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RationaleAlcohol use disorder remains a leading cause of preventable deaths, and current treatments have limited efficacy. Glucagon-like peptide 1 (GLP-1) receptor agonists can reduce alcohol drinking in preclinical studies, but mechanisms are still not fully understood, and data in female subjects are scarce.ObjectivesTo assess whether the GLP-1 receptor agonist exendin-4 could decrease alcohol-seeking behavior in the absence of alcohol consumption or intoxication, to compare the potency and efficacy of exendin-4 in the reduction of alcohol seeking vs. alcohol taking, and to compare effects between male and female mice.MethodsMale and female C57BL/6J mice were trained to self-administer 20% alcohol under an FR 1 schedule of reinforcement. After extinction, systemic exendin-4 (saline, 1.8, and 3.2 μg/kg) was tested in cue-induced reinstatement of alcohol seeking. Effects of exendin-4 on alcohol self-administration were tested in a separate group.ResultsExendin-4 suppressed reinstatement of alcohol seeking to extinction levels, at both doses, in the male mice, but had no effect in the female mice. Both doses of exendin-4 also significantly decreased alcohol self-administration in male mice; females again showed less pronounced effects.ConclusionsIn male mice, exendin-4 appeared more effective at suppressing alcohol seeking in the absence of alcohol relative to alcohol self-administration, consistent with modulation of alcohol reward or inhibitory control, rather than satiety or aversive effects of alcohol. We saw marked sex differences with less effect of exendin-4 in female mice, and it will be important to include both sexes in further investigations into GLP-1 receptor agonists. Rationale: Alcohol use disorder remains a leading cause of preventable deaths, and current treatments have limited efficacy. Glucagon-like peptide 1 (GLP-1) receptor agonists can reduce alcohol drinking in preclinical studies, but mechanisms are still not fully understood, and data in female subjects are scarce. Objectives: To assess whether the GLP-1 receptor agonist exendin-4 could decrease alcohol-seeking behavior in the absence of alcohol consumption or intoxication, to compare the potency and efficacy of exendin-4 in the reduction of alcohol seeking vs. alcohol taking, and to compare effects between male and female mice. Methods: Male and female C57BL/6J mice were trained to self-administer 20% alcohol under an FR 1 schedule of reinforcement. After extinction, systemic exendin-4 (saline, 1.8, and 3.2 μg/kg) was tested in cue-induced reinstatement of alcohol seeking. Effects of exendin-4 on alcohol self-administration were tested in a separate group. Results: Exendin-4 suppressed reinstatement of alcohol seeking to extinction levels, at both doses, in the male mice, but had no effect in the female mice. Both doses of exendin-4 also significantly decreased alcohol self-administration in male mice; females again showed less pronounced effects. Conclusions: In male mice, exendin-4 appeared more effective at suppressing alcohol seeking in the absence of alcohol relative to alcohol self-administration, consistent with modulation of alcohol reward or inhibitory control, rather than satiety or aversive effects of alcohol. We saw marked sex differences with less effect of exendin-4 in female mice, and it will be important to include both sexes in further investigations into GLP-1 receptor agonists.

Persistent alcohol use despite negative consequences is a key feature of alcohol use disorder (AUD) and is typically assessed using punishment in animal models. This study examined relapse-like behavior in male and female alcohol-preferring iP rats following punishment-imposed voluntary abstinence to alcohol seeking. We focused on alcohol seeking in the punishment-associated environment after prolonged abstinence. Finally, we sought to understand the predictability of relapse-like behavior by examining AUD comorbidities, namely, anxiety-like behavior and the response to repeated, moderate punishment. We found no sex differences in operant self-administration of alcohol. However, we did find a reduced propensity to relapse in the punishment-associated environment in female rats following prolonged abstinence. Relapse propensity was associated with the response to punishment during operant training, but not prior anxiety-like behavior. Together these results highlight the importance of studying sex differences in relapse to alcohol seeking. In addition, the behavioral response to a negative consequence may be a predictor of relapse, particularly in females. Improving our understanding of the sexually dimorphic responses in alcohol seeking may be a powerful tool for designing personalized, or at least sex-specific, approaches to treatment and rehabilitation programs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BACKGROUND Accumulating clinical evidence suggests that women with prior exposure to adverse childhood experiences are more susceptible to heavy drinking and other health-related behaviors. Yet, preclinical studies investigating sex-dependent effects of adolescent adverse social experiences (ASEs) on later alcohol-seeking behavior are lacking. This is mainly due to the unavailability of valid animal models and a shortage of studies that compare effects in males and females. Therefore, we sought to investigate the sex-dependent effects of ASE on adult alcohol-seeking behavior, locomotion, and reward sensitivity in male and female rats. METHODS We recently developed a rat model for childhood/adolescent peer rejection that allows us to study the long-term consequences of ASEs. Adolescent Wistar rats were reared from postnatal day (pd) 21 to pd 50 either within a group of Fischer 344 rats (ASE) or within a group of Wistar rats (control). Wistar rats housed with Fischer 344 rats do not reciprocate social play in adolescence. This reduced play across adolescence mimics peer rejection and results in chronic dysregulation of social and pain-related behaviors. We tested adult male and female rats in the reinstatement paradigm for cue-induced alcohol-seeking behavior, circadian locomotor activity, and sucrose consumption long after the termination of the peer rejection condition. RESULTS Peer rejection induced persistent sex-dependent changes in alcohol cue-induced reinstatement. Females showed an increased reinstatement effect while peer-rejected males demonstrated a decrease. Sex differences were observed in locomotor activity or reward sensitivity to sucrose. CONCLUSIONS Peer rejection has long-lasting sex-dependent consequences on alcohol-seeking behavior without affecting locomotion or sweet reward sensitivity. Our results suggest that peer-rejected female rats represent a vulnerable population in which to study relapse-like behaviors that are similar to clinical findings, while males seem to buffer the peer rejection effect and demonstrate resilience to later life alcohol-seeking behaviors, as measured by the reinstatement effect. Finally, we provide a novel approach to investigate the molecular and neurobiological underpinnings of ASEs on alcohol and other drug-seeking behaviors.

