Psilocybin reduces alcohol self-administration via selective left nucleus accumbens activation in rats.

The use of psilocybin to treat alcohol use disorder is very promising, but the mechanisms of action remain poorly understood. We combined behavioral, pharmacological and gene expression analyses to decipher the mechanisms of action of psilocybin, for the first time injected into the brain. Male Long Evans rats underwent chronic operant ethanol self-administration before testing the effect of intraperitoneal psilocybin or directly within the nucleus accumbens core or the ventral tegmental area. Transcripts from the dopaminergic system were quantified in the nucleus accumbens and prefrontal cortex. Psilocybin significantly reduced (50%) ethanol self-administration when injected 4 hours before the session either intraperitoneally (1mg/kg) or directly within the left nucleus accumbens (0.15µg) but not the right nucleus accumbens or the left ventral tegmental area. The effect of intraperitoneal injection of psilocybin was prevented by intra left nucleus accumbens injection of 0.3µg of the 5-HT2AR antagonist ketanserin. In rats that self-administered ethanol but not in those self-administering saccharin, dopamine D2 receptor mRNA were increased in both the nucleus accumbens and the prefrontal cortex by psilocybin, while D1R mRNA was increased only in the prefrontal cortex. As in humans, psilocybin reduced ethanol self-administration in rats through the 5-HT2AR within the left nucleus accumbens possibly through increased D2R expression. Our results open unexpected perspectives regarding the hemispheric lateralization of psychedelic effects.

Epigenetic drugs and psychedelics as emerging therapies for alcohol use disorder: insights from preclinical studies.

Alcohol use disorder (AUD) is a public health issue that affects millions of people worldwide leading to physical, mental and socio-economic consequences. While current treatments for AUD have provided relief to individuals, their effectiveness on the long term is often limited, leaving a number of affected individuals without sustainable solutions. In this review, we aim to explore two emerging approaches for AUD: psychedelics and epigenetic drugs (i.e., epidrugs). By examining preclinical studies, different animal species and procedures, we delve into the potential benefits of each of these treatments in terms of addictive behaviors (alcohol drinking and seeking, motivation to drink alcohol and prevention of relapse). Because psychedelics and epidrugs may share common and complementary mechanisms of action, there is an exciting opportunity for exploring synergies between these approaches and their parallel effectiveness in treating AUD and the diverse associated psychiatric conditions.

[Interest and mechanisms of action of ketamine in alcohol addiction- A review of clinical and preclinical studies]. / Intérêt et mécanismes d'action de la kétamine dans le traitement de l'addiction à l'alcool ­ Revue des études cliniques et précliniques.

Alcohol Use Disorder (AUD) is a psychiatric condition characterized by chronic and excessive drinking despite negative consequences on overall health and social or occupational functioning. There are currently limited treatment options available for AUD, and the effects size and the response rates to these treatments are often low to moderate. The World Health Organization has identified the development of medications to treat AUD as one of its 24 priorities. This past decade was marked by a renewed interest in psychedelic use in psychiatry. At the centre of this renaissance, ketamine, an atypical psychedelic already used in the treatment of major depression, is an NMDA receptor antagonist that exists as a racemic compound made of two enantiomers, S-ketamine, and R-ketamine. Each form can be metabolized into different metabolites, some of which having antidepressant properties. In this article, we review both clinical and preclinical studies on ketamine and its metabolites in the treatment of AUD. Preclinical as well as clinical studies have revealed that ketamine is effective in reducing withdrawal symptoms and alcohol craving. Convergent data showed that antidepressant properties of ketamine largely contribute to the decreased likelihood of alcohol relapse, especially in patients undergoing ketamine-assisted psychotherapies. Its effectiveness is believed to be linked with its ability to regulate the glutamatergic pathway, enhance neuroplasticity, rewire brain resting state network functional connectivity and decrease depressive-like states. However, it remains to further investigate (i) why strong differences exist between male and female responses in preclinical studies and (ii) the respective roles of each of the metabolites in the ketamine effects in both genders. Interestingly, current studies are also focusing on ketamine addiction and the comorbidity between alcohol addiction and depression occurring more frequently in females.

