Groupe de Recherche sur l'Alcool et les Pharmacodépendances

BACKGROUND AND AIMS: Since mid-March 2020, over 3 billion people have been confined as a result of the COVID-19 pandemic. Problematic eating behaviors are likely to be impacted by the pandemic through multiple pathways. This study examined the relationships between stress related to lockdown measures and binge eating and dietary restriction in a population of French students during the first week of confinement. METHODS: A sample of undergraduate students (N = 5,738) completed an online questionnaire 7 days after lockdown measures were introduced. The survey comprised variables related to lockdown measures and the COVID-19-pandemic, mood, stress, body image, binge eating and dietary restriction during the past 7 days, as well as intent to binge eat and restrict in the following 15 days. RESULTS: Stress related to the lockdown was associated with greater likelihood of binge eating and dietary restriction over the past week and intentions to binge eat and restrict over the next 15 days. Greater exposure to COVID-19-related media was associated with increased eating restriction over the past week. Binge eating and restriction (past and intentions) were associated with established risk factors, including female gender, low impulse regulation, high body dissatisfaction, and having a concurrent probable eating disorder. DISCUSSION AND CONCLUSION: The higher the stress related to the first week of confinement, the higher the risk of problematic eating behaviors among students, particularly those characterized by eating-related concerns. Screening for risk factors and providing targeted interventions might help decrease problematic eating behaviors among those who are most vulnerable.

BACKGROUND: Ethanol addiction has been conceptualized as a progression from occasional, impulsive use to compulsive behavior. Ethanol-dependence is a chronic pathology with repeated cycles of withdrawal, craving, and relapse. Specific molecular and cellular mechanisms underlie these transition stages. METHODS: This review aimed at elucidating whether there are also adaptations in the pattern of brain regions responding to ethanol. This paper reviews the evidence in rodents for activation of specific brain regions, assessed by induction of IEG expression, following acute and chronic ethanol exposure. RESULTS: The review sheds light on the specific patterns of response in regions of the brain to different types of ethanol exposure and shows that activation of specific brain regions may occur in particular phases of the development of ethanol addiction. Some brain regions respond consistently following acute or chronic treatments or withdrawal: the prefrontal cortex; nucleus accumbens; lateral septum; hippocampus; perioculomotor urocortin-containing cells population (pIIIu), also known as Edinger-Westphal nucleus; central nucleus of the amygdala; and the paraventricular nucleus of hypothalamus. The two last brain areas are particularly activated by relapse-inducing stressors. It is of interest that the amygdala, hippocampus, and prefrontal cortex, which belong to the reward system, are activated by cue-induced relapse to ethanol self-administration in rodents and humans, while activation of these regions is reversed with anti-craving compounds. Following chronic exposure, IEG induction desensitizes while withdrawal reactivates these regions. DISCUSSION: Some responding regions are implicated in reward related processes (VTA, extended amygdala, hypothalamus, hippocampus, prelimbic cortex, ventral part of lateral septum) and some others in aversive-related processes (area postrema, nucleus of solitary tract). CONCLUSION: A better understanding of the neural circuits affected by ethanol and their adaptations during the development of ethanol addiction will provide new opportunities for developing appropriate therapies.

Background Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters.MethodsWe did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples.Findings2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).InterpretationWe have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis.