Alcohol addiction is a chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse consequences. A main challenge of addiction treatment is to prevent relapse, which occurs in more than >50% of newly abstinent patients with alcohol disorder within 3 months. In people suffering from alcohol addiction, stressful events, drug-associated cues and contexts, or re-exposure to a small amount of alcohol trigger a chain of behaviors that frequently culminates in relapse. In this review, we first present the preclinical models that were developed for the study of alcohol seeking behavior, namely the reinstatement model of alcohol relapse and compulsive alcohol seeking under a chained schedule of reinforcement. We then provide an overview of the neurobiological findings obtained using these animal models, focusing on the role of opioids systems, corticotropin-release hormone and neurokinins, followed by dopaminergic, glutamatergic, and GABAergic neurotransmissions in alcohol seeking behavior. Funding Agencies|Swedish Research Council, VR projectSwedish Research Council [2018-02320]

The corticostriatal circuitry and its glutamate-γ-aminobuturic acid (GABA) interactions play an essential role in regulating neuronal excitability during reward-seeking behavior. However, the contribution of GABAergic interneurons in the corticostriatal circuitry remains unclear. To investigate the role of GABAergic interneurons, we focused on parvalbumin-expressing fast-spiking interneurons (Pv-FSI) in the corticostriatal circuitry using the designer receptors exclusively activated by designer drugs approach in a Pv-Cre mouse model. We hypothesize that Pv-FSI activation elicits changes in cortical glutamate levels and reward-seeking behaviors. To determine molecular and behavioral effects of Pv-FSI, we performed microdialysis and operant conditioning tasks for sucrose and alcohol rewards. In addition, we also examined how alcohol reward itself affects Pv-FSI functioning. Interestingly, our microdialysis results demonstrate that alcohol exposure inhibits Pv-FSI functioning in the medial prefrontal cortex (mPFC) and this consequently can regulate glutamate levels downstream in the nucleus accumbens. For sucrose reward-seeking behaviors, Pv-FSI activation in the mPFC increases sucrose self-administration whereas it does not promote alcohol seeking. For alcohol rewards, however, Pv-FSI activation in the mPFC results in increased compulsive head entry in operant chambers during devaluation procedures. Overall, our results suggest that not only do Pv-FSI contribute to changes in the cortical microcircuit and reward-seeking behaviors but also that alcohol affects Pv-FSI neurotransmission. Therefore, Pv-FSI has prompted interest in their role in maintaining a balance in neuronal excitation/inhibition and in regulating reward-seeking processes such as compulsivity, all of which are important factors for excessive alcohol seeking.

Alcohol Use Disorder (AUD) is among the most prevalent mental illnesses, and due to the low efficacy of the current medication, it is essential to find new biological targets that could modulate alcohol consumption. Since Galanin (1−15) [GAL(1−15)] produces a loss of motivational behaviour by an artificial reinforcer and decreases the preference an alcohol consumption in a voluntary alcohol intake, we have studied the role of GAL(1−15) in alcohol-seeking behaviour and the involvement of the corticomesolimbic system as well as the role of GAL(1−15) in context-induced alcohol relapse. In rats, we have studied GAL(1−15)-effects on alcohol-seeking in self-administration, in fixed-ratio (FR1) and progressive-ratio (PR), and the involvement of GAL receptors using siRNA GALR1 or GALR2 knockdown animals. We have analysed the transcriptional changes of C-Fos, dopamine receptors, GAL receptors and 5HT1A receptors in the corticomesolimbic system. Also, we have examined the effect of GAL(1−15) in context-induced alcohol relapse. GAL(1−15) substantially reduced alcohol-seeking behaviour in the operant self-administration model in an FR1 protocol and at the breaking point in a PR schedule. GALR1and GALR2 were involved in these effects, as indicated by the analysis by GALR2 antagonist and GALR1 and GALR2 knockdown animals. Notably, the mechanism of GAL(1−15)-mediated actions involved changes in C-Fos, Dopamine receptors and 5HT1A expression in the ventral tegmental area, accumbens nucleus and prefrontal cortex. Significantly, GAL(1−15) reduced the context-induced alcohol relapse. These results open up the possibility to use GAL(1−15) as a novel strategy in AUD. This work was supported by grants awarded by Spanish Ministry of Economy PID2020-114392RB-100, PDC2021-121566-100 and by Junta de Andalucía P20-00026-R and PI-0083-2019. Partial funding for open access charge: Universidad de Málaga

In humans, stimuli associated with alcohol availability can provoke relapse during abstinence. In this study, we investigated the role of discriminative stimuli (DS) in the control of alcohol seeking in two types of behavioral tests. The first test examined the ability of an alcohol-associated DS to promote alcohol seeking (relapse) after punishment-imposed abstinence in the presence of a different DS. Following this, we tested whether the differentially associated DS can promote and suppress alcohol self-administration in a within-session discrimination task. During the within-session discrimination task, we also tested the rate of alcohol self-administration when two DS are presented in a compound. We first trained Long-Evans male rats (n = 24) to self-administer alcohol in the presence of one DS (reward-associated discriminative stimulus, rewDS) and then punished that behavior in the presence of a different DS (punishment-associated discriminative stimulus, punDS). On the test, we found that rats tested with the rewDS showed higher alcohol seeking than rats tested with the punDS. This result shows that a single Cue DS can promote alcohol seeking in a manner comparable to contexts. Subsequently, we trained 16 of these rats in a within-session trial-based discrimination task, comprised of intervening 2-min trials of rewDS, punDS, or conflict with rewDS and punDS in compound and a reduced probability of punishment. We found that alcohol self-administration is bi-directionally regulated by the rewDS and punDS. In conflict trials, alcohol self-administration was at a rate that was intermediate between the rewDS and punDS trials. In a final test, rats were presented with one of the three trial conditions and perfused for Fos immunohistochemistry. We found Fos expression was higher in the rats tested in the conflict condition in three interconnected sub-cortical brain regions. This study demonstrated the important role that alcohol-associated DS plays an important role in promoting relapse to alcohol seeking after punishment-imposed abstinence. We also implemented a within-session discrimination task that allows for the study of alcohol seeking under motivational conflict, which may be relevant for alcohol use despite negative consequences. The results from the Fos data suggest that higher alcohol seeking in approach-avoidance motivational conflict is associated with activation of sub-cortical regions but not cortical regions.

An improved understanding of the molecular basis of alcohol seeking despite the catastrophic consequences of alcohol abuse is likely to enrich our treatments for Alcohol Use Disorders (AUD) and comorbidities. The compulsive seeking is characterized by an imbalance between the superior drive to substance and disruption in control of substance use. To model the development of compulsive engagement of alcohol seeking, we exploit two distinct behavioral programs of C. elegans in conflict, ethanol preference and avoidance of aversive stimulus, simultaneously. We demonstrate that C. elegans exhibited the recapitulation of the pivotal features of compulsive alcohol seeking in mammals, which are repeated attempts, endurance, and finally aversion-resistant ethanol seeking. We find that the neuropeptide signaling via SEB-3, CRF receptor-like GPCR, facilitates the development of ethanol preference and compels animals to seek ethanol compulsively. Furthermore, our functional genomic approach and behavioral elucidation suggest the interaction between neuropeptidergic signaling, SEB-3 and TKR-1, Neurokinin receptor orthologue, to progress compulsive ethanol seeking behavior.

Alcohol dependence is associated with aberrant decision-making processes, particularly in the presence of alcohol-related environmental cues. For instance, alcohol cues can trigger alcohol seeking, consumption, and even relapse behavior. Recently, works have suggested that alcohol dependence may induce more general alterations in cued processes that support adaptive behavior, including enhanced cue control of volitional behavior unrelated to alcohol use. Here we examine this hypothesis by combining prior exposure to chronic intermittent ethanol and repeated withdrawal (CIE) procedures with a Pavlovian-to-instrumental transfer (PIT) task in mice. The PIT task entails training a Pavlovian association, separately training an instrumental contingency, and a final test during which the Pavlovian cue and instrumental action are combined for the first time. We first tested two variants of the PIT procedure in ethanol-naive mice, differing in part in the duration of Pavlovian conditioned cues (short or long). We found in the PIT test that the short cue procedure produced negative transfer, whereas the long cue procedure produced positive transfer. We then used the long cue variant to examine PIT behavior in mice previously exposed to either CIE or air vapor. We found that prior CIE exposure strengthened PIT behavior, with enhanced instrumental responding during presentation of the food-associated cue. We further found that this enhancement in CIE mice persisted even after devaluation of the food outcome. Our findings suggest that ethanol dependence can enhance the influence of reward-predictive cues on ongoing behavior. Greater non-alcohol cue control of behavior may reflect the effect of chronic ethanol exposure on neural circuitry critical for cue-guided behavior in general.