Title: Intérêt et mécanismes d'action de la kétamine dans le traitement de l'addiction à l'alcool ­ Revue des études cliniques et précliniques. Abstract: Le Trouble de l'Usage d'Alcool (TUA) est une maladie psychiatrique caractérisée par une consommation chronique et excessive d'alcool malgré des conséquences négatives sur la santé et le fonctionnement social ou professionnel. Les options de traitements du TUA sont actuellement limitées et les tailles d'effet et taux de réponse à ces traitements sont souvent faibles à modérés. L'Organisation Mondiale de la Santé a identifié le développement des médicaments pour traiter le TUA comme l'une de ses 24 priorités. Cette dernière décennie a été marquée par un intérêt renouvelé pour l'utilisation de psychédéliques en psychiatrie. La kétamine, un psychédélique atypique déjà utilisé dans le traitement de la dépression majeure, est au centre de cette renaissance. Cet antagoniste des récepteurs NMDA existe sous deux formes énantiomères, la S-kétamine et la R-kétamine, qui peuvent être métabolisées en différents dérivés, dont certains ont montré des propriétés antidépressives. Cet article de revue vise à faire le bilan des études cliniques et précliniques sur l'utilisation de la kétamine et de ses métabolites dans le traitement du TUA. L'ensemble de ces études montre que la kétamine est efficace pour réduire les symptômes de sevrage et les envies irrépressibles d'alcool. Les propriétés antidépressives avérées de la kétamine contribuent à la diminution du risque de rechute dans le mésusage d'alcool, notamment chez les patients suivant des psychothérapies. Son efficacité est supposée être liée à sa capacité à réguler la voie glutamatergique, à améliorer la neuroplasticité, à réorganiser la connectivité fonctionnelle des réseaux d'état de repos (resting state networks) du cerveau et à réduire les états dépressifs. Bien que ces premiers résultats soient prometteurs, la mise en évidence de différences importantes entre les sexes, et la méconnaissance du rôle de chacun des métabolites dans les effets observés justifient la poursuite des recherches précliniques pour mieux comprendre comment agissent véritablement la kétamine et ses métabolites sur le TUA. En clinique, les études récentes s'intéressent désormais à la dépendance à la kétamine et à la dépression comorbide, ainsi qu'à l'influence du sexe, une comorbidité plus forte entre la dépendance à l'alcool et la dépression semblant exister chez la femme.

Sex-related differences in the efficacy of Baclofen enantiomers on self-administered alcohol in a binge drinking pattern and dopamine release in the core of the nucleus accumbens.

Introduction: Clinical studies on the effectiveness of Baclofen in alcohol use disorder (AUD) yielded mixed results possibly because of differential effects of the enantiomers and sex-related differences. Here we examined the effect of the different Baclofen enantiomers on alcohol intake and on evoked dopamine release in the core of the nucleus accumbens (NAcc) in male and female Long Evans rats. Methods: Rats were trained to chronically self-administer 20% alcohol solution in daily binge drinking sessions and were treated with the different forms of Baclofen [RS(±), R(+) and S(-)]. The effects on the evoked dopamine release within the core of the nucleus accumbens were measured in brain slices from the same animals and the alcohol naïve animals using the fast scan cyclic voltammetry technique. Results: RS(±)-Baclofen reduced alcohol intake regardless of sex but more females were non-responders to the treatment. R(+)-Baclofen also reduced alcohol intake regardless of sex but females were less sensitive than males. S(-)-Baclofen did not have any effect on average but in some individuals, especially in the females, it did increase alcohol intake by at least 100%. There were no sex differences in Baclofen pharmacokinetic but a strong negative correlation was found in females with a paradoxical effect of increased alcohol intake with higher blood Baclofen concentration. Chronic alcohol intake reduced the sensitivity to the effect of Baclofen on evoked dopamine release and S(-)-Baclofen increased dopamine release specifically in females. Discussion: Our results demonstrate a sex-dependent effect of the different forms of Baclofen with no or negative effects (meaning an increase in alcohol self-administration) in subgroup of females that could be linked to a differential effect on dopamine release and should warrant future clinical studies on alcohol use disorder pharmacotherapy that will deeply analyze sex difference.

Sex-specific decision-making impairments and striatal dopaminergic changes after binge drinking history in rats.

Binge drinking (BD) is a harmful behavior for health and is a predictive factor for the development of alcohol addiction. Weak decision-making (DM) capacities could play a role in the vulnerability to BD which in turn would lead to DM impairments, thus perpetuating BD. Longitudinal preclinical studies are however lacking and necessary to understand this complex relationship. Both DM and BD are influenced by sex and involve dopamine release in the core of the nucleus accumbens, a central mechanism regulated by dopamine D2/3 autoreceptors. In this context, we used an operant self-administration procedure of BD in male and female rats, and longitudinally assessed DM capacity, memory and anxiety-like behavior. To better understand the mechanisms potentially involved in the relationship between DM and BD, ex vivo dopamine transmission was assessed short term after the end of the binge exposure in the core of the nucleus accumbens (NAc) using the fast-scan cyclic voltammetry (FSCV) technique and the D2/3 agonist quinpirole. We found important basal sex differences in DM, with female rats showing better performances at baseline. Choice processes were impaired exclusively in males after BD history, associated with a decrease in impulse control in both sexes, while memory and anxiety-like behavior were not affected. Our neurobiological results demonstrate that BD did not affect basal dopamine signaling in the NAc core, regardless of the sex, but reveal changes in the sensitivity to the inhibitory effects of quinpirole in females. DM impairments were neither associated with changes in basal dopamine signaling nor pre-synaptic D2 activity. Overall, our findings show that BD affects both DM processes and dopamine transmission in the core of the NAc in a sex-related manner, further suggesting that these effects may play a role in the vicious cycle leading to BD perpetuation and the early onset of AUD. Our results may inform novel strategies for therapeutic and prevention interventions.

Plasma tau, NfL, GFAP and UCHL1 as candidate biomarkers of alcohol withdrawal-associated brain damage: A pilot study.

In this translational study, we investigated the plasma tau protein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which are established biomarkers of neurological injury, as predictive biomarkers of alcohol withdrawal-associated brain toxicity. In the clinical study, patients with severe alcohol use disorder (AUD) on D1 of hospitalization for alcohol cessation (AC) (N = 36) were compared to severe AUD patients with at least 3 months of abstinence (N = 16). Overall, patients were 40 men (76.9%), aged 49.8 years [SD ±9.9]. Tau, NfL, GFAP and UCHL1 levels were measured using SIMOA and analysed with a quasipoisson regression model adjusted for age and sex. The NfL level was higher in the AC group (p = 0.013). In the AC group, the tau (p = 0.021) and UCHL1 (p = 0.021) levels were positively associated with the dose of diazepam per weight, and the tau (p = 0.045), NfL (p = 4.9 × 10-3 ) and UCHL1 (p = 0.036) levels were higher in the presence of signs of Wernicke's encephalopathy (n = 9). In the preclinical study, NfL and GFAP levels were assessed in the alcohol deprivation effect (ADE) procedure (N = 17) and control Wistar rats (N = 15). Furthermore, ADE rats were prospectively assessed: after 24 h (T1) and 3 weeks of AC (T2) (paired-samples Wilcoxon and Mann-Whitney tests). The NfL level was higher in the ADE model than in the control rats at both T1 and T2 (p = 0.033 and p = 1.3 × 10-3 ) and higher at T2 than at T1 (p = 0.040). Plasma tau, NfL and UCHL1 are potential biomarkers of brain suffering during alcohol withdrawal.

Validity and usefulness of the short form of the Drinking Motives Questionnaire Revised (DMQ-R SF) among patients with schizophrenia.

OBJECTIVE: Drinking motives are considered to be major predictors of alcohol consumption and alcohol-related problems. However, these motives have been poorly investigated in patients with schizophrenia. The aim of the present study among patients with schizophrenia was twofold: 1) assess the validity of the short form of the Drinking Motives Questionnaire-Revised (DMQ-R SF); and 2) investigate the relationship between drinking motives and comorbid alcohol use disorder (AUD). METHOD: A total of 179 patients with schizophrenia were approached to participate in the study. DSM-5 criteria were used to identify patients with comorbid AUD (AUD+; n = 42) and non-abstainers patients without comorbid AUD (AUD-; n = 71). RESULTS: A confirmatory factor analysis conducted on items of the DMQ-R SF for the whole sample revealed adequate goodness-of-fit values, while internal consistency indices were globally satisfactory. Group comparisons revealed higher use of alcohol and other substances, as well as stronger drinking motives among AUD + patients, while groups were comparable concerning clinical features of schizophrenia, including psychotic symptom dimensions and severity. Regression analysis showed that the Alcohol Use Disorder Identification Test score was significantly associated with two internal drinking motives: enhancement and coping. CONCLUSIONS: Findings suggest that the DMQ-R SF is a reliable tool for assessing drinking motives among patients with schizophrenia. Enhancement and coping motives seem to play a major role in comorbid AUD among these patients. Community-based and clinical treatment programs should take the drinking motives of dual-diagnosis patients into consideration, in order to improve their outcomes.

Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism.

Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood, and new effective pharmacological treatments are desired. Here, using a bidirectional neuromodulation approach, we demonstrate a causal link between reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. A neuron-specific prefrontal mGluR2 knockdown in rats generated a phenotype of reduced cognitive flexibility and excessive alcohol seeking. Conversely, virally restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. In the search for a pharmacological intervention with high translational potential, psilocybin was capable of restoring mGluR2 expression and reducing relapse behavior. Last, we propose a FDG-PET biomarker strategy to identify mGluR2 treatment-responsive individuals. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving and provided a personalized mGluR2 mechanism-based intervention strategy for medication development for alcoholism.

Interstrain differences in voluntary binge-like drinking behavior and in two acute ethanol injections-induced synaptic plasticity deficits in rats.

Propensity to drink alcohol and to initiate binge drinking behavior is driven by genetic factors. Recently, we proposed an original animal model useful in the study of voluntary binge-like drinking (BD) in outbred Long-Evans rats by combining intermittent access to 20% ethanol in a two-bottle choice (IA2BC) paradigm to 15-min daily sessions of 20% ethanol operant self-administration. We sought to compare three strains of outbred rats (Long-Evans, Sprague-Dawley, and Wistar) in our BD model. Because we found different propensity to BD between strains, we also sought to test interstrain differences using another procedure of two acute ethanol exposures known to alter long-term depression of hippocampal synaptic plasticity. Our results demonstrate that in both IA2BC and operant procedures, the Long-Evans strain consumed the highest, Wistar the lowest amount of ethanol, and the Sprague-Dawley was intermediate. Long-Evans rats were also the fastest consuming with the shortest time to reach 50% of their maximum consumption in 15 min. When we tested the acute effects of ethanol, long-term depression in hippocampus was abolished specifically in Long-Evans rats with no impact in the two other strains. Thus, our study reveals that the Long-Evans strain is the ideal strain in our recently developed animal model useful in the study of BD. In addition, with the other paradigm of forced acute ethanol exposure, the Long-Evans strain displayed an increase in sensitivity to the deleterious effect of BD on hippocampal synaptic plasticity. Further studies are needed in order to investigate why Long-Evans rats are more prone to BD.

Is R(+)-Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side.

For several decades, studies conducted to evaluate the efficacy of RS(±)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(±)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(±)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(±)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(±)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake.

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice.

G protein-coupled receptors (GPCRs) constitute the largest class of cell surface signaling receptors and regulate major neurobiological processes. Accordingly, GPCRs represent primary targets for the treatment of brain disorders. Several human genetic polymorphisms affecting GPCRs have been associated to different components of alcohol use disorder (AUD). Moreover, GPCRs have been reported to contribute to several features of alcohol-related behaviors in animal models. Besides traditional pharmacological tools, genetic-based approaches mostly aimed at deleting GPCR genes provided substantial information on how key GPCRs drive alcohol-related behaviors. In this review, we summarize the alcohol phenotypes that ensue from genetic manipulation, in particular gene deletion, of key GPCRs in rodents. We focused on GPCRs that belong to fundamental neuronal systems that have been shown as potential targets for the development of AUD treatment. Data are reviewed with particular emphasis on alcohol reward, seeking, and consumption which are behaviors that capture essential aspects of AUD. Literature survey indicates that in most cases, there is still a gap in defining the intracellular transducers and the functional crosstalk of GPCRs as well as the neuronal populations in which their signaling regulates alcohol actions. Further, the implication of only a few orphan GPCRs has been so far investigated in animal models. Combining advanced pharmacological technologies with more specific genetically modified animals and behavioral preclinical models is likely necessary to deepen our understanding in how GPCR signaling contributes to AUD and for drug discovery.