Substituted cathinones are synthetic analogs of cathinone that can be considered as derivatives of phenethylamines with a beta-keto group on the side chain. They appeared in the recreational drug market in the mid-2000s and now represent a large class of new popular drugs of abuse. Initially considered as legal highs, their legal status is variable by country and is rapidly changing, with government institutions encouraging their control. Some cathinones (such as diethylpropion or pyrovalerone) have been used in a medical setting and bupropion is actually indicated for smoking cessation. Substituted cathinones are widely available from internet websites, retail shops, and street dealers. They can be sold under chemical, evocative or generic names, making their identification difficult. Fortunately, analytical methods have been developed in recent years to solve this problem. Available as powders, substituted cathinones are self-administered by snorting, oral injestion, or intravenous injection. They act as central nervous system stimulants by causing the release of catecholamines (dopamine, noradrenaline, and serotonin) and blocking their reuptake in the central and peripheral nervous system. They may also decrease dopamine and serotonin transporter function as nonselective substrates or potent blockers and may inhibit monoamine oxidase effects. Nevertheless, considerable differences have been found in the potencies of the different substituted cathinones in vitro. Desired effects reported by users include increased energy, empathy, and improved libido. Cardiovascular (tachycardia, hypertension) and psychiatric/neurological signs/symptoms (agitation, seizures, paranoia, and hallucinations) are the most common adverse effects reported. Severe toxicity signs compatible with excessive serotonin activity, such as hyperthermia, metabolic acidosis, and prolonged rhabdomyolysis, have also been observed. Reinforcing potential observed in animals predicts a high potential for addiction and abuse in users. In case of overdose, no specific antidote exists and no curative treatment has been approved by health authorities. Therefore, management of acute toxic effects is mainly extrapolated from experience with cocaine/amphetamines.

Aims The aim of this study was to assess the use and factors associated with the misuse of gabapentin and pregabalin in the general French population, through a cohort study in the EGB (General Sample of Beneficiaries), a national representative sample of the French general population. Methods New users of gabapentin and pregabalin were identified from June 2006 to December 2014, and new users of duloxetine served as control group. Misuse was defined as a use of higher daily doses than recommended. Cox proportional hazard regression models were performed to identify associated factors of misuse. Results Misuse was more frequent in the 8692 new users of pregabalin (12.8%) than in the 1963 gabapentin (6.6%) or the 3214 duloxetine new users (9.7%) ( P < 0.001). Factors associated with misuse were pregabalin (hazard ratio [HR] 1.48; 95% confidence interval [CI] [1.29–1.69]), age (HR [18–45] versus > 70 years 1.98 [1.70–2.31] and HR [58–70] versus > 70 years 1.25 [1.06–1.47]), multiple prescribers (HR 2 or 3 versus 1 prescriber 1.29 [1.15–1.45]; HR 4 or more versus 1 prescriber 1.54 [1.30–1.83]), cancer (1.28 [1.11–1.47]), multiple sclerosis (1.53 [1.07–2.18]), neuropathy (1.85 [1.19–2.89]), depression (1.26 [1.07–1.49]) and methadone (2.61 [1.16–5.84]). After this first episode of drug misuse, 11.6% of gabapentin and 10.7% of pregabalin misusers developed a primary addiction. Conclusion In a cohort of new users, misuse is more likely to occur in new users of pregabalin, with different associated factors of misuse compared to gabapentin and duloxetine. Health professionals and prescribers must be aware of this misuse potential, which could lead to abuse and dependence.

UNLABELLED: We identified, in the transcriptome analysis of patients with alcoholic hepatitis (AH), osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, western blotting and enzyme-linked immunosorbent assay. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN(-/-) mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells (HSCs) and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH, compared to normal livers and other types of chronic liver diseases, and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and matrix metalloproteinase 7) and cleaved OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C single-nucleotide polymorphism of the OPN gene, compared to patients with alcohol abuse without liver disease. Importantly, OPN(-/-) mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by lipopolysaccharide and stimulated inflammatory actions in HSCs. CONCLUSION: Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target.

Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

RATIONALE: Binge drinking (BD), characterized by recurring alternations between intense intoxication episodes and abstinence periods, is the most frequent alcohol consumption pattern in youth and is growing in prevalence among older adults. Many studies have underlined the specific harmful impact of this habit by showing impaired abilities in a wide range of cognitive functions among binge drinkers, as well as modifications of brain structure and function. AIMS: Several controversies and inconsistencies currently hamper the harmonious development of the field and the recognition of BD as a specific alcohol consumption pattern. The main concern is the absence of consensual BD conceptualization, leading to variability in experimