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Bibliography on: Taste-Aversion Learning

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ESP: PubMed Auto Bibliography 18 Sep 2020 at 01:55 Created: 

Taste-Aversion Learning

The notion of "conditioned taste aversions" refers to animals' ability to preferentially associate taste with illness, despite the passage of a significant time between ingestion and illness. When first described, this pattern seemed so at variance with the tenets of classical learning theory that one early reviewer claimed "results like that are no more likely than birdshit in a cuckoo clock." Now, however, the reality of the phenomenon is well established and has demonstrated relevance in practical areas ranging from rodent control to chemotherapy.

Created with PubMed® Query: "taste aversion" or "bait shyness" NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2020-09-16

Galistu A, PS D'Aquila (2020)

Memantine effects on ingestion microstructure and the effect of administration time: A within-subject study.

PloS one, 15(9):e0239270 pii:PONE-D-20-19768.

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.

RevDate: 2020-08-28

Arieli E, Gerbi R, Shein-Idelson M, et al (2020)

Temporally-precise basolateral amygdala activation is required for the formation of taste memories in gustatory cortex.

The Journal of physiology [Epub ahead of print].

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 affect, 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.

SIGNIFICANCE: Consumption of a novel taste poses a threat to animals and humans, as it may be poisonous. To bridge the time-gap between the food consumption and malaise, brain circuits must first identify and then store the novel taste's information in memory. The precise neuronal activity and circuits that drive the creation of the novel-taste memory are still unclear. We used sub-second neuronal inhibition and neuronal recording in rats to study the role of short-span neuronal activity in memory formation. We managed to describe both the temporal specificity and the inter-region pathway by which neuronal activity is transformed into memory across different brain regions of the taste system. Our findings may explain similar activity-to-memory transformation in other modalities. This article is protected by copyright. All rights reserved.

RevDate: 2020-08-11

Levitan D, Liu C, Yang T, et al (2020)

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory.

eLife, 9: pii:61036 [Epub ahead of print].

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.

RevDate: 2020-07-30

Hurley SW, RM Carelli (2020)

Activation of Infralimbic to Nucleus Accumbens Shell Pathway Suppresses Conditioned Aversion in Male but not Female Rats.

The Journal of neuroscience : the official journal of the Society for Neuroscience pii:JNEUROSCI.0137-20.2020 [Epub ahead of print].

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 homologue, 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 (CTA) paradigm in males and female rats. In naïve rats, no significant differences in appetitive or aversive 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 taste reactivity (TR) in male but not female rats. Interestingly, when allowed to freely ingest water and sucrose in a 2-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 statementNegative 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.

RevDate: 2020-07-29

Abe K, Kuroda M, Narumi Y, et al (2020)

Cortico-amygdala interaction determines the insular cortical neurons involved in taste memory retrieval.

Molecular brain, 13(1):107 pii:10.1186/s13041-020-00646-w.

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.

RevDate: 2020-07-26

Angulo R, Bustamante J, CA Arévalo-Romero (2020)

Age, sex and pre-exposure effects on acquisition and generalization of conditioned taste aversion in rats.

Behavioural brain research pii:S0166-4328(20)30512-X [Epub ahead of print].

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.

RevDate: 2020-07-18

Miranda MI, Rangel-Hernández A, Vera-Rivera G, et al (2020)

Taste association capabilities differ in high- and low-yawning rats versus outbred Sprague-Dawley rats after prolonged sugar consumption.

Animal cognition pii:10.1007/s10071-020-01415-x [Epub ahead of print].

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.

RevDate: 2020-07-13

Angulo R, Bustamante J, Estades V, et al (2020)

Sex Differences in Cue Competition Effects With a Conditioned Taste Aversion Preparation.

Frontiers in behavioral neuroscience, 14:107.

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.

RevDate: 2020-07-11

Lai Y, Despouy E, Sandoz JC, et al (2020)

Degradation of an appetitive olfactory memory via devaluation of sugar reward is mediated by 5-HT signaling in the honey bee.

Neurobiology of learning and memory pii:S1074-7427(20)30122-2 [Epub ahead of print].

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.

RevDate: 2020-07-11

Molero-Chamizo A, GN Rivera-Urbina (2020)

Taste Processing: Insights from Animal Models.

Molecules (Basel, Switzerland), 25(14): pii:molecules25143112.

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.