Face validity of a pre-clinical model of operant binge drinking: just a question of speed.

Binge drinking (BD) is often defined as a large amount of alcohol consumed in a 'short' period of time or 'per occasion'. In clinical research, few researchers have included the notion of 'speed of drinking' in the definition of BD. Here, we aimed to describe a novel pre-clinical model based on voluntary operant BD, which included both the quantity of alcohol and the rapidity of consumption. In adult Long-Evans male rats, we induced BD by regularly decreasing the duration of ethanol self-administration from 1-hour to 15-minute sessions. We compared the behavioral consequences of BD with the behaviors of rats subjected to moderate drinking or heavy drinking (HD). We found that, despite high ethanol consumption levels (1.2 g/kg/15 minutes), the total amounts consumed were insufficient to differentiate HD from BD. However, consumption speed could distinguish between these groups. The motivation to consume was higher in BD than in HD rats. After BD, we observed alterations in locomotor coordination in rats that consumed greater than 0.8 g/kg, which was rarely observed in HD rats. Finally, chronic BD led to worse performance in a decision-making task, and as expected, we observed a lower stimulated dopaminergic release within nucleus accumbens slices in poor decision makers. Our BD model exhibited good face validity and can now provide animals voluntarily consuming very rapidly enough alcohol to achieve intoxication levels and thus allowing the study of the complex interaction between individual and environmental factors underlying BD behavior.

Animal models of binge drinking, current challenges to improve face validity.

Binge drinking (BD), i.e., consuming a large amount of alcohol in a short period of time, is an increasing public health issue. Though no clear definition has been adopted worldwide the speed of drinking seems to be a keystone of this behavior. Developing relevant animal models of BD is a priority for gaining a better characterization of the neurobiological and psychobiological mechanisms underlying this dangerous and harmful behavior. Until recently, preclinical research on BD has been conducted mostly using forced administration of alcohol, but more recent studies used scheduled access to alcohol, to model more voluntary excessive intakes, and to achieve signs of intoxications that mimic the human behavior. The main challenges for future research are discussed regarding the need of good face validity, construct validity and predictive validity of animal models of BD.

Evaluation of alcohol use disorders pharmacotherapies in a new preclinical model of binge drinking.

Binge drinking is defined as a pattern of drinking leading to intoxication in a single short session and is a serious but preventable public health problem. Only few animal models of voluntary binge drinking using an operant paradigm are available in outbred animals and in general they do not display good face validity. We recently set up a new model of binge drinking behavior using an operant self-administration paradigm in which rats drink to intoxication level in 15-min daily session. Here we tested the current pharmacotherapies of alcohol use disorder: Acamprosate, (R)-Baclofen, gamma-hydroxybutyric acid, Nalmefene and Naltrexone. Our results show that all drugs are effective in reducing ethanol drinking. All drugs except Acamprosate also reduced the motivational properties of ethanol (breakpoint). (R)-Baclofen and gamma-hydroxybutyric acid were effective on ethanol intake at doses devoid of side effects. Among the tested drugs only (R)-Baclofen, gamma-hydroxybutyric acid and Naltrexone reduced reacquisition after a period of abstinence. Interestingly, the efficacy of all drugs except Nalmefene to reduce ethanol drinking was slightly and positively correlated with the basal level of drinking thus revealing heavy drinking as a predictive factor. In summary, all current alcohol use disorder pharmacotherapies were effective in our model of binge drinking behavior thus bringing new data regarding its good predictive validity. The tested drugs display some specificity regarding their effect on motivation, reacquisition and also in terms of individual factors such as basal drinking level. Our new model opens promising perspectives about the development of pharmacotherapies targeting binge drinking behavior.

Interest of new alkylsulfonylhydrazide-type compound in the treatment of alcohol use disorders.

RATIONALE: Recent preclinical research suggested that histone deacetylase inhibitors (HDACIs) and specifically class I HDAC selective inhibitors might be useful to treat alcohol use disorders (AUDs). OBJECTIVE: The objective of this study was to find a new inhibitor of the HDAC-1 isoenzyme and to test its efficacy in an animal model of AUDs. METHODS: In the present study, we prepared new derivatives bearing sulfonylhydrazide-type zinc-binding group (ZBG) and evaluated these compounds in vitro on HDAC-1 isoenzyme. The most promising compound was tested on ethanol operant self-administration and relapse in rats. RESULTS: We showed that the alkylsulfonylhydrazide-type compound (ASH) reduced by more than 55% the total amount of ethanol consumed after one intracerebroventricular microinjection, while no effect was observed on motivation of the animals to consume ethanol. In addition, one ASH injection in the central amygdala reduced relapse. CONCLUSIONS: Our study demonstrated that a new compound designed to target HDAC-1 is effective in reducing ethanol intake and relapse in rats and further confirm the interest of pursuing research to study the exact mechanism by which such inhibitor may be useful to treat AUDs.

Pharmacological activation of mGlu4 and mGlu7 receptors, by LSP2-9166, reduces ethanol consumption and relapse in rat.

Addiction is a chronic and highly relapsing disorder hypothesized to be produced by an imbalance between excitatory and inhibitory neurotransmission. For more than a decade, emerging evidence indicates that manipulation of glutamatergic neurotransmission, by group III mGlu receptors (mGlu4/7/8), could be a promising approach to develop therapeutic agents for the treatment of addiction. Thus, the aim of the present study is to determine whether LSP2-9166, a mixed mGlu4/mGlu7 orthosteric agonist, could reduce ethanol self-administration, ethanol motivation and reacquisition after protracted abstinence in a preclinical model of excessive ethanol intake. Male Long Evans rats were chronically trained to consume large amount of ethanol in operant cages for several weeks. Once they reached a stable level of consumption (about 1 g of pure ethanol/kg bodyweight/15min), the effect of LSP2-9166 was evaluated on different aspects of the operant self-administration behavior. In this study, we found that the intracerebroventricular infusion of LSP2-9166 dose dependently reduced ethanol consumption, motivation for ethanol and reacquisition of ethanol self-administration after abstinence. Together, these results support recent preclinical findings showing that pharmacological modulation of mGlu receptors may serve as an effective treatment for reducing ethanol consumption and relapse.

Effect of N-acetylcysteine on motivation, seeking and relapse to ethanol self-administration.

Alcohol use disorder is a chronic and highly relapsing disorder, characterized by a loss of control over alcohol consumption and craving. Several studies suggest a key role of glutamate in this disorder. In recent years, the modulation of cystine/glutamate exchange via the xc- system has emerged as a new therapeutic alternative for reducing the excitatory glutamatergic transmission observed after ethanol self-administration in both rats and humans. The objective of this study was to determine whether a treatment with N-acetylcysteine (NAC), a cystine prodrug, could reduce ethanol self-administration, ethanol-seeking behavior and reacquisition of ethanol self-administration. Male Long Evans rats were trained to self-administer 20 percent ethanol in operant cages for several weeks. Once the consumption surpassed 1 g of ethanol/kg body weight/15 minutes, the effect of an acute intraperitoneal injection of NAC (0, 25, 50 or 100 mg/kg) 1 hour before the beginning of each test was evaluated on different aspects of the operant self-administration behavior. We demonstrated antimotivational properties of NAC (100 mg/kg), as ethanol-reinforced responding was reduced in a fixed ratio (-35 percent) and in a progressive ratio schedule (-81 percent). NAC also reduced ethanol-seeking behavior (-77 percent) evaluated as extinction responding in a single extinction session. NAC was able to reduce reacquisition in rats that were abstinent for 17 days, while NAC had no effect on ethanol relapse in rats previously exposed to six extinction sessions. Overall, our results demonstrate that NAC limits motivation, seeking behavior and reacquisition in rats, making it a potential new treatment for the maintenance of abstinence.

Class I HDAC Inhibitors: Potential New Epigenetic Therapeutics for Alcohol Use Disorder (AUD).

Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity. More effort is required to improve the selectivity, pharmacokinetics, and toxicity profiles of HDACIs to achieve a better understanding of their efficacy in reducing addictive behavior.