine whether specific mechanisms also regulate memory allocation in other brain regions and whether CREB also has a role in this process, we studied insular cortical memory representations for conditioned taste aversion (CTA). In this task, an animal learns to associate a taste (conditioned stimulus [CS]) with the experience of malaise (such as that induced by LiCl; unconditioned stimulus [US]). The insular cortex is required for CTA memory formation and retrieval. CTA learning activates a subpopulation of neurons in this structure, and the insular cortex and the basolateral amygdala (BLA) interact during CTA formation. Here, we used a combination of approaches, including viral vector transfections of insular cortex, arc fluorescence in situ hybridization (FISH), and designer receptors exclusively activated by designer drugs (DREADD) system, to show that CREB levels determine which insular cortical neurons go on to encode a given conditioned taste memory.}, } @article {pmid25451308, year = {2014}, author = {Rodríguez-Serrano, LM and Ramírez-León, B and Rodríguez-Durán, LF and Escobar, ML}, title = {Acute infusion of brain-derived neurotrophic factor in the insular cortex promotes conditioned taste aversion extinction.}, journal = {Neurobiology of learning and memory}, volume = {116}, number = {}, pages = {139-144}, doi = {10.1016/j.nlm.2014.10.007}, pmid = {25451308}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*drug effects ; Brain-Derived Neurotrophic Factor/*pharmacology ; Cerebral Cortex/*drug effects ; Conditioning, Classical/*drug effects ; Extinction, Psychological/*drug effects ; Male ; Rats ; Rats, Wistar ; Taste/*drug effects ; }, abstract = {Brain-derived neurotrophic factor (BDNF) has emerged as one of the most potent molecular mediators not only for synaptic plasticity, but also for the behavioral organism-environment interactions. Our previous studies in the insular cortex (IC), a neocortical region that has been related with acquisition and retention of conditioned taste aversion (CTA), have demonstrated that intracortical microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the basolateral amygdaloid nucleus (Bla)-IC projection and enhances the retention of CTA memory of adult rats in vivo. The aim of the present study was to analyze whether acute BDNF-infusion in the IC modifies the extinction of CTA. Accordingly, animals were trained in the CTA task and received bilateral IC microinfusions of BDNF before extinction training. Our results showed that taste aversion was significantly reduced in BDNF rats from the first extinction trial. Additionally, we found that the effect of BDNF on taste aversion did not require extinction training. Finally we showed that the BDNF effect does not degrade the original taste aversion memory trace. These results emphasize that BDNF activity underlies memory extinction in neocortical areas and support the idea that BDNF is a key regulator and mediator of long-term synaptic modifications.}, } @article {pmid25451307, year = {2014}, author = {Mita, K and Yamagishi, M and Fujito, Y and Lukowiak, K and Ito, E}, title = {An increase in insulin is important for the acquisition conditioned taste aversion in Lymnaea.}, journal = {Neurobiology of learning and memory}, volume = {116}, number = {}, pages = {132-138}, doi = {10.1016/j.nlm.2014.10.006}, pmid = {25451307}, issn = {1095-9564}, support = {MOP 64339//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Conditioning, Classical/*drug effects/physiology ; Food Deprivation/physiology ; Glucose/analysis ; Hemolymph/chemistry ; Hypoglycemic Agents/*pharmacology ; Insulin/*pharmacology ; Lymnaea ; Motivation/drug effects/physiology ; Taste/*physiology ; }, abstract = {Conditioned taste aversion (CTA) in Lymnaea is brought about by pairing a sucrose solution (the conditioned stimulus, CS) with an electric shock (the unconditioned stimulus, US). Following repeated CS-US pairings, CTA occurs and it is consolidated into long-term memory (LTM). The best CTA is achieved, if snails are food-deprived for 1 day before training commences. With a longer period of food deprivation (5 days), learning and memory formation does not occur. It has been hypothesized that the levels of insulin in the central nervous system (CNS) are very important for CTA to occur. To test his hypothesis, we injected insulin directly into 5-day food-deprived snails. The injection of insulin, as expected, resulted in a decrease in hemolymph glucose concentration. Consistent with our hypothesis with insulin injection, learning and memory formation of CTA occurred. That is, the 'insulin spike' is more important than an increase in hemolymph glucose concentration for CTA-LTM. If we injected an insulin receptor antibody into the snails before the insulin injection, learning was formed but memory formation was not, which is consistent with our previous study. Therefore, a rise in the insulin concentration (i.e., insulin spike) in the CNS is considered to be a key determining factor in the process of CTA-LTM.}, } @article {pmid25447753, year = {2015}, author = {Tsuboi, H and Hirai, Y and Maezawa, H and Notani, K and Inoue, N and Funahashi, M}, title = {Effects of treadmill exercise on the LiCl-induced conditioned taste aversion in rats.}, journal = {Physiology & behavior}, volume = {138}, number = {}, pages = {1-5}, doi = {10.1016/j.physbeh.2014.10.015}, pmid = {25447753}, issn = {1873-507X}, mesh = {Animals ; Association Learning ; *Avoidance Learning ; *Conditioning, Classical ; Drinking Behavior ; Drinking Water ; *Extinction, Psychological ; Lithium Chloride/administration & dosage ; Male ; *Motor Activity ; Rats, Sprague-Dawley ; Saccharin/administration & dosage ; *Taste Perception ; Time Factors ; }, abstract = {Studies have shown that exercise can enhance learning and memory. Conditioned taste aversion (CTA) is an avoidance behavior induced by associative memory of the taste sensation for something pleasant or neutral with a negative visceral reaction caused by the coincident action of a toxic substance that is tasteless or administered systemically. We sought to measure the effects of treadmill exercise on CTA in rats by investigating the effects of exercise on acquisition, extinction and spontaneous recovery of CTA. We made two groups of rats: an exercise group that ran on a treadmill, and a control group that did not have structured exercise periods. To condition rats to disfavor a sweet taste, consumption of a 0.1% saccharin solution in place of drinking water was paired with 0.15M LiCl (2% body weight, i.p.) to induce visceral discomfort. We measured changes of saccharin consumption during acquisition and extinction of CTA. The exercise and no-exercise groups both acquired CTA to similar levels and showed maximum extinction of CTA around 6 days after acquisition. This result indicates that exercise affects neither acquisition nor extinction of CTA. However, in testing for preservation of CTA after much longer extinction periods that included exercise or not during the intervening period, exercising animals showed a significantly lower saccharin intake, irrespective of having exercised or not during the conditioning phase of the trial. This result suggests that exercise may help to preserve aversive memory (taste aversion in this example) as evidence by the significant spontaneous recovery of aversion in exercising animals.}, } @article {pmid25447516, year = {2015}, author = {Hishimura, Y}, title = {Interactions with conspecific attenuate conditioned taste aversions in mice.}, journal = {Behavioural processes}, volume = {111}, number = {}, pages = {34-36}, doi = {10.1016/j.beproc.2014.11.006}, pmid = {25447516}, issn = {1872-8308}, mesh = {Animals ; Avoidance Learning/*physiology ; Conditioning, Operant/*physiology ; Drinking ; *Interpersonal Relations ; Lithium Chloride/pharmacology ; Male ; Mice ; Mice, Inbred ICR ; Saccharin/pharmacology ; Stress, Psychological/psychology ; Sweetening Agents/pharmacology ; Taste/*physiology ; }, abstract = {Social animals both increase and decrease their stress levels by interacting with conspecifics. The present study examines the effect of interaction with a conspecific on conditioned taste aversion in 32 male mice. Subjects were injected with lithium chloride immediately after drinking saccharin solution for 30 min. They were then exposed to a male conspecific for 3h following the poisoning. In the subsequent three consecutive days of two-bottle tests involving a choice between saccharin solution and water, they showed attenuated conditioned taste aversion compared with controls exposed to no conspecific after poisoning. These results confirm social interaction with a conspecific reduces conditioned taste aversion in mice. The implications of these findings are discussed with regard to social buffering effect and stress-induced analgesia.}, } @article {pmid25447298, year = {2015}, author = {Feifel, D and Shilling, PD and Hillman, J and Maisel, M and Winfield, J and Melendez, G}, title = {Peripherally administered oxytocin modulates latent inhibition in a manner consistent with antipsychotic drugs.}, journal = {Behavioural brain research}, volume = {278}, number = {}, pages = {424-428}, pmid = {25447298}, issn = {1872-7549}, support = {R01 MH080910/MH/NIMH NIH HHS/United States ; R01 MH103421/MH/NIMH NIH HHS/United States ; R01MH080910/MH/NIMH NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Antipsychotic Agents/*administration & dosage ; Avoidance Learning/*drug effects ; Conditioning, Classical/drug effects ; Dose-Response Relationship, Drug ; Drug Administration Routes ; Food Deprivation ; *Inhibition, Psychological ; Lithium Chloride/pharmacology ; Oxytocin/*administration & dosage ; Rats ; Reflex, Startle/*drug effects ; }, abstract = {BACKGROUND: Peripherally administered oxytocin (OT) has produced antipsychotic drug (APD)-like effects in animal tests that are predictive of APD efficacy. However, these effects have mainly been demonstrated using animal models of schizophrenia-like deficits in prepulse inhibition (PPI) of the startle reflex. Another schizophrenia-relevant abnormality that is the basis of a predictive animal test for APD efficacy is deficient latent inhibition (LI). LI is the normal suppression of a classically conditioned response when the subject is pre-exposed to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (UCS). Conditioned taste aversion (CTA), the normal avoidance of ingesting a food or liquid by animals when its taste is associated with an aversive experience, was used to test whether OT facilitates LI consistent with APDs.

METHODS: Brown Norway rats, known to naturally display attenuated LI, were aversively conditioned on two consecutive exposures to flavored drinking water (0.1% saccharin) by pairing it with malaise-inducing lithium chloride injections. Concurrent with conditioning, rats received subcutaneous OT (0.02, 0.1, 0.5mg/kg) or saline. Some rats were pre-exposed to the flavored water prior to its aversive conditioning (pre-exposed) while others were not (non pre-exposed). Two days after aversive conditioning the amount of flavored water consumed during a 20-min session was recorded.

RESULTS: As expected, LI, defined as greater consumption by pre-exposed vs. non pre-exposed rats was only weakly exhibited in Brown Norway rats and OT enhanced LI by reducing CTA in pre-exposed rats in a dose-dependent manner, with the 0.02 mg/kg dose producing the strongest effect.

CONCLUSIONS: The facilitation of LI by OT is consistent with the effects produced by APDs and provides further support for the notion that OT has therapeutic potential for schizophrenia.}, } @article {pmid25416606, year = {2015}, author = {Arriola, N and Alonso, G and Vázquez, GA and Rodríguez, G}, title = {Pavlovian discrimination in rats using voluntary exposure to a lithium chloride procedure.}, journal = {Laboratory animals}, volume = {49}, number = {3}, pages = {201-208}, doi = {10.1177/0023677214558702}, pmid = {25416606}, issn = {1758-1117}, mesh = {Animals ; *Conditioning, Classical ; Drinking/drug effects ; Lithium Chloride/*pharmacology ; Male ; Random Allocation ; Rats/*physiology ; Rats, Sprague-Dawley ; Sucrose/*pharmacology ; *Taste ; }, abstract = {In a conditioned taste aversion (CTA) procedure, the consumption of a flavor is followed by the administration of a toxin (e.g. lithium chloride, LiCl), resulting in the future avoidance of the flavor. CTA studies typically make use of forced-exposure paradigms where a volume of the toxin dependent upon the weight of the animal is injected. The use of forced paradigms can be problematic when extended training is required, such as in stimulus discrimination training involving similar flavors, since the animals can be exposed to a high amount of the toxin. In the present study we confirmed the viability of an alternative voluntary-exposure paradigm that more closely mimics natural conditions and is more considerate of the welfare of the animals as a useful tool for investigating discrimination training. In three experiments, rats received free access to either a flavor (sucrose in Experiments 1a and 1b, and saccharin in Experiment 2) or a compound of the flavor mixed with LiCl. The presence of LiCl in the compound induced post-consumption illness. Rats acquired an aversion to the flavor + LiCl compound, thus reducing both their consumption of, and exposure to, LiCl, and gradually increased their consumption of the flavor alone. The present paradigm is more similar to natural conditions than the forced-exposure paradigm as it allows the animals to experience a direct relationship between the amount of the flavor consumed and the magnitude of the illness induced by the toxin.}, } @article {pmid25367561, year = {2015}, author = {Gaztañaga, M and Aranda-Fernández, PE and Díaz-Cenzano, E and Chotro, MG}, title = {Latent inhibition and facilitation of conditioned taste aversion in preweanling rats.}, journal = {Developmental psychobiology}, volume = {57}, number = {1}, pages = {96-104}, doi = {10.1002/dev.21263}, pmid = {25367561}, issn = {1098-2302}, mesh = {Animals ; Animals, Newborn ; *Avoidance Learning ; *Conditioning, Psychological ; Female ; *Inhibition, Psychological ; Male ; Rats ; Rats, Wistar ; Taste ; }, abstract = {Early in ontogeny, taste preexposure has been found to induce latent inhibition as well as produce a facilitation of conditioned taste aversion (CTA). In this study, the effect of taste preexposure on CTA was investigated in 13-14 day old rats as a function of taste preexposure (0, 1, or 3 trials) and unconditioned stimulus intensity (LiCl: 0, 0.15, or 0.30 M). After one conditioning trial, with the low intensity US, an aversion was only observed after taste preexposure (facilitation). When using the strong US, an aversion was found without preexposure while latent inhibition was observed with 3 preexposure trials. In conclusion, stimulus preexposure can either facilitate conditioning or produce latent inhibition in infant rats, depending on the amount of stimulus preexposure and the intensity of the US.}, } @article {pmid25355215, year = {2014}, author = {Ounallah-Saad, H and Sharma, V and Edry, E and Rosenblum, K}, title = {Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {34}, number = {44}, pages = {14624-14632}, pmid = {25355215}, issn = {1529-2401}, mesh = {Adenine/analogs & derivatives/pharmacology ; Animals ; Avoidance Learning/drug effects/physiology ; Cerebral Cortex/drug effects/*physiology ; Eukaryotic Initiation Factor-2/metabolism ; Indoles/pharmacology ; Learning/drug effects/*physiology ; Mice ; Phosphorylation ; RNA, Small Interfering ; Rats ; Taste/drug effects/*physiology ; eIF-2 Kinase/antagonists & inhibitors/genetics/*metabolism ; }, abstract = {Protein translation initiation is controlled by levels of eIF2α phosphorylation (p-eIF2α) on Ser51. In addition, increased p-eIF2α levels impair long-term synaptic plasticity and memory consolidation, whereas decreased levels enhance them. Levels of p-eIF2α are determined by four kinases, of which protein kinase RNA-activated (PKR), PKR-like endoplastic reticulum kinase (PERK), and general control nonderepressible 2 are extensively expressed in the mammalian mature brain. Following identification of PERK as the major kinase to determine basal levels of p-eIF2α in primary neuronal cultures, we tested its function as a physiological constraint of memory consolidation in the cortex, the brain structure suggested to store, at least in part, long-term memories in the mammalian brain. To that aim, insular cortex (IC)-dependent positive and negative forms of taste learning were used. Genetic reduction of PERK expression was accomplished by local microinfusion of a lentivirus harboring PERK Short hairpin RNA, and pharmacological inhibition was achieved by local microinfusion of a PERK-specific inhibitor (GSK2606414) to the rat IC. Both genetic reduction of PERK expression and pharmacological inhibition of its activity reduced p-eIF2α levels and enhanced novel taste learning and conditioned taste aversion, but not memory retrieval. Moreover, enhanced extinction was observed together with enhanced associative memory, suggesting increased cortical-dependent behavioral plasticity. The results suggest that, by phosphorylating eIF2α, PERK functions in the cortex as a physiological constraint of memory consolidation, and its downregulation serves as cognitive enhancement.}, } @article {pmid25324744, year = {2014}, author = {Joels, G and Lamprecht, R}, title = {Fear memory formation can affect a different memory: fear conditioning affects the extinction, but not retrieval, of conditioned taste aversion (CTA) memory.}, journal = {Frontiers in behavioral neuroscience}, volume = {8}, number = {}, pages = {324}, pmid = {25324744}, issn = {1662-5153}, abstract = {The formation of fear memory to a specific stimulus leads to subsequent fearful response to that stimulus. However, it is not apparent whether the formation of fear memory can affect other memories. We study whether specific fearful experience leading to fear memory affects different memories formation and extinction. We revealed that cued fear conditioning, but not unpaired or naïve training, inhibited the extinction of conditioned taste aversion (CTA) memory that was formed after fear conditioning training in rats. Fear conditioning had no effect on retrieval of CTA memory but specifically impaired its extinction. Extinguished fear memory, after fear extinction training, had no effect on future CTA memory extinction. Fear conditioning had no effect on CTA memory extinction if CTA memory was formed before fear conditioning. Conditioned taste aversion had no effect on fear conditioning memory extinction. We conclude that active cued fear conditioning memory can affect specifically the extinction, but not the formation, of future different memory.}, } @article {pmid25300672, year = {2014}, author = {Parkes, SL and De la Cruz, V and Bermúdez-Rattoni, F and Coutureau, E and Ferreira, G}, title = {Differential role of insular cortex muscarinic and NMDA receptors in one-trial appetitive taste learning.}, journal = {Neurobiology of learning and memory}, volume = {116}, number = {}, pages = {112-116}, doi = {10.1016/j.nlm.2014.09.008}, pmid = {25300672}, issn = {1095-9564}, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Cerebral Cortex/*drug effects/metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Male ; Muscarinic Antagonists/pharmacology ; Rats ; Rats, Wistar ; Receptors, Muscarinic/*metabolism ; Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors ; Saccharin/pharmacology ; Scopolamine/pharmacology ; Taste/*physiology ; Valine/analogs & derivatives/pharmacology ; }, abstract = {Our current understanding of the neurobiology of taste learning and memory has been greatly facilitated by the use of a reliable behavioural model, conditioned taste aversion (CTA). This model has revealed that the insular cortex (IC), specifically muscarinic and N-methyl-d-aspartate (NMDA) receptor activation in the IC, is critical for the formation of aversive taste memories. In contrast, current models of appetitive taste learning are less adequate, relying on the use of neophobic tastes (attenuation of neophobia) or on the integration of appetitive and aversive taste memories (latent inhibition of CTA). While these models have implicated IC muscarinic receptors, the involvement of NMDA receptors in the IC remains unclear. Here, we examined the role of both muscarinic and NMDA receptors in appetitive taste learning using a simple paradigm that is independent of neophobic and aversive components. First, we demonstrated that a single exposure to a novel taste, saccharin 0.1%, is sufficient to promote an appetitive taste memory as revealed by an increase in saccharin consumption during the second presentation. This increase was blocked by bilateral infusion in the IC of the muscarinic receptor antagonist, scopolamine. In contrast, infusion of the NMDA receptor antagonist, AP5, did not block appetitive taste learning but did abolish CTA. Therefore, common and distinct molecular substrates within the IC mediate appetitive versus aversive learning about the same taste.}, } @article {pmid25289087, year = {2014}, author = {Shi, J}, title = {Evaluating the various phases of cisplatin-induced emesis in rats.}, journal = {Oncology letters}, volume = {8}, number = {5}, pages = {2017-2022}, pmid = {25289087}, issn = {1792-1074}, abstract = {Use of cisplatin as a chemotherapeutic agent causes acute and delayed emesis. Kaolin, saccharin solution and normal feed consumption have been evaluated as an index of cisplatin-induced emesis in rats; however, the most preferable of these methods for evaluating the various phases of emesis remains unclear. In the current study, kaolin, saccharin solution and normal feed consumption following cisplatin administration (6 mg/kg intraperitoneally) were simultaneously investigated in rats. Kaolin consumption increased significantly following cisplatin administration and was attenuated by granisetron administration 0-24 h following the injection. Saccharin solution consumption, however, decreased significantly 0-48 h following cisplatin administration, however, was attenuated by administration of granisetron within 0-24 h only. A reduced intake of normal feed was observed in the control group and was reversed by granisetron within the 0-72 h period. The present study indicates that kaolin consumption may be evaluated as an index of cisplatin-induced acute emesis and saccharin solution consumption may be evaluated as an index of delayed emesis, while normal feed consumption as an indicator of anorexia nervosa may be suitable to evaluate all phases of emesis and serve as an indicator of quality of life.}, } @article {pmid25282171, year = {2014}, author = {Ouhaz, Z and Ba-M'hamed, S and Bennis, M}, title = {Haloperidol treatment at pre-exposure phase reduces the disturbance of latent inhibition in rats with neonatal ventral hippocampus lesions.}, journal = {Comptes rendus biologies}, volume = {337}, number = {10}, pages = {561-570}, doi = {10.1016/j.crvi.2014.07.005}, pmid = {25282171}, issn = {1768-3238}, mesh = {Animals ; *Animals, Newborn ; Antipsychotic Agents ; Behavior, Animal ; Conditioning, Psychological ; Disease Models, Animal ; Haloperidol/*administration & dosage ; Hippocampus/*drug effects/*growth & development ; Lidocaine/administration & dosage ; Motor Activity ; Rats ; Rats, Sprague-Dawley ; Schizophrenia/*chemically induced/prevention & control ; Schizotypal Personality Disorder/prevention & control ; Taste ; }, abstract = {Animals with neonatal ventral hippocampal lesions develop during or after adolescence abnormal behaviors related to schizophrenia such as anxiety and latent inhibition disruption. The aim of this study was to test whether haloperidol injection prior to pre-exposure session in the latent inhibition test would facilitate latent inhibition. Lesioned animals showed a significant decrease in the number and duration of social interactions, a decrease in the marbles buried, a significant increase in locomotor activity, and a disruption of latent inhibition. In the conditioned taste aversion test, injection of haloperidol produced the recovery of latent inhibition. These findings demonstrate that neonatal lidocaine lesion of the ventral hippocampus can induce behavioral changes related to schizophrenia, and injection of haloperidol, when restricted only to a three-day pre-exposure, is sufficient to facilitate latent inhibition.}, } @article {pmid25269859, year = {2015}, author = {Molero-Chamizo, A}, title = {Excitotoxic lesion of the posterior part of the dorsal striatum does not affect the typically dopaminergic phenomenon of latent inhibition in conditioned taste aversion.}, journal = {Neuroscience research}, volume = {91}, number = {}, pages = {8-12}, doi = {10.1016/j.neures.2014.09.006}, pmid = {25269859}, issn = {1872-8111}, mesh = {Animals ; *Avoidance Learning ; Behavior, Animal ; Conditioning, Psychological ; Corpus Striatum/*physiology ; Dopamine/*physiology ; Feeding Behavior ; *Inhibition, Psychological ; Male ; Rats, Wistar ; *Taste ; }, abstract = {The stimulation or blockade of dopaminergic activity interrupts or increases, respectively, the phenomenon of latent inhibition in different paradigms. Furthermore, the involvement of the nucleus accumbens in latent inhibition has been demonstrated in several learning paradigms, including conditioned taste aversion. However, the role of the dorsal striatum in the pre-exposure effect on the acquisition of taste aversion remains unclear. In order to determine whether this region of the striatum is a structure necessary for latent inhibition of conditioned taste aversion, excitotoxic lesions were made in the posterior part of the dorsal striatum of Wistar rats. Subsequently, half of the animals was pre-exposed to the flavor, and the magnitude of the taste aversion was compared to that of sham animals pre-exposed and non-pre-exposed to the same flavor. The results showed that the excitotoxic lesion in this area of the dorsal striatum, compared to sham animals, left latent inhibition of the conditioned taste aversion intact. These data suggest that the posterior part of the dorsal striatum is not necessary for the acquisition of latent inhibition, at least in the conditioned taste aversion paradigm.}, } @article {pmid25251840, year = {2015}, author = {García-Medina, NE and Vera, G and Miranda, MI}, title = {Chemical stimulation or glutamate injections in the nucleus of solitary tract enhance conditioned taste aversion.}, journal = {Behavioural brain research}, volume = {278}, number = {}, pages = {202-209}, doi = {10.1016/j.bbr.2014.09.023}, pmid = {25251840}, issn = {1872-7549}, mesh = {Animals ; Basolateral Nuclear Complex/*drug effects/*metabolism ; Conditioning, Classical/drug effects ; Glutamic Acid/metabolism ; Injections, Intraperitoneal ; Lithium Chloride/administration & dosage/pharmacology ; Male ; Memory/*drug effects ; Microdialysis ; Norepinephrine/metabolism ; Rats ; Rats, Sprague-Dawley ; Solitary Nucleus/drug effects/*metabolism ; Stimulation, Chemical ; Taste/*drug effects ; }, abstract = {Taste memory depends on motivational and post-ingestional consequences after a single taste-illness pairing. During conditioned taste aversion (CTA), the taste and visceral pathways reach the nucleus of the solitary tract (NTS), which is the first relay in the CNS and has a vital function in receiving vagal chemical stimuli and humoral signals from the area postrema that receives peripheral inputs also via vagal afferent fibers. The specific aim of the present set of experiments was to determine if the NTS is involved in the noradrenergic and glutamatergic activation of the basolateral amygdala (BLA) during CTA. Using in vivo microdialysis, we examined whether chemical NTS stimulation induces norepinephrine (NE) and/or glutamate changes in the BLA during visceral stimulation with intraperitoneal (i.p.) injections of low (0.08 M) and high (0.3 M) concentrations of lithium chloride (LiCl) during CTA training. The results showed that strength of CTA can be elicited by chemical NTS stimulation (Ringer's high potassium solution; 110 mM KCl) and by intra-NTS microinjections of glutamate, immediately after, but not before, low LiCl i.p. injections that only induce a week aversive memory. However visceral stimulation (with low or high i.p. LiCl) did not induce significantly more NE release in the amygdala compared with the NE increment induced by NTS potassium depolarization. In contrast, high i.p. concentrations of LiCl and chemical NTS stimulation induced a modest glutamate sustained release, that it is not observed with low LiCl i.p. injections. These results indicate that the NTS mainly mediates the visceral stimulus processing by sustained releasing glutamate in the BLA, but not by directly modulating NE release in the BLA during CTA acquisition, providing new evidence that the NTS has an important function in the transmission of signals from the periphery to brain systems that process aversive memory formation.}, } @article {pmid25241211, year = {2014}, author = {Quintero, E and Vargas, JP and Diaz, E and Escarabajal, MD and Carrasco, M and López, JC}, title = {c-Fos positive nucleus reveals that contextual specificity of latent inhibition is dependent of insular cortex.}, journal = {Brain research bulletin}, volume = {108}, number = {}, pages = {74-79}, doi = {10.1016/j.brainresbull.2014.08.008}, pmid = {25241211}, issn = {1873-2747}, mesh = {Animals ; Avoidance Learning/*physiology ; Cerebral Cortex/metabolism/*physiology ; Conditioning, Psychological ; *Inhibition, Psychological ; Male ; Proto-Oncogene Proteins c-fos/*metabolism ; Rats, Wistar ; Taste Perception/*physiology ; }, abstract = {The present study analyzed the functional activity of granular and agranular insular cortices in contextual specificity of latent inhibition using a conditioned taste aversion paradigm. c-Fos immunolabeling was examined in insular cortex in preexposed and no preexposed groups under similar and different context conditions. Result showed that the exposition to a novel taste increased c-fos activity in insular cortex. However, a context shift caused an increase in immunolabeling in animals preexposed to saccharine. These results suggest insular cortex is part of a complex system to evaluate taste-response, and it may read the meaning of taste stimuli depending on the context.}, } @article {pmid25232100, year = {2014}, author = {Kimbrough, A and Biggs, LM}, title = {BDNF signaling potentiates transmission of information from the basolateral amygdala to infralimbic prefrontal cortex during conditioned taste aversion extinction.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {34}, number = {38}, pages = {12617-12618}, pmid = {25232100}, issn = {1529-2401}, support = {T32 DC000044/DC/NIDCD NIH HHS/United States ; T32-00044//PHS HHS/United States ; }, mesh = {Amygdala/*physiology ; Animals ; Avoidance Learning/*physiology ; Brain-Derived Neurotrophic Factor/*metabolism ; Extinction, Psychological/*physiology ; Humans ; Male ; Prefrontal Cortex/*physiology ; Signal Transduction/*physiology ; Taste/*physiology ; }, } @article {pmid25231850, year = {2014}, author = {Hurtado, MM and García, R and Puerto, A}, title = {Tiapride impairs the aversive effect of electrical stimulation of the parabrachial complex in a conditioned place task.}, journal = {Acta neurobiologiae experimentalis}, volume = {74}, number = {3}, pages = {307-316}, pmid = {25231850}, issn = {1689-0035}, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Behavior, Animal/drug effects ; Brain/*drug effects/pathology ; Conditioning, Psychological/*physiology ; Dopamine/metabolism ; *Electric Stimulation ; Male ; Rats, Wistar ; Reward ; Tiapride Hydrochloride/administration & dosage/*pharmacology ; }, abstract = {The parabrachial complex has been related to various rewarding or aversive behavioral processes, including taste aversion learning and conditioned place aversion. This study examined the effect of tiapride, an antagonist of D2/D3 dopaminergic receptors, on place aversion induced by electrical stimulation of the external lateral parabrachial (LPBe) nucleus. Results obtained show that brain-stimulated animals avoid the area of the maze associated with electrical stimulation but show no such behavioral rejection when they receive an injection of 30 mg/kg tiapride. Furthermore, tiapride did not appear to affect the horizontal motor activity (crossing) of the animals. These results are discussed in the context of the different natural and artificial modalities used to induce aversive behavior and their relationship with dopamine systems.}, } @article {pmid25223979, year = {2014}, author = {Risco, S and Mediavilla, C}, title = {Orexin-1 receptor antagonist in central nucleus of the amygdala attenuates the acquisition of flavor-taste preference in rats.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {126}, number = {}, pages = {7-12}, doi = {10.1016/j.pbb.2014.09.002}, pmid = {25223979}, issn = {1873-5177}, mesh = {Animals ; Avoidance Learning/drug effects/physiology ; Benzoxazoles/administration & dosage/*pharmacology ; Central Amygdaloid Nucleus/*drug effects/physiology ; Food Preferences/*drug effects/physiology ; Lithium Chloride/pharmacology ; Male ; Microinjections ; Naphthyridines ; *Orexin Receptor Antagonists ; Orexin Receptors/physiology ; Rats ; Saccharin/pharmacology ; Taste Perception/*drug effects ; Urea/administration & dosage/*analogs & derivatives/pharmacology ; }, abstract = {Previous studies demonstrated that the intracerebroventricular administration of SB-334867-A, a selective antagonist of orexin OX1R receptors, blocks the acquisition of saccharin-induced conditioned flavor preference (CFP) but not LiCl-induced taste aversion learning (TAL). Orexinergic fibers from the lateral hypothalamus end in the central nucleus of the amygdala (CeA), which expresses orexin OX1R receptors. Taste and sensory inputs also are present in CeA, which may contribute to the development of taste learning. This study analyzed the effect of two doses (1.5 and 6μg/0.5μl) of SB-334867-A administered into the CeA on flavor-taste preference induced by saccharin and on TAL induced by a single administration of LiCl (0.15M, 20ml/kg, i.p.). Outcomes indicate that inactivation of orexinergic receptors in the CeA attenuates flavor-taste preference in a two-bottle test (saccharin vs. water). Intra-amygdalar SB-334867-A does not affect gustatory processing or the preference for the sweet taste of saccharin given that SB-334867-A- and DMSO-treated groups (control animals) increased the intake of the saccharin-associated flavor across training acquisition sessions. Furthermore, SB-334867-A in the CeA does not block TAL acquisition ruling out the possibility that functional inactivation of OX1R receptors interferes with taste processing. Orexin receptors in the CeA appear to intervene in the association of a flavor with orosensory stimuli, e.g., a sweet and pleasant taste, but could be unnecessary when the association is established with visceral stimuli, e.g., lithium chloride. These data suggest that orexinergic projections to the CeA may contribute to the reinforcing signals facilitating the acquisition of taste learning and the change in hedonic evaluation of the taste, which would have important implications for the OX1R-targeted pharmacological treatment of eating disorders.}, } @article {pmid25209712, year = {2014}, author = {Revillo, DA and Gaztañaga, M and Aranda, E and Paglini, MG and Chotro, MG and Arias, C}, title = {Context-dependent latent inhibition in preweanling rats.}, journal = {Developmental psychobiology}, volume = {56}, number = {7}, pages = {1507-1517}, doi = {10.1002/dev.21236}, pmid = {25209712}, issn = {1098-2302}, mesh = {Age Factors ; Animals ; Conditioning, Classical/*physiology ; *Inhibition, Psychological ; Learning/*physiology ; Rats ; }, abstract = {Preexposure to a conditioned stimulus (CS) usually weakens conditioning, an effect known as latent inhibition. Similar to other learning interference effects, latent inhibition has been characterized as context-dependent, which means that the magnitude of this effect can be attenuated by changing the context between the different phases of the procedure (e.g., preexposure and conditioning). Latent inhibition has been found with a variety of procedures in infant rats, but the few studies that examined the context-dependency of this phenomenon during this ontogenetic period found no context-change effect. The present study explored the context-dependency of latent inhibition during infancy using a conditioned taste aversion preparation and employing contexts enriched with distinctive odors to increase the possible efficacy of the context manipulation. Experiment 1 showed that three preexposures to the CS (saccharin) were sufficient to retard conditioning to the same CS, although this effect was also observed in a control group preexposed to an alternative taste stimulus (saline), in comparison with a non-preexposed control group. In Experiment 2a, the CS-preexposure effect was found to be specific to the preexposed CS when the number of preexposures was increased. This effect was revealed as context-dependent in Experiment 2b, since it was attenuated by changing the context between preexposure and conditioning. The present result is consistent with recent studies showing the context-dependency of extinction in preweanling rats, thus demonstrating these animals' capacity to learn about context early on in their development.}, } @article {pmid25173061, year = {2014}, author = {Nakajima, S and Katayama, T}, title = {Running-based pica in rats. Evidence for the gastrointestinal discomfort hypothesis of running-based taste aversion.}, journal = {Appetite}, volume = {83}, number = {}, pages = {178-184}, doi = {10.1016/j.appet.2014.08.031}, pmid = {25173061}, issn = {1095-8304}, mesh = {Abdominal Pain/chemically induced/etiology/*physiopathology/prevention & control ; Aluminum Silicates/administration & dosage ; Animals ; *Avoidance Learning ; Behavior, Animal ; Clay ; *Disease Models, Animal ; Dysgeusia/chemically induced/*etiology/physiopathology/prevention & control ; Emetics/administration & dosage/toxicity ; Injections, Intraperitoneal ; Kaolin/administration & dosage ; Lithium Chloride/administration & dosage/toxicity ; Male ; *Models, Biological ; Motor Activity ; Nausea/chemically induced/etiology/physiopathology/prevention & control ; Physical Exertion ; Pica/*etiology ; Rats, Wistar ; *Stress, Physiological ; }, abstract = {Voluntary running in an activity wheel establishes aversion to paired taste in rats. A proposed mechanism underlying this taste aversion learning is gastrointestinal discomfort caused by running. We tested this hypothesis by measuring the pica behavior (kaolin clay intake) of rats, because it is known that rats engage in pica behavior after various nausea-inducing treatments including irradiation, motion sickness, and injection of emetic drugs such as lithium chloride (LiCl). Following a demonstration of the already-known phenomenon of LiCl-based pica in Experiment 1, we successfully showed running-based pica behavior in Experiment 2 where the running treatment was compared with a non-running control treatment (i.e., confinement in a locked wheel). These results suggest that not only LiCl but also running induces nausea in rats, supporting the gastrointestinal discomfort hypothesis of running-based taste aversion learning.}, } @article {pmid25128878, year = {2014}, author = {Gramsch, C and Kattoor, J and Icenhour, A and Forsting, M and Schedlowski, M and Gizewski, ER and Elsenbruch, S}, title = {Learning pain-related fear: neural mechanisms mediating rapid differential conditioning, extinction and reinstatement processes in human visceral pain.}, journal = {Neurobiology of learning and memory}, volume = {116}, number = {}, pages = {36-45}, doi = {10.1016/j.nlm.2014.08.003}, pmid = {25128878}, issn = {1095-9564}, mesh = {Adult ; Brain/*physiopathology ; Brain Mapping ; Conditioning, Classical/*physiology ; Extinction, Psychological/*physiology ; Fear/*physiology/psychology ; Female ; Humans ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging ; Male ; Neurons/physiology ; Visceral Pain/*physiopathology/psychology ; Young Adult ; }, abstract = {BACKGROUND AND AIMS: There exists converging evidence to support a role of pain-related fear in the pathophysiology and treatment of chronic pain conditions. Pain-related fear is shaped by associative learning and memory processes, which remain poorly characterized especially in the context of abdominal pain such as in irritable bowel syndrome (IBS). Therefore, using event-related functional magnetic resonance imaging (fMRI), we assessed the neural mechanisms mediating the formation, extinction and reinstatement of abdominal pain-related fear in healthy humans. Employing painful rectal distensions as clinically-relevant unconditioned stimuli (US), in this fear conditioning study we tested if differential excitatory and inhibitory learning is evocable after very few CS-US learning trials ("rapid conditioning"), and explored the underlying neural substrates of these learning and memory processes.

METHODS: In N=24 healthy men and women, "rapid" fear acquisition was accomplished by pairing visual conditioned stimuli (CS(+)) with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS(-)) were presented without US (differential delay conditioning with five CS(+) and five CS(-) presentations and a 80% reinforcement ratio). During extinction, all CS were presented without US. Subsequently, a reinstatement procedure was implemented, defined as the retrieval of an extinguished memory after unexpected and unpaired exposure to the US, followed by CS presentations. For each phase, changes in perceived CS-US contingency and CS unpleasantness were assessed with visual analogue scales and compared with analyses of variance. fMRI data were analyzed using whole-brain analyses (at p<.001 uncorrected) and in regions-of-interest analyses with familywise error correction of alpha (pFWE<.05). Differential neural activation in response to the CS during each experimental phase (i.e., CS(+)>CS(-); CS(+)
RESULTS: A significant valence change (i.e. increased CS(+) unpleasantness) was observed following acquisition, indicating successful differential aversive learning. On the other hand, CS-US contingency awareness was not fully established. These behavioral results were paralleled by differential activation of the putamen (pFWE<.05), insula (pFWE<.05) and secondary somatosensory cortex (S2, p<.001 uncorrected) in response to the CS(+) during acquisition. The same analysis with a linear parametric modulation confirmed but also strengthened the resulting activations, which were all highly significant in ROI analyses at pFWE<.05. Extinction and reinstatement involved differential activation in response to the CS(-), involving the cingulate cortex and primary motor cortex (M1) during extinction and the posterior cingulate cortex (PCC) during reinstatement (all p<.001 uncorrected), without obvious effects upon linear parametric modulation analysis.

CONCLUSIONS: Abdominal pain stimuli are effective US that elicit conditioned pain-related fear even after very few learning experiences without full contingency awareness. These findings extend similar evidence of "rapid learning" in response to interoceptive US (e.g., conditioned taste aversion, conditioned nausea), and have implications for the pathophysiology and treatment of chronic abdominal pain such as in IBS.}, } @article {pmid25076870, year = {2014}, author = {Burke, CJ and Dreher, JC and Seymour, B and Tobler, PN}, title = {State-dependent value representation: evidence from the striatum.}, journal = {Frontiers in neuroscience}, volume = {8}, number = {}, pages = {193}, pmid = {25076870}, issn = {1662-4548}, } @article {pmid24990860, year = {2014}, author = {Noble, EE and Billington, CJ and Kotz, CM and Wang, C}, title = {Oxytocin in the ventromedial hypothalamic nucleus reduces feeding and acutely increases energy expenditure.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {307}, number = {6}, pages = {R737-45}, pmid = {24990860}, issn = {1522-1490}, support = {T32 DK083250/DK/NIDDK NIH HHS/United States ; T32DK-083250/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Anti-Obesity Agents/*administration & dosage ; Dose-Response Relationship, Drug ; Eating/drug effects ; Energy Metabolism/*drug effects ; Fasting ; Feeding Behavior/*drug effects ; Injections, Intraventricular ; Male ; Motor Activity/drug effects ; Oxytocin/*administration & dosage ; Rats ; Rats, Sprague-Dawley ; Satiety Response/drug effects ; Time Factors ; Ventromedial Hypothalamic Nucleus/*drug effects/metabolism ; }, abstract = {Central oxytocin reduces food intake and increases energy expenditure. The ventromedial hypothalamic nucleus (VMN) is associated with energy balance and contains a high density of oxytocin receptors. We hypothesized that oxytocin in the VMN is a negative regulator of energy balance acting to reduce feeding and increase energy expenditure. To test this idea, oxytocin or vehicle was injected directly into the VMN of Sprague-Dawley rats during fasted and nonfasted conditions. Energy expenditure (via indirect calorimetry) and spontaneous physical activity (SPA) were recorded simultaneously. Animals were also exposed to a conditioned taste aversion test, to determine whether oxytocin's effects on food intake were associated with malaise. When food was available during testing, oxytocin-induced elevations in energy expenditure lasted for 1 h, after which overall energy expenditure was reduced. In the absence of food during the testing period, oxytocin similarly increased energy expenditure during the first hour, but differences in 12-h energy expenditure were eliminated, implying that the differences may have been due to the thermic effects of feeding (digestion, absorption, and metabolic processing). Oxytocin acutely elevated SPA and reduced feeding at doses that did not cause a conditioned taste aversion during both the fed and fasted states. Together, these data suggest that oxytocin in the VMN promotes satiety and acutely elevates energy expenditure and SPA and implicates the VMN as a relevant site for the antiobesity effects of oxytocin.}, } @article {pmid24974748, year = {2014}, author = {Neuwirthová, J and Gál, B and Smilek, P and Kostřica, R}, title = {[Importance of taste in maintaining homeostasis and pathological impact of orosensory reflexes distraction in relation to sweet taste after non-caloric sweeteners consumption].}, journal = {Vnitrni lekarstvi}, volume = {60}, number = {5-6}, pages = {454-457}, pmid = {24974748}, issn = {0042-773X}, mesh = {Appetite Regulation ; Homeostasis ; Humans ; *Sweetening Agents ; *Taste ; }, abstract = {Taste signals and their reflexes have important signalling function in nature. They protect organism against toxic substances in food with help of taste aversion, they help to cope nutrition deficiencies through taste preferences, on the other hand, they act in many postprandial reflexes to maintain energy homeostasis. It is well-known that sweet taste is important oro-sensory stimulus for mammals. It acts as predictor of caloric food intake even before its entry into stomach and circulation. Taste and other oro-sensory signals from oral cavity affect not only the intake regulation, but also influence hormonal, neural and metabolic pathways to maintain homeostasis. The aim is to utilize effectively food energy and prevent energy instability of organism. Oro-sensory reflexes mediated by taste cells develop naturally from the first contact with sweet breast milk in infancy. It has been proven that the attenuation of reflexes due to the use of artificial sweeteners that don´t bring any caloric value to human body leads to hormonal and energetic dysregulation of organism and may contribute to metabolic syndrome.}, } @article {pmid24853379, year = {2014}, author = {Sanjuán, Mdel C and Nelson, JB and Alonso, G}, title = {An easy-to-hard effect after nonreinforced preexposure in a sweetness discrimination.}, journal = {Learning & behavior}, volume = {42}, number = {3}, pages = {209-214}, pmid = {24853379}, issn = {1543-4508}, mesh = {Animals ; Avoidance Learning/*physiology ; Behavior, Animal/physiology ; Discrimination Learning/*physiology ; Rats ; Rats, Wistar ; Taste/*physiology ; }, abstract = {Experiments 1A and 1B used a taste-aversion procedure with rats to demonstrate that exposure to easily discriminated flavors along a dimension (1 % and 10 % sucrose) can facilitate learning a subsequent hard discrimination (4 % and 7 % sucrose) when one of those flavors is paired with illness. Experiment 1A compared the effects of preexposure to the easily discriminated flavors against exposure to the same stimuli used in the discrimination training or no exposure at all. Experiment 1B replicated the conditions in Experiment 1A, with 2 additional days of training and unrestricted access to the flavors on CS+/CS- trials in discrimination training. Contrary to findings with multidimensional stimuli (Scahill & Mackintosh, Journal of Experimental Psychology: Animal Behavior Processes, 30, 96-103, 2004; Suret & McLaren, The Quarterly Journal of Experimental Psychology, 56B, 30-42, 2003), we found that preexposure to the easily discriminable stimuli varying along a single dimension of sweetness facilitated subsequent discrimination training over the other conditions in each experiment. We discuss the results in terms of the ideas presented by Gibson (1969) and Mackintosh (Psychological Review, 82, 276-298, 1975) and in terms of hedonic variables not considered by theories of perceptual learning.}, } @article {pmid24849362, year = {2014}, author = {Xin, J and Ma, L and Zhang, TY and Yu, H and Wang, Y and Kong, L and Chen, ZY}, title = {Involvement of BDNF signaling transmission from basolateral amygdala to infralimbic prefrontal cortex in conditioned taste aversion extinction.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {34}, number = {21}, pages = {7302-7313}, pmid = {24849362}, issn = {1529-2401}, mesh = {Amygdala/drug effects/*physiology ; Animals ; Antibodies/pharmacology ; Avoidance Learning/drug effects/*physiology ; Brain-Derived Neurotrophic Factor/genetics/immunology/*metabolism/pharmacology ; Carbazoles/pharmacology ; Enzyme Inhibitors/pharmacology ; Extinction, Psychological/drug effects/*physiology ; Gene Expression Regulation/drug effects ; Humans ; Indole Alkaloids/pharmacology ; Male ; Prefrontal Cortex/drug effects/*physiology ; Rats ; Rats, Wistar ; Receptor, trkB/genetics/metabolism ; Signal Transduction/*physiology ; Taste/*physiology ; Time Factors ; }, abstract = {Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), play a critical role in memory extinction. However, the detailed role of BDNF in memory extinction on the basis of neural circuit has not been fully understood. Here, we aim to investigate the role of BDNF signaling circuit in mediating conditioned taste aversion (CTA) memory extinction of the rats. We found region-specific changes in BDNF gene expression during CTA extinction. CTA extinction led to increased BDNF gene expression in the basolateral amygdala (BLA) and infralimbic prefrontal cortex (IL) but not in the central amygdaloid nucleus (CeA) and hippocampus (HIP). Moreover, blocking BDNF signaling or exogenous microinjection of BDNF into the BLA or IL could disrupt or enhance CTA extinction, which suggested that BDNF signaling in the BLA and IL is necessary and sufficient for CTA extinction. Interestingly, we found that microinjection of BDNF-neutralizing antibody into the BLA could abolish the extinction training-induced BDNF mRNA level increase in the IL, but not vice versa, demonstrating that BDNF signaling is transmitted from the BLA to IL during extinction. Finally, the accelerated extinction learning by infusion of exogenous BDNF in the BLA could also be blocked by IL infusion of BDNF-neutralizing antibody rather than vice versa, indicating that the IL, but not BLA, is the primary action site of BDNF in CTA extinction. Together, these data suggest that BLA-IL circuit regulates CTA memory extinction by identifying BDNF as a key regulator.}, } @article {pmid24847227, year = {2014}, author = {Marotta, R and Fenu, S and Scheggi, S and Vinci, S and Rosas, M and Falqui, A and Gambarana, C and De Montis, MG and Acquas, E}, title = {Acquisition and expression of conditioned taste aversion differentially affects extracellular signal regulated kinase and glutamate receptor phosphorylation in rat prefrontal cortex and nucleus accumbens.}, journal = {Frontiers in behavioral neuroscience}, volume = {8}, number = {}, pages = {153}, pmid = {24847227}, issn = {1662-5153}, abstract = {Conditioned taste aversion (CTA) can be applied to study associative learning and its relevant underpinning molecular mechanisms in discrete brain regions. The present study examined, by immunohistochemistry and immunocytochemistry, the effects of acquisition and expression of lithium-induced CTA on activated Extracellular signal Regulated Kinase (p-ERK) in the prefrontal cortex (PFCx) and nucleus accumbens (Acb) of male Sprague-Dawley rats. The study also examined, by immunoblotting, whether acquisition and expression of lithium-induced CTA resulted in modified levels of phosphorylation of glutamate receptor subunits (NR1 and GluR1) and Thr(34)- and Thr(75-Dopamine-and-cAMP-Regulated) PhosphoProtein (DARPP-32). CTA acquisition was associated with an increase of p-ERK-positive neurons and phosphorylated NR1 receptor subunit (p-NR1) in the PFCx, whereas p-GluR1, p-Thr(34)- and p-Thr(75)-DARPP-32 levels were not changed in this brain region. CTA expression increased the number of p-ERK-positive neurons in the shell (AcbSh) and core (AcbC) but left unmodified p-NR1, p-GluR1, p-Thr(34)- and p-Thr(75-DARPP-32) levels. Furthermore, post-embedding immunogold quantitative analysis in AcbSh revealed that CTA expression significantly increased nuclear p-ERK immunostaining as well as p-ERK-labeled axo-spinous contacts. Overall, these results indicate that ERK and NR1, but not GluR1 and DARPP-32, are differentially phosphorylated as a consequence of acquisition and expression of aversive associative learning. Moreover, these results confirm that CTA represents an useful approach to study the molecular basis of associative learning in rats and suggest the involvement of ERK cascade in learning-associated synaptic plasticity.}, } @article {pmid24841742, year = {2014}, author = {Cunningham, CL}, title = {Genetic relationship between ethanol-induced conditioned place preference and other ethanol phenotypes in 15 inbred mouse strains.}, journal = {Behavioral neuroscience}, volume = {128}, number = {4}, pages = {430-445}, pmid = {24841742}, issn = {1939-0084}, support = {P60 AA010760/AA/NIAAA NIH HHS/United States ; R01 AA007702/AA/NIAAA NIH HHS/United States ; R01AA007702/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking/*genetics ; Animals ; Conditioning, Classical/*drug effects ; Ethanol/*pharmacology ; *Genotype ; Male ; Mice ; Mice, Inbred Strains ; Motor Activity/drug effects ; *Phenotype ; Reward ; }, abstract = {The genetic relationships between different behaviors used to index the rewarding or reinforcing effects of alcohol are poorly understood. To address this issue, ethanol-induced conditioned place preference (CPP) was tested in a genetically diverse panel of inbred mouse strains, and strain means from this study and other inbred strain studies were used to examine the genetic correlation between CPP and several ethanol-related phenotypes, including activity measures recorded during CPP training and testing. Mice from each strain were exposed to a well-characterized unbiased place conditioning procedure using ethanol doses of 2 or 4 g/kg; an additional group from each strain was exposed to saline alone on all trials. Genotype had a significant effect on CPP, basal locomotor activity, ethanol-stimulated activity, and the effect of repeated ethanol exposure on activity. Correlational analyses showed significant negative genetic correlations between CPP and sweetened ethanol intake and between CPP and test session activity, as well as a significant positive genetic correlation between CPP and chronic ethanol withdrawal severity. Moreover, there was a trend toward a positive genetic correlation between CPP and ethanol-induced conditioned taste aversion. These genetic correlations suggest overlap in the genetic mechanisms underlying CPP and each of these traits. The patterns of genetic relationships suggest a greater impact of ethanol's aversive effects on drinking and a greater impact of ethanol's rewarding effects on CPP. Overall, these data support the idea that genotype influences ethanol's rewarding effect, a factor that may contribute importantly to addictive vulnerability.}, } @article {pmid24840626, year = {2015}, author = {Gámiz, F and Recio, SA and Iliescu, AF and Gallo, M and de Brugada, I}, title = {Effects of dietary choline availability on latent inhibition of flavor aversion learning.}, journal = {Nutritional neuroscience}, volume = {18}, number = {6}, pages = {275-280}, doi = {10.1179/1476830514Y.0000000129}, pmid = {24840626}, issn = {1476-8305}, mesh = {Animals ; Behavior, Animal/drug effects ; Choline/*administration & dosage ; Conditioning, Classical/*drug effects ; Diet ; *Inhibition, Psychological ; Male ; Rats ; Rats, Wistar ; Taste/*physiology ; }, abstract = {OBJECTIVE: It has been previously reported that dietary choline supplementation might affect latent inhibition (LI) using a conditioned suppression procedure in rats. We have assessed the effect of dietary choline on LI of flavor aversion learning.

METHOD: Adult male Wistar rats received a choline supplemented (5 g/kg), deficient (0 g/kg), or standard (1.1 g/kg) diet for 3 months. After this supplementation period, all rats went through a conditioned taste aversion (CTA) procedure, half of them being pre-exposed to the conditioned stimulus before the conditioning.

RESULTS: The results indicated that choline deficiency prevents LI of conditioned flavor aversion to cider vinegar (3%) induced by a LiCl (0.15 M; 2% body weight) intraperitoneal injection, while choline supplementation enhances CTA leading to slower extinction.

DISCUSSION: The role of the brain systems modulating attentional processes is discussed.}, } @article {pmid24819821, year = {2014}, author = {Sullivan, RM and Dufresne, MM and Siontas, D and Chehab, S and Townsend, J and Laplante, F}, title = {Mesocortical dopamine depletion and anxiety-related behavior in the rat: sex and hemisphere differences.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {54}, number = {}, pages = {59-66}, doi = {10.1016/j.pnpbp.2014.05.002}, pmid = {24819821}, issn = {1878-4216}, support = {MOP-93589//Canadian Institutes of Health Research/Canada ; }, mesh = {Adrenocorticotropic Hormone/blood ; Animals ; Anxiety/pathology/*physiopathology ; Dietary Sucrose/administration & dosage ; Dopamine/*metabolism ; Estrous Cycle/physiology ; Exploratory Behavior/physiology ; Functional Laterality/*physiology ; Maze Learning/physiology ; Motor Activity/physiology ; Neuropsychological Tests ; Oxidopamine ; Predatory Behavior ; Prefrontal Cortex/pathology/*physiopathology ; Rats, Sprague-Dawley ; Restraint, Physical ; *Sex Characteristics ; Stress, Psychological/physiopathology ; Taste Perception/physiology ; }, abstract = {The mesocortical dopamine (DA) system of the rat plays an important role in prefrontal cortex (PFC) regulation of stress and emotion and exhibits functional hemispheric asymmetry for such processing. Since few studies examine sex differences in this context, we compared the effects of left vs. right unilateral PFC DA depletion in males and females in several behavioral situations associated with anxiety or aversion. Adult rats received unilateral injections of 6-hydroxydopamine (6-OHDA) or vehicle in the ventromedial (vm) PFC. Behavioral tests included a predator odor burying test, elevated plus maze and sucrose consumption with simple taste aversion. Tissue analysis confirmed that vmPFCs injected with 6-OHDA were depleted of DA (75-85%) compared to controls. Burying behavior and sucrose consumption were affected only by left lesions, similarly in both sexes. However, risk assessment behaviors were affected by right lesions in opposite directions in males and females. Behaviors modified preferentially by the left cortex thus showed less evidence of sex differences than those modulated by the right. While mesocortical DA depletion effects are lateralized, the nature of these effects can vary with sex and specific behavior. Such findings may be clinically significant, given the large gender differences in the incidence of mood and anxiety disorders, which also show many lateralized prefrontal abnormalities.}, } @article {pmid24813806, year = {2014}, author = {Lin, JY and Arthurs, J and Reilly, S}, title = {Conditioned taste aversion, drugs of abuse and palatability.}, journal = {Neuroscience and biobehavioral reviews}, volume = {45}, number = {}, pages = {28-45}, pmid = {24813806}, issn = {1873-7528}, support = {R01 DC006456/DC/NIDCD NIH HHS/United States ; R56 DC006456/DC/NIDCD NIH HHS/United States ; DC006456/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Avoidance Learning/*drug effects/physiology ; Conditioning, Psychological/*drug effects/physiology ; Food Preferences/*drug effects/physiology/psychology ; Humans ; Illicit Drugs ; Substance-Related Disorders/*physiopathology/psychology ; Taste Perception/*drug effects/physiology ; }, abstract = {We consider conditioned taste aversion to involve a learned reduction in the palatability of a taste (and hence in amount consumed) based on the association that develops when a taste experience is followed by gastrointestinal malaise. The present article evaluates the well-established finding that drugs of abuse, at doses that are otherwise considered rewarding and self-administered, cause intake suppression. Our recent work using lick pattern analysis shows that drugs of abuse also cause a palatability downshift and, therefore, support conditioned taste aversion learning.}, } @article {pmid24813701, year = {2014}, author = {Wang, Y and Song, Z and Everaert, N and De Ketelaere, B and Willemsen, H and Decuypere, E and Buyse, J}, title = {The anorectic effects of alpha-lipoicacid are mediated by central AMPK and are not due to taste aversion in chicken (Gallus gallus).}, journal = {Physiology & behavior}, volume = {132}, number = {}, pages = {66-72}, doi = {10.1016/j.physbeh.2014.04.047}, pmid = {24813701}, issn = {1873-507X}, mesh = {AMP-Activated Protein Kinases/genetics/*metabolism ; Agouti-Related Protein/metabolism ; Animals ; Appetite Depressants/*pharmacology ; Avoidance Learning/*drug effects ; Chickens ; Dose-Response Relationship, Drug ; Eating/*drug effects ; Gene Expression Regulation/drug effects ; Hypothalamus/drug effects/*enzymology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Male ; Neuropeptide Y/metabolism ; Pro-Opiomelanocortin/metabolism ; Protein Subunits/genetics/metabolism ; RNA, Messenger/metabolism ; Taste/*drug effects ; Thioctic Acid/*pharmacology ; Thyrotropin-Releasing Hormone/metabolism ; Time Factors ; }, abstract = {AMP-activated protein kinase (AMPK) is an evolutionary conserved cellular energy sensor, which plays a pivotal role in mammalian energy homeostasis. The present study was aimed to explore the possible involvement of hypothalamic AMPK in feed intake regulation of broiler chickens. Hence, diets with 0, 0.05% or 0.1% α-lipoicacid (α-LA), a known AMPK inhibitor in mammals, were provided to broiler chicks for 7days. Alpha-LA exerted an anorectic effect, and the conditioned taste aversion test demonstrated that the effect was due to the alteration in satiety and not taste effects. However, the curtailed feed intake induced by α-LA disappeared on day 7. Hypothalamic AMPKα1 mRNA levels were significantly decreased by the dietary α-LA in concert with the reduced abundance in total AMPKα protein. The phosphorylated AMPKα was also decreased to a similar extend, resulting in an unaltered phosphorylated AMPKα/total AMPKα ratio. In addition, hypothalamic corticotropin releasing hormone mRNA levels were enhanced by α-LA. Interestingly, the mRNA expressions of hypothalamic orexigenic agouti-related peptide and neuropeptide Y were up-regulated, while the anorexigenic proopiomelanocortin and its transcription regulator hypoxia-inducible factor-1α were down-regulated, probably as a physiological reaction in order to counteract the altered energy balance. In conclusion, dietary α-LA decreased feed intake of broiler chicks. The anorectic effect was due to the reduced hypothalamic phosphorylated AMPKα as reflected in its decreased mRNA and protein levels. However, the anorectic effect of α-LA was progressively diminished after 7days of treatment, likely by a physiological counteractive feedback via changing neuropeptides involved in energy balance regulation.}, } @article {pmid24762441, year = {2014}, author = {Sisley, S and Gutierrez-Aguilar, R and Scott, M and D'Alessio, DA and Sandoval, DA and Seeley, RJ}, title = {Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect.}, journal =