RevDate: 2020-06-30

Blednov YA, Da Costa A, Mayfield J, et al (2020)

Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice.

Addiction biology [Epub ahead of print].

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.

RevDate: 2020-06-30

Yamamura T, Nakamura F, Yasuo T, et al (2020)

Effect of the duration of a conditioned stimulus on component recognition in binary taste mixtures in rats.

Journal of oral biosciences pii:S1349-0079(20)30084-0 [Epub ahead of print].

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.

RevDate: 2020-07-01

Molero-Chamizo A, GN Rivera-Urbina (2020)

Temporal specificity of latent inhibition in rats with daily water restriction prior to taste conditioning.

Acta neurobiologiae experimentalis, 80(2):99-107.

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.

RevDate: 2020-07-02

Hao L, Kshatriya D, Li X, et al (2020)

Acute feeding suppression and toxicity of raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] in mice.

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 143:111512 pii:S0278-6915(20)30402-6 [Epub ahead of print].

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.

RevDate: 2020-05-30

Csikós V, Varró P, Bódi V, et al (2020)

The mycotoxin deoxynivalenol activates GABAergic neurons in the reward system and inhibits feeding and maternal behaviours.

Archives of toxicology pii:10.1007/s00204-020-02791-6 [Epub ahead of print].

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.

RevDate: 2020-06-09

Huang ACW, Yu YH, He ABH, et al (2020)

Interactions between prelimbic cortex and basolateral amygdala contribute to morphine-induced conditioned taste aversion in conditioning and extinction.

Neurobiology of learning and memory, 172:107248.

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.

RevDate: 2020-05-11

Nakai J, Totani Y, Kojima S, et al (2020)

Features of behavioral changes underlying conditioned taste aversion in the pond snail Lymnaea stagnalis.

Invertebrate neuroscience : IN, 20(2):8 pii:10.1007/s10158-020-00241-7.

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.

RevDate: 2020-05-07

Steinfeld MR, ME Bouton (2020)

Context and renewal of habits and goal-directed actions after extinction.

Journal of experimental psychology. Animal learning and cognition pii:2020-31145-001 [Epub ahead of print].

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).

RevDate: 2020-05-29

Keating AV, Soto J, Forbes C, et al (2020)

Multi-Methodological Quantitative Taste Assessment of Anti-Tuberculosis Drugs to Support the Development of Palatable Paediatric Dosage Forms.

Pharmaceutics, 12(4):.

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.

RevDate: 2020-05-19

Sandoval-Sánchez AR, Cedillo Zavaleta LN, Jiménez JC, et al (2020)

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.

Pharmacology, biochemistry, and behavior, 193:172932.

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.

RevDate: 2020-04-16

Nakajima S (2020)

Effect of pretrial running on running-based taste aversion learning in rats.

Journal of experimental psychology. Animal learning and cognition pii:2020-25425-001 [Epub ahead of print].

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).

RevDate: 2020-05-15

Totani Y, Nakai J, Dyakonova VE, et al (2020)

Induction of LTM following an Insulin Injection.

eNeuro, 7(2):.

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.

RevDate: 2020-04-02

Amaya KA, Stott JJ, KS Smith (2020)

Sign-tracking behavior is sensitive to outcome devaluation in a devaluation context-dependent manner: implications for analyzing habitual behavior.

Learning & memory (Cold Spring Harbor, N.Y.), 27(4):136-149.

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.

RevDate: 2020-04-22

Xu LH, Yang Y, Liu HX, et al (2020)

Inner Ear Arginine Vasopressin-Vasopressin Receptor 2-Aquaporin 2 Signaling Pathway Is Involved in the Induction of Motion Sickness.

The Journal of pharmacology and experimental therapeutics, 373(2):248-260.

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.

RevDate: 2020-02-24

László BR, Hormay E, Szabó I, et al (2020)

Disturbance of taste reactivity and other behavioral alterations after bilateral interleukin-1β microinjection into the cingulate cortex of the rat.

Behavioural brain research, 383:112537.

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.

RevDate: 2020-03-31
CmpDate: 2020-03-31

Chia J, K Scott (2020)

Activation of specific mushroom body output neurons inhibits proboscis extension and sucrose consumption.

PloS one, 15(1):e0223034.

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.

RevDate: 2020-05-05

Derman RC, Bass CE, CR Ferrario (2020)

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.

Psychopharmacology, 237(5):1249-1266.

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.

RevDate: 2020-01-17

Liu DW, Ma L, Zhang XH, et al (2019)

Conditioned taste aversion memory extinction temporally induces insular cortical BDNF release and inhibits neuronal apoptosis.

Neuropsychiatric disease and treatment, 15:2403-2414.

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.

RevDate: 2020-05-19

Bouton ME, Broomer MC, Rey CN, et al (2020)

Unexpected food outcomes can return a habit to goal-directed action.

Neurobiology of learning and memory, 169:107163.

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).

RevDate: 2020-04-02

Trask S, Shipman ML, Green JT, et al (2020)

Some factors that restore goal-direction to a habitual behavior.

Neurobiology of learning and memory, 169:107161.

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.

RevDate: 2020-03-23

Alapin JM, Dines M, R Lamprecht (2020)

EphB2 receptor forward signaling is needed for normal long-term memory formation in aged mice.

Neurobiology of aging, 86:11-15.

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 EphB2lacZ/lacZ mice devoid of EphB2 forward signaling. We found that the ability to create CTA long-term memory is unaffected in young EphB2lacZ/lacZ mice. However, the ability to form an increased long-term CTA memory shown in old wild-type mice is impaired in old EphB2lacZ/lacZ mice. The inability to form enhanced CTA long-term memory in EphB2-/- and EphB2lacZ/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.

RevDate: 2020-02-26

Keefer SE, GD Petrovich (2020)

The basolateral amygdala-medial prefrontal cortex circuitry regulates behavioral flexibility during appetitive reversal learning.

Behavioral neuroscience, 134(1):34-44.

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).

RevDate: 2020-07-03

Torruella-Suárez ML, Vandenberg JR, Cogan ES, et al (2020)

Manipulations of Central Amygdala Neurotensin Neurons Alter the Consumption of Ethanol and Sweet Fluids in Mice.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 40(3):632-647.

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.

RevDate: 2020-04-02

Basu S, Alapin JM, Dines M, et al (2020)

Long-term memory is maintained by continuous activity of Arp2/3 in lateral amygdala.

Neurobiology of learning and memory, 167:107115.

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.

RevDate: 2020-02-26

Ali J, Chiang M, Lee JB, et al (2020)

Is rat a good model for assessment of particulate-based taste-masked formulations?.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 146:1-9.

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.

RevDate: 2020-02-26

Song L, Chen K, Yan J, et al (2019)

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.

Physiology & behavior, 212:112709.

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.

RevDate: 2020-07-01
CmpDate: 2020-07-01

Kayyal H, Yiannakas A, Kolatt Chandran S, et al (2019)

Activity of Insula to Basolateral Amygdala Projecting Neurons is Necessary and Sufficient for Taste Valence Representation.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(47):9369-9382.

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.

RevDate: 2020-06-02

Har-Paz I, Roisman N, Michaelson DM, et al (2019)

Extra-Hippocampal Learning Deficits in Young Apolipoprotein E4 Mice and Their Synaptic Underpinning.

Journal of Alzheimer's disease : JAD, 72(1):71-82.

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.

RevDate: 2020-02-26

He ABH, Huang CL, Kozłowska A, et al (2019)

Involvement of neural substrates in reward and aversion to methamphetamine addiction: Testing the reward comparison hypothesis and the paradoxical effect hypothesis of abused drugs.

Neurobiology of learning and memory, 166:107090.

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.

RevDate: 2020-02-05
CmpDate: 2020-02-05

Nakajima S (2019)

Further demonstration of running-based food avoidance learning in laboratory mice (Mus musculus).

Behavioural processes, 168:103962.

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.

RevDate: 2020-05-12

Osorio-Gómez D, Bermúdez-Rattoni F, K Guzmán-Ramos (2019)

Artificial taste avoidance memory induced by coactivation of NMDA and β-adrenergic receptors in the amygdala.

Behavioural brain research, 376:112193.

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.

RevDate: 2020-02-25

Cunningham CL (2019)

Genetic Relationships Between Ethanol-Induced Conditioned Place Aversion and Other Ethanol Phenotypes in 15 Inbred Mouse Strains.

Brain sciences, 9(8):.

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.

RevDate: 2020-06-04
CmpDate: 2020-06-04

Galistu A, PS D'Aquila (2020)

Daily memantine treatment blunts hedonic response to sucrose in rats.

Psychopharmacology, 237(1):103-114.

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.

RevDate: 2020-06-19
CmpDate: 2020-04-02

Wills AJ, Edmunds CER, Le Pelley ME, et al (2019)

Dissociable learning processes, associative theory, and testimonial reviews: A comment on Smith and Church (2018).

Psychonomic bulletin & review, 26(6):1988-1993.

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.

RevDate: 2020-04-08
CmpDate: 2020-04-06

Harris AC, Muelken P, Swain Y, et al (2019)

Non-nicotine constituents in e-cigarette aerosol extract attenuate nicotine's aversive effects in adolescent rats.

Drug and alcohol dependence, 203:51-60.

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.

RevDate: 2019-11-25
CmpDate: 2019-11-25

Cui Y, Wu H, Li Q, et al (2019)

Impairment of Bitter Taste Sensor Transient Receptor Potential Channel M5-Mediated Aversion Aggravates High-Salt Intake and Hypertension.

Hypertension (Dallas, Tex. : 1979), 74(4):1021-1032.

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.

RevDate: 2020-02-25

Ruiz F, Keeley A, Léglise P, et al (2019)

Sex Differences in Medicine Acceptability: A New Factor to Be Considered in Medicine Formulation.

Pharmaceutics, 11(8):.

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.

RevDate: 2020-04-08
CmpDate: 2020-04-08

Olvera MJ, MI Miranda (2019)

Specific inter-stimulus interval effect of NMDA receptor activation in the insular cortex during conditioned taste aversion.

Neurobiology of learning and memory, 164:107043.

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.

RevDate: 2019-12-02
CmpDate: 2019-12-02

Tobajas J, Gómez-Ramírez P, María-Mojica P, et al (2019)

Selection of new chemicals to be used in conditioned aversion for non-lethal predation control.

Behavioural processes, 166:103905.

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.

RevDate: 2020-04-15
CmpDate: 2020-04-15

Tobajas J, Gómez-Ramírez P, Ferreras P, et al (2020)

Conditioned food aversion in domestic dogs induced by thiram.

Pest management science, 76(2):568-574.

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.

RevDate: 2019-09-06
CmpDate: 2019-09-05

Li LM, Liao YY, ES Jiang (2019)

[The electrophysiological response of chorda tympani nerve to taste stimuli in rats with conditioned taste aversion to saltiness].

Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 35(3):239-244.

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.

RevDate: 2020-03-09
CmpDate: 2020-03-05

Inui T, Sugishita T, Inui-Yamamoto C, et al (2019)

The Basolateral Nucleus of the Amygdala Executes the Parallel Processes of Avoidance and Palatability in the Retrieval of Conditioned Taste Aversion in Male Rats.

eNeuro, 6(4):.

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.

RevDate: 2020-03-09
CmpDate: 2020-03-09

Tanaka DH, Li S, Mukae S, et al (2019)

Genetic Access to Gustatory Disgust-Associated Neurons in the Interstitial Nucleus of the Posterior Limb of the Anterior Commissure in Male Mice.

Neuroscience, 413:45-63.

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.

RevDate: 2020-03-09
CmpDate: 2020-02-24

Schier LA, Hyde KM, AC Spector (2019)

Conditioned taste aversion versus avoidance: A re-examination of the separate processes hypothesis.

PloS one, 14(6):e0217458.

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.

RevDate: 2020-03-09
CmpDate: 2020-02-25

Devineni AV, Sun B, Zhukovskaya A, et al (2019)

Acetic acid activates distinct taste pathways in Drosophila to elicit opposing, state-dependent feeding responses.

eLife, 8:.

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.

RevDate: 2020-03-11
CmpDate: 2020-03-11

González-Sánchez H, Tovar-Díaz J, Morin JP, et al (2019)

NMDA receptor and nitric oxide synthase activity in the central amygdala is involved in the acquisition and consolidation of conditioned odor aversion.

Neuroscience letters, 707:134327.

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.

RevDate: 2020-05-27
CmpDate: 2020-05-27

Dannenhoffer CA, LP Spear (2019)

Excitatory/inhibitory balance across ontogeny contributes to age-specific behavioral outcomes of ethanol-like challenge in conditioned taste aversion.

Developmental psychobiology, 61(8):1157-1167.

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.

RevDate: 2020-06-23
CmpDate: 2020-06-23

Grau-Perales AB, Gómez-Chacón B, M Gallo (2019)

Differential activity pattern of c-Fos in the nucleus accumbens between adult and aged rats during flavor recognition memory.

Behavioural brain research, 371:111935.

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.

RevDate: 2020-02-25

Totani Y, Aonuma H, Oike A, et al (2019)

Monoamines, Insulin and the Roles They Play in Associative Learning in Pond Snails.

Frontiers in behavioral neuroscience, 13:65.

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.

RevDate: 2020-01-13
CmpDate: 2020-01-13

Williams RSB, PLR Andrews (2019)

Advice on avoiding the Valley of Death: insights from a 3Rs model of aversive and emetic compound identification.

ALTEX, 36(3):466-469.

RevDate: 2020-06-01
CmpDate: 2019-12-23

Ratner C, He Z, Grunddal KV, et al (2019)

Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway.

Diabetes, 68(6):1329-1340.

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.

RevDate: 2020-03-10
CmpDate: 2020-03-10

Keeley A, Teo M, Ali Z, et al (2019)

In Vitro Dissolution Model Can Predict the in Vivo Taste Masking Performance of Coated Multiparticulates.

Molecular pharmaceutics, 16(5):2095-2105.

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.

RevDate: 2020-06-12
CmpDate: 2020-06-12

Saalfield J, L Spear (2019)

Fos activation patterns related to acute ethanol and conditioned taste aversion in adolescent and adult rats.

Alcohol (Fayetteville, N.Y.), 78:57-68.

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.

RevDate: 2020-05-05
CmpDate: 2020-05-05

Pohjanvirta R, S Mahiout (2019)

Aryl hydrocarbon receptor is indispensable for β-naphthoflavone-induced novel food avoidance and may be involved in LiCl-triggered conditioned taste aversion in rats.

Physiology & behavior, 204:58-64.

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.

RevDate: 2019-10-07
CmpDate: 2019-10-07

Katzman DK, Norris ML, N Zucker (2019)

Avoidant restrictive food intake disorder: First do no harm.

The International journal of eating disorders, 52(4):459-461.

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.

RevDate: 2020-06-23
CmpDate: 2020-05-11

Patel S, Alvarez-Guaita A, Melvin A, et al (2019)

GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

Cell metabolism, 29(3):707-718.e8.

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.

RevDate: 2020-03-10

Crabbe JC, Metten P, Savarese AM, et al (2019)

Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice.

Brain sciences, 9(1):.

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.

RevDate: 2020-03-10

Gore-Langton JK, LP Spear (2019)

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.

Alcohol (Fayetteville, N.Y.), 79:59-69.

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.

RevDate: 2020-03-09
CmpDate: 2019-05-20

Mura E, Taruno A, Yagi M, et al (2018)

Innate and acquired tolerance to bitter stimuli in mice.

PloS one, 13(12):e0210032.

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.

RevDate: 2020-02-25

Zhou D, Zhao Y, Hook M, et al (2018)

Ethanol's Effect on Coq7 Expression in the Hippocampus of Mice.

Frontiers in genetics, 9:602.

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.

RevDate: 2019-03-20
CmpDate: 2019-03-20

Nakajima S (2019)

Food avoidance learning based on voluntary wheel running in laboratory mice (Mus musculus).

Behavioural processes, 159:31-36.

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.

RevDate: 2020-01-16
CmpDate: 2020-01-16

Serita T, Miyahara M, Tanimizu T, et al (2019)

Dietary magnesium deficiency impairs hippocampus-dependent memories without changes in the spine density and morphology of hippocampal neurons in mice.

Brain research bulletin, 144:149-157.

Magnesium (Mg2+) is an essential mineral for maintaining biological functions. One major action of Mg2+ 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, Mg2+ has been shown to play critical roles in learning and memory, and synaptic plasticity. However, the effects of dietary Mg2+ 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.

RevDate: 2020-03-10

Barney TM, Vore AS, Gano A, et al (2019)

The influence of central interleukin-6 on behavioral changes associated with acute alcohol intoxication in adult male rats.

Alcohol (Fayetteville, N.Y.), 79:37-45.

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.

RevDate: 2019-07-31
CmpDate: 2019-07-31

Barik A, MJ Krashes (2018)

Remembering a Bad Taste.

Neuron, 100(4):765-767.

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 PBNCGRP neurons in both the acquisition and the expression of CTA.

RevDate: 2020-03-20
CmpDate: 2020-03-20

Delay ER, Weaver B, Lane DR, et al (2019)

Dried bonito dashi: Contributions of mineral salts and organic acids to the taste of dashi.

Physiology & behavior, 199:127-136.

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.

RevDate: 2018-12-14
CmpDate: 2018-12-14

Bernal-Gamboa R, Rosas JM, J Nieto (2018)

Extinction makes acquisition context-specific in conditioned taste aversion regardless of the context where acquisition and testing take place.

Journal of experimental psychology. Animal learning and cognition, 44(4):385-395.

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).

RevDate: 2019-12-10
CmpDate: 2018-12-14

Thrailkill EA, Trask S, Vidal P, et al (2018)

Stimulus control of actions and habits: A role for reinforcer predictability and attention in the development of habitual behavior.

Journal of experimental psychology. Animal learning and cognition, 44(4):370-384.

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).

RevDate: 2020-02-05

Yasumatsu K, Iwata S, Inoue M, et al (2019)

Fatty acid taste quality information via GPR120 in the anterior tongue of mice.

Acta physiologica (Oxford, England), 226(1):e13215.

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.

RevDate: 2019-12-10
CmpDate: 2019-03-21

Schoenberg HL, Sola EX, Seyller E, et al (2019)

Female rats express habitual behavior earlier in operant training than males.

Behavioral neuroscience, 133(1):110-120.

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).

RevDate: 2019-11-21
CmpDate: 2019-08-12

Chen JY, Campos CA, Jarvie BC, et al (2018)

Parabrachial CGRP Neurons Establish and Sustain Aversive Taste Memories.

Neuron, 100(4):891-899.e5.

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 CGRPPBN neurons to either the central nucleus of the amygdala or the bed nucleus of the stria terminalis can also induce robust CTA. CGRPPBN 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 CGRPPBN neurons after conditioning. Inhibition of these neurons or inactivation of the Grin1 gene after conditioning attenuates CTA expression. Our results indicate that CGRPPBN neurons not only play a key role for learning food aversions but also contribute to the maintenance and expression of those memories.

RevDate: 2020-03-09
CmpDate: 2019-09-16

Arthurs J, Lin JY, S Reilly (2018)

Inhibiting gustatory thalamus or medial amygdala has opposing effects on taste neophobia.

Neurobiology of learning and memory, 156:24-32.

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.

RevDate: 2019-12-07
CmpDate: 2019-08-19

Flores VL, Parmet T, Mukherjee N, et al (2018)

The role of the gustatory cortex in incidental experience-evoked enhancement of later taste learning.

Learning & memory (Cold Spring Harbor, N.Y.), 25(11):587-600.

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.

RevDate: 2019-12-10
CmpDate: 2018-12-18

Kivell BM, Paton KF, Kumar N, et al (2018)

Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.

Molecules (Basel, Switzerland), 23(10):.

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.

RevDate: 2020-02-25
CmpDate: 2019-02-21

Tai S, Vasiljevik T, Sherwood AM, et al (2018)

Assessment of rimonabant-like adverse effects of purported CB1R neutral antagonist / CB2R agonist aminoalkylindole derivatives in mice.

Drug and alcohol dependence, 192:285-293.

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.

RevDate: 2019-01-30
CmpDate: 2019-01-30

Molero-Chamizo A (2018)

Effects of extensive amygdaloid lesions on conditioned taste aversion in rats.

Acta neurobiologiae experimentalis, 78(3):242-250.

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.

RevDate: 2020-02-25
CmpDate: 2019-03-28

Nakajima S (2019)

Food aversion learning based on voluntary running in non-deprived rats: a technique for establishing aversive conditioning with minimized discomfort.

Experimental animals, 68(1):71-79.

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.

RevDate: 2019-03-04
CmpDate: 2019-03-04

Soto J, Keeley A, Keating AV, et al (2018)

Rats can predict aversiveness of Active Pharmaceutical Ingredients.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 133:77-84.

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 (R2 = 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.

RevDate: 2019-04-16
CmpDate: 2019-04-16

Rodríguez-Blanco LA, Rivera-Olvera A, ML Escobar (2019)

Consolidation of an aversive taste memory requires two rounds of transcriptional and epigenetic regulation in the insular cortex.