Positive allosteric modulators (PAMs) of the GABAB receptor constitute a class of pharmacological agents gaining increasing attention in the alcohol research field because of their ability to suppress several alcohol-related behaviors in rodents. CMPPE is a novel GABAB PAM, still limitedly characterized in vivo. It was therefore of interest to test its ability to affect operant, oral self-administration of alcohol and cue-induced reinstatement of alcohol seeking in alcohol-preferring rats. To this end, female Sardinian alcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions (under the FR5 [Experiment 1] and progressive ratio [PR; Experiment 2] schedules of reinforcement) preceded by treatment with CMPPE (0, 2.5, 5, and 10 mg/kg; intraperitoneally [i.p.]). In Experiment 3, once lever-responding had stabilized, rats underwent an extinction responding phase and then a single reinstatement session during which lever-responding was resumed by the non-contingent presentation of a complex of alcohol-associated cues; CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) was administered before the reinstatement session. Selectivity of CMPPE action was assessed by evaluating the effect of CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) on self-administration of a chocolate solution in male Wistar rats (Experiment 4). In Experiments 1 and 2, treatment with 5 and 10 mg/kg CMPPE reduced lever-responding and breakpoint for alcohol. In Experiment 3, treatment with 5 and 10 mg/kg CMPPE suppressed reinstatement of alcohol seeking. In Experiment 4, no dose of CMPPE affected lever-responding for the chocolate solution. These results extend to CMPPE the ability of all previously tested GABAB PAMs to affect alcohol-motivated behaviors in rodents and confirm that these effects are a shared feature of the entire class of GABAB PAMs. This conclusion is of relevance in view of the forthcoming transition of GABAB PAMs to clinical testing.

To better approximate the human condition, animal models of relapse to drug and alcohol seeking have increasingly employed negative consequences to generate abstinence. Here we report the first demonstration of relapse to punishment-suppressed alcohol seeking induced by loss of non-drug reward (i.e., resurgence). We also report the first examination of potential sex differences in any form of relapse to alcohol seeking following suppression by punishment. Male and female rats first pressed a lever for 20 % oral alcohol. Next, lever pressing for one group continued to produce alcohol, but also produced occasional footshock. For another group, lever pressing similarly produced alcohol and occasional footshock, and a nose-poke response produced alternative non-drug reward (i.e., food). Males showed similar suppression of alcohol seeking by punishment alone and punishment + alternative non-drug reward, whereas females showed less suppression by punishment alone. Finally, when alternative reinforcement and punishment were suspended, resurgence occurred for both sexes in the group that previously had access to non-drug reward. Exposure to and then removal of punishment alone did not produce relapse for males, but it did for females. These results suggest that loss of alternative non-drug reward can generate relapse to alcohol seeking following abstinence induced by negative consequences. Future research should further examine the role of potential sex differences in sensitivity to punishment and how such differences may contribute to relapse more broadly.

Aims Recently we developed a model to study alcohol-seeking behaviour after withdrawal in a social context in female mice. The model raised several questions that we were eager to address to improve methodology. Methods In our model, female mice were group-housed in automated cages with three conditioned (CS+) corners and water in both sides of one separate non-conditioned corner. Water was available with opened doors at all the time of training. We established conditioning by pairing alcohol drinking with light cues. Here, we introduced prolonged access to increasing concentrations of alcohol instead of intermittent access. To study motivation to drink alcohol, we carried out the extinction tests on withdrawal days 1 (WD1) and 10 (WD10). During tests, the light cues were present in conditioned corners, but there was no liquid in the bottles. Results We found that the number of visits and nosepokes in the CS+ corner in the alcohol group was much higher than in the water group. Also, during training, the consumption of alcohol was increasing. In the extinction tests, we found that the number of nosepokes in the CS+ corner increased in the alcohol group on both WD1 and WD10. Conclusions Our study supports that alcohol-seeking behaviour after withdrawal can be modelled and studied in group-housed animals and environments without social isolation.

Preclinical models of alcohol use disorder (AUD) have advanced theoretical, mechanistic, and pharmacological study of the human condition. "Liking" and "wanting" behaviors reflect core processes underlying several models of AUD. However, the development and application of translational models of these preclinical approaches are at an incipient stage. The goal of this study was to examine how intravenous free-access and progressive-ratio, operant-response human alcohol self-administration paradigms can be used as translational human model parallels of preclinical "liking" and "wanting." Participants were 40 adults (mean age = 23.7, SD = 2.0; 45% female) of European descent who reported 12.6 drinking days (SD = 5.2) out of the previous 30 (average = 4.1 drinks per drinking day [SD = 1.7]). Individuals diverged in their alcohol self-administration behavior, such that free-access and progressive-ratio paradigm outcomes were not significantly correlated (p = 0.44). Free-access alcohol seeking was related to enjoying alcohol (p 0.001), but not craving (p = 0.48), whereas progressive-ratio seeking at similar levels of alcohol exposure was related to craving (p = 0.02), but not enjoying (p = 0.30). Family history of alcoholism, venturesomeness traits, and disinhibition traits were unrelated (ps 0.70) to preferred level of breath alcohol concentration (BrAC) in the free-access session, a measure of liking alcohol. Family history of alcoholism, disinhibition traits, and recent drinking history were significantly related (ps 0.05) to alcohol seeking in the progressive-ratio paradigm, a measure of wanting alcohol. We conclude that intravenous alcohol self-administration paradigms show promise in modeling behaviors that characterize and parallel alcohol "liking" and "wanting" in preclinical models. These paradigms provide a translational link between preclinical methods and clinical trials.

Excessive drinking is an important behavioural characteristic of alcohol addiction, but not the only one. Individuals addicted to alcohol crave alcoholic beverages, spend time seeking alcohol despite negative consequences, and eventually drink to intoxication. With prolonged use, control over alcohol seeking devolves to anterior dorsolateral striatum, dopamine-dependent mechanisms implicated in habit learning and individuals in whom alcohol-seeking relies more on these mechanisms are more likely to persist in seeking alcohol despite the risk of punishment. Here, we tested the hypothesis that the development of habitual alcohol-seeking predicts the development of compulsive seeking and that, once developed, it is associated with compulsive alcohol drinking. Male alcohol-preferring rats were pre-exposed intermittently to a two-bottle choice procedure, and trained on a seeking–taking chained schedule of alcohol reinforcement until some individuals developed punishment-resistant seeking behaviour. The associative basis of their seeking responses was probed with an outcome-devaluation procedure, early or late in training. After seeking behaviour was well established, subjects that had developed greater resistance to outcome-devaluation (were more habitual) were more likely to show punishment-resistant (compulsive) alcohol seeking. These individuals also drank more alcohol, despite quinine adulteration, even though having similar alcohol preference and intake before and during instrumental training. They were also less sensitive to changes in the contingency between seeking responses and alcohol outcome, providing further evidence of recruitment of the habit system. We therefore provide direct behavioural evidence that compulsive alcohol seeking emerges alongside compulsive drinking in individuals that have preferentially engaged the habit system.

Made available in DSpace on 2021-06-25T11:06:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-02-01 Drug addiction is a chronic mental disorder characterized by frequent relapses. Contextual cues associated with drug use to play a critical causal role in drug-seeking behavior. The hippocampus has been implicated in encoding drug associative memories. Here we examine whether the dorsal hippocampus mediates context-induced reinstatement of alcohol-seeking. Male Long-Evans rats were trained to self-administer alcohol in Context A. Alcohol self-administration was extinguished in a distinct context (Context B). On the test day, animals were re-exposed to the alcohol Context A or the extinction Context B. Next, to assess a causal role for the dorsal hippocampus in context-induced alcohol-seeking, on the test day, we injected cobalt chloride (CoCl2; a nonselective synapse inhibitor) or vehicle into the dorsal hippocampus, and 15 min later, rats were tested by re-exposing them to the drug-associated context. The re-exposure to the alcohol-associated Context A reinstated alcohol seeking and increased Fos-positive cells in the dorsal hippocampus neurons (CA1, CA3, and Dentate Gyrus). Pharmacological inactivation with cobalt chloride of the dorsal hippocampus attenuated the reinstatement of alcohol-seeking. Our data suggest that the dorsal hippocampus may be involved in context-induced alcohol-seeking behavior. Department of Pharmacology Universidade Federal de São Paulo - UNIFESP Psychology Laboratory Psychology Department Universidade Federal de São Carlos - UFSCar Laboratory of Pharmacology São Paulo State University (Unesp) School of Pharmaceutical Sciences Biomedical Sciences Institute Universidade Federal de Uberlândia - UFU Uberlândia Laboratory of Pharmacology São Paulo State University (Unesp) School of Pharmaceutical Sciences

BackgroundAccumulating clinical evidence suggests women with prior exposure to adverse childhood experiences are more susceptible to alcohol relapse and other health-related issues. Yet, preclinical studies investigating sex-dependent effects of adolescent adverse social experiences (ASEs) on later alcohol-seeking behavior are lacking. This is mainly due to a lack of valid animal models and a shortage of studies comparing sexes. Therefore, we sought to investigate the sex-dependent effects of ASE on adult alcohol-seeking behavior, locomotion and reward sensitivity in both male and female rats.MethodsWe recently developed a rat model for adolescent peer-rejection which allows us to study the long-term consequences of ASEs. Peer-rejection interferes with adolescent rats‘ability to engage in adequate and reciprocal play behaviors that result in persistent dysregulation of social and pain-related behavior. Adolescent Wistar rats were reared from postnatal day (pd) 21 to pd 50 either within a group of Fischer 344 rats (ASE) or with Wistar rats (control). Adult male and female rats were tested in the reinstatement paradigm for cue-induced alcohol-seeking behavior, circadian locomotor activity, and sucrose consumption in adulthood long-after the termination of the peer-rejection condition.ResultsPeer-rejection induced persistent sex-dependent changes to cue-induced reinstatement. Females showed an increased reinstatement effect while peer-rejected males demonstrated a decrease. No differences were observed in circadian locomotor activity or reward sensitivity to sucrose.ConclusionsPeer-rejection has lasting sex-dependent consequences on alcohol-seeking behavior without affecting locomotion or sweet reward sensitivity. Our results suggest that peer-rejected female rats represent a vulnerable population to study relapse-like behaviors similar to clinical findings. While males seem to buffer the peer-rejection effect and demonstrate resilience to later-life alcohol-seeking behaviors, measured by the reinstatement effect. Finally, we provide a novel approach to investigate the molecular and neurobiological underpinnings of ASEs on alcohol and other drug-seeking behaviors.

Chemogenetic suppression of a neuronal ensemble that encodes a lasting alcohol cue memory attenuates cue-induced relapse., Alcohol use disorder is characterized by a high risk of relapse during periods of abstinence. Relapse is often triggered by retrieval of persistent alcohol memories upon exposure to alcohol-associated environmental cues, but little is known about the neuronal circuitry that supports the long-term storage of alcohol cue associations. We found that a small ensemble of neurons in the medial prefrontal cortex (mPFC) of mice was activated during cue-paired alcohol self-administration (SA) and that selective suppression of these neurons 1 month later attenuated cue-induced relapse to alcohol seeking. Inhibition of alcohol seeking was specific to these neurons as suppression of a non–alcohol-related or sucrose SA–activated mPFC ensemble did not affect relapse behavior. Hence, the mPFC neuronal ensemble activated during cue-paired alcohol consumption functions as a lasting memory trace that mediates cue-evoked relapse long after cessation of alcohol intake, thereby providing a potential target for treatment of alcohol relapse vulnerability.

Given the significant cost of alcohol use disorder (AUD), identifying risk factors for alcohol seeking represents a research priority. Prominent addiction theories emphasize the role of motivation in the alcohol seeking process, which has largely been studied using preclinical models. In order to bridge the gap between preclinical and clinical studies, this study examined predictors of motivation for alcohol self-administration using a novel paradigm. Heavy drinkers (n = 67) completed an alcohol infusion consisting of an alcohol challenge (target breath alcohol = 60 mg%) and a progressive-ratio alcohol self-administration paradigm (maximum breath alcohol 120 mg%; ratio requirements range = 20-3 139 response). Growth curve modeling was used to predict breath alcohol trajectories during alcohol self-administration. K-means clustering was used to identify motivated (n = 41) and unmotivated (n = 26) self-administration trajectories. The data were analyzed using two approaches: a theory-driven test of a-priori predictors and a data-driven, machine learning model. In both approaches, steeper delay discounting, indicating a preference for smaller, sooner rewards, predicted motivated alcohol seeking. The data-driven approach further identified phasic alcohol craving as a predictor of motivated alcohol self-administration. Additional application of this model to AUD translational science and treatment development appear warranted.

Alcohol-use disorders are chronically relapsing conditions characterized by cycles of use, abstinence and relapse. The ventral pallidum (VP) is a key node in the neural circuits controlling relapse to alcohol seeking and a key target of pharmacotherapies for relapse prevention. There has been a significant increase in our understanding of the molecular, anatomical, pharmacological and functional properties of the ventral pallidum, laying foundations for a new understanding of its role in relapse to alcohol seeking and motivation. Here we review these advances, placing special emphasis on how advances in understanding in the cellular and circuit architectures of ventral pallidum contributes to the relapse to alcohol seeking. We show how this knowledge improves mechanistic understanding of current relapse prevention pharmacotherapies, how it may be used to tailor these against different forms of relapse and how it may help provide insights into the mental health problems frequently co-morbid with alcohol-use disorders.

The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. Here we show how different forms of relapse to alcohol-seeking are assembled from activity across the ventral tegmental area and the nucleus accumbens. Using gCaMP and dLight fibre photometry, we show that self-administration and two forms of relapse (renewal/context-induced reinstatement and reacquisition) are associated with recruitment across the mesolimbic dopamine system. Using a variety of interventions, we show that this activity is causal to both forms of relapse. Finally, we use dissimilarity matrices to identify mesolimbic dopamine signatures of self-administration, extinction, and relapse. We show that signatures of relapse can be identified from heterogeneous activity profiles across the mesolimbic dopamine system and that these signatures differ for different forms of relapse.

Summary Despite many years of work on dopaminergic mechanisms of alcohol addiction, much of the evidence remains mostly correlative in nature. Fortunately, recent technological advances have provided the opportunity to explore the causal role of alterations in neurotransmission within circuits involved in addictive behaviors. Here, we address this critical gap in our knowledge by integrating an optogenetic approach and an operant alcohol self-administration paradigm to assess directly how accumbal dopamine (DA) release dynamics influences the appetitive (seeking) component of alcohol-drinking behavior. We show that appetitive reward-seeking behavior in rats trained to self-administer alcohol can be shaped causally by ventral tegmental area-nucleus accumbens (VTA-NAc) DA neurotransmission. Our findings reveal that phasic patterns of DA release within this circuit enhance a discrete measure of alcohol seeking, whereas tonic patterns of stimulation inhibit this behavior. Moreover, we provide mechanistic evidence that tonic-phasic interplay within the VTA-NAc DA circuit underlies these seemingly paradoxical effects., Graphical Abstract, Highlights • VTA-NAc DA transmission can bidirectionally modulate motivated behavior • Optogenetic increases in phasic DA release in the NAc enhance alcohol seeking • Optogenetic increases in tonic DA release in the NAc inhibit alcohol seeking • Phasic DA release can be decreased by the concurrent tonic activation, Animal Physiology; Neuroscience; Behavioral Neuroscience

Background Animal models are critical for studying causal explanations of relapse. Using a Pavlovian conditioning procedure with alcohol, we examined relapse after extinction triggered by either re-exposure to alcohol (reinstatement) or a delay between extinction and test (spontaneous recovery). Methods Male, Long-Evans rats were acclimated to 15% alcohol in the home-cage using an intermittent-access 2-bottle choice procedure. Next, they received Pavlovian conditioning sessions in which an auditory-conditioned stimulus (CS; 20 second white noise; 8 trials/session; variable time 240 seconds) was paired with 15% alcohol (0.3 ml/CS; 2.4 ml/session) that was delivered into a fluid port for oral ingestion. In subsequent extinction and test sessions, CS presentations occurred as before, but without alcohol. Results In experiment 1, exposure to either alcohol or water in the fluid port following extinction reinstated CS-elicited port entries at test 24 hours later. In a follow-up study using the same procedure (experiment 2), reinstatement was more robustly stimulated by alcohol, compared to a familiar lemon-flavored liquid. In experiment 3, systemic alcohol injections (0, 0.5, or 1.0 g/kg, intraperitoneal) administered either 24 hours or 15 minutes before test did not reinstate CS-elicited alcohol-seeking. Importantly, enzymatic assays in experiment 4 revealed detectable levels of alcohol in the blood following oral alcohol intake or intraperitoneal injection, suggesting that a pharmacological effect was likely with either route of administration. Last, in experiment 5, a 23-day delay between extinction and test resulted in a robust spontaneous recovery of CS-elicited alcohol-seeking. Conclusions The reinstatement and spontaneous recovery effects revealed herein provide evidence of viable new behavioral paradigms for testing interventions against relapse.

Athina Markou spent a research period in my laboratory, then in the Department of Anatomy in Cambridge University, in 1991 to help us establish a cocaine-seeking procedure. Thus we embarked on developing a second-order schedule of intravenous cocaine reinforcement to investigate the neural basis of the pronounced effects of cocaine-associated conditioned stimuli on cocaine seeking. This brief review summarizes the fundamental aspects of cocaine seeking measured using this approach and the importance of the methodology in enabling us to define the neural mechanisms and circuitry underlying conditioned reinforcement and cocaine, heroin, and alcohol seeking. The shift over time and experience of control over drug seeking from a limbic cortical-ventral striatal circuit underlying goal-directed drug seeking to a dorsal striatal system mediating habitual drug seeking are also summarized. The theoretical implications of these data are discussed, thereby revealing the ways in which the outcomes of a collaboration can endure.

Acute negative mood powerfully motivates alcohol-seeking behavior, but it remains unclear whether sensitivity to this effect is greater in drinkers who report depression symptoms, drinking to cope, and subjective reactivity. To examine these questions, 128 young adult alcohol drinkers (ages 18–25) completed questionnaires of alcohol use disorder symptoms, depression symptoms, and drinking to cope with negative affect. Baseline alcohol choice was measured by preference to enlarge alcohol versus food thumbnail images in two-alternative forced-choice trials. Negative mood was then induced by depressive statements and music, before alcohol choice was tested. Subjective reactivity was indexed by increased sadness pre- to post-mood induction. Baseline alcohol choice correlated with alcohol dependence symptoms (p = .001), and drinking coping motives (ps ≤ .01). Mood induction increased alcohol choice and subjective sadness overall (ps < .001). The mood-induced increase in alcohol choice was associated with depression symptoms (p = .007), drinking to cope (ps ≤ .03), and subjective reactivity (p = .007). The relationship between mood-induced alcohol choice and drinking to cope remained significant after covarying for other drinking motives. Furthermore, the three predictors (depression, drinking to cope, and subjective reactivity) accounted for unique variance in mood-induced alcohol choice (ps ≥ .03), and collectively accounted for 18% of the variance (p < .001). These findings validate the pictorial alcohol choice task as sensitive to the relative value of alcohol and acute negative mood. The findings also accord with the core prediction of negative reinforcement theory that sensitivity to the motivational impact of negative mood on alcohol-seeking behavior may be an important mechanism that links depression and alcohol dependence., Public Health Significance Negative mood is a key trigger for alcohol-seeking behavior, which may underpin vulnerability to alcohol dependence. The current study demonstrated, for the first time, that sensitivity to the motivational impact of negative mood on alcohol-seeking behavior is greater in young adults who report depression symptoms, drinking to cope, and subjective reactivity to negative events. Such sensitivity to negative mood-induced alcohol-seeking could increase vulnerability to alcohol dependence in these individuals.

Corticotropin releasing factor (CRF) is a neuropeptide that plays a key role in behavioral and physiological responses to stress. A large body of animal literature implicates CRF acting at type 1 CRF receptors (CRFR1) in consumption by alcohol dependent subjects, stress-induced reinstatement of alcohol seeking, and possibly binge alcohol consumption. These studies have encouraged recent pilot studies of CRFR1 antagonists in humans with alcohol use disorder (AUD). It was a great disappointment to many in the field that these studies failed to show an effect of these compounds on stress-induced alcohol craving. Here, we examine these studies to explore potential limitations, and discuss preclinical and human literature to ask whether CRFR1 is still a valid drug target to pursue for the treatment of alcohol use disorder.

Alcohol induces many alterations in the brain that are thought to contribute to alcohol addiction. Most of the known alterations are induced in all neurons of a brain area or all neurons of a given cell type, regardless of whether they were activated during behavior. While these alterations can have important modulatory effects on behavior, they cannot explain why animals respond specifically to alcohol-paired cues as opposed to all other non-paired cues and evoke highly specific goal-directed learned responses in models of drug craving. As an alternative, we hypothesize another class of alterations that are induced only within sparsely distributed patterns of neurons, called neuronal ensembles, that are selectively activated by alcohol-specific cues during behavior and encode the long-term memories underlying these learned behaviors in animal models of alcohol addiction. Here we review recent studies and techniques used to identify the role of neuronal ensembles in animal models of different phases of the alcohol addiction cycle. This article is part of the Special Issue entitled "Alcoholism".

Environmental stimuli that reliably accompany alcohol intake can become associated with the pharmacological effects of alcohol through classical (Pavlovian) conditioning. Of growing interest to addiction researchers is whether or not this process results in the attribution of incentive salience to alcohol-predictive cues, which could motivate alcohol-seeking behavior and relapse. To evaluate this question, we present a review of rodent behavioral studies that examined the capacity of alcohol-predictive cues to (i) support sign-tracking behavior, (ii) serve as conditioned reinforcers, and (iii) produce Pavlovian-to-instrumental transfer. A second, emerging area of research is focused on delineating the role of context in alcohol-seeking behavior and relapse. Here, we review studies showing that alcohol-associated contexts (i) support conditioned place preference, (ii) renew extinguished alcohol-seeking behavior, and (iii) modulate alcohol-seeking responses elicited by discrete alcohol-predictive cues. These behavioral effects may be mediated by unique psychological processes, and have important implications for cue-reactivity studies and neurobiological research.

Contains fulltext : 175064.pdf (Publisher’s version ) (Closed access) Alcohol use disorder (AUD) is characterized by excessive alcohol use and persistent alcohol seeking despite knowledge of its negative consequences. Importantly, AUD typically develops after chronic excessive alcohol use in a subgroup of individuals who drink alcohol, suggesting that AUD results from an interaction between individual vulnerability and prolonged alcohol exposure. The present study assessed the contribution of prolonged exposure to alcohol and individual levels of alcohol intake to the development of loss of control over alcohol seeking in a conditioned suppression model. To investigate the impact of prolonged alcohol exposure, conditioned suppression of alcohol seeking was assessed after 2 and 4 months of intermittent alcohol access (IAA) in a subgroup of rats drinking moderate amounts of alcohol. We observed that suppression of alcohol seeking was reduced after 4 months compared with 2 months of IAA. The influence of individual levels of alcohol intake on loss of control over alcohol seeking was subsequently determined by assessing conditioned suppression in subgroups of low and high alcohol drinking rats. Unlike the low alcohol drinking rats, the high alcohol drinking rats showed aversion-resistant alcohol seeking after 2 months of IAA, although both groups showed comparable levels of conditioned freezing. These findings show that the development of loss of control over alcohol seeking, a key characteristic of AUD in humans, is dependent on both the extent of alcohol exposure and the individual's propensity to consume alcohol.