Behavioural brain research, 356:371-374.

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.

RevDate: 2020-05-10
CmpDate: 2019-09-23

Lin JY, Arthurs J, S Reilly (2018)

The effects of amygdala and cortical inactivation on taste neophobia.

Neurobiology of learning and memory, 155:322-329.

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.

RevDate: 2020-03-09
CmpDate: 2019-05-01

Weera MM, Agim ZS, Cannon JR, et al (2019)

Genetic correlations between nicotine reinforcement-related behaviors and propensity toward high or low alcohol preference in two replicate mouse lines.

Genes, brain, and behavior, 18(3):e12515.

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.

RevDate: 2019-10-22
CmpDate: 2019-10-21

Moschak TM, Wang X, RM Carelli (2018)

A Neuronal Ensemble in the Rostral Agranular Insula Tracks Cocaine-Induced Devaluation of Natural Reward and Predicts Cocaine Seeking.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 38(39):8463-8472.

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.

RevDate: 2019-09-01
CmpDate: 2019-07-26

Kubilius RA, Kaplick PM, CT Wotjak (2018)

Highway to hell or magic smoke? The dose-dependence of Δ9-THC in place conditioning paradigms.

Learning & memory (Cold Spring Harbor, N.Y.), 25(9):446-454.

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. Δ9-tetrahydrocannabinol (Δ9-THC), the prime psychoactive compound of the cannabis sativa, as well as cannabimimetics that resemble the pharmacological properties and psychological effects of Δ9-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 Δ9-THC (rewarding versus aversive) has been abundantly reported in place conditioning (PC) paradigms, and might be best attributed to a dose-dependence of Δ9-THC, most PC studies with Δ9-THC feature no significant effects at all. Therefore, after decades of rigorous research, it still remains undetermined whether Δ9-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 Δ9-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 Δ9-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) Δ9-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 Δ9-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 Δ9-THC substantiate the dose-dependent biphasic effects of Δ9-THC in PC. A standardized experimental design would advance evidence-based practice in future PC studies with Δ9-THC and facilitate the pointed establishment of rewarding and aversive effects of the substance.

RevDate: 2019-11-20

Agee LA, MH Monfils (2018)

Effect of demonstrator reliability and recency of last demonstration on acquisition of a socially transmitted food preference.

Royal Society open science, 5(6):172391.

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.

RevDate: 2019-12-10
CmpDate: 2019-04-18

Gartner SN, Klockars A, Prosser C, et al (2018)

Identification of central mechanisms underlying anorexigenic effects of intraperitoneal L-tryptophan.

Neuroreport, 29(15):1293-1300.

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.

RevDate: 2019-11-20

Chambers KC (2018)

Conditioned taste aversions.

World journal of otorhinolaryngology - head and neck surgery, 4(1):92-100.

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.

RevDate: 2019-09-23
CmpDate: 2019-09-23

Loney GC, Pautassi RM, Kapadia D, et al (2018)

Nicotine affects ethanol-conditioned taste, but not place, aversion in a simultaneous conditioning procedure.

Alcohol (Fayetteville, N.Y.), 71:47-55.

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.

RevDate: 2019-11-07
CmpDate: 2019-11-07

Lavi K, Jacobson GA, Rosenblum K, et al (2018)

Encoding of Conditioned Taste Aversion in Cortico-Amygdala Circuits.

Cell reports, 24(2):278-283.

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.

RevDate: 2019-11-20

Aonuma H, Totani Y, Sakakibara M, et al (2018)

Comparison of brain monoamine content in three populations of Lymnaea that correlates with taste-aversive learning ability.

Biophysics and physicobiology, 15:129-135.

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.

RevDate: 2019-11-20

Angulo R (2018)

Pre-exposure Schedule Effects on Generalization of Taste Aversion and Palatability for Thirsty and Not Thirsty Rats.

Frontiers in psychology, 9:878.

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.

RevDate: 2019-04-16
CmpDate: 2019-04-16

Caynas-Rojas S, Rodríguez-García G, Delint-Ramírez I, et al (2019)

Differential function of medial prefrontal cortex catecholaminergic receptors after long-term sugar consumption.

Behavioural brain research, 356:495-503.

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.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

Electronic Scholarly Publishing
961 Red Tail Lane
Bellingham, WA 98226

E-mail: RJR8222 @

Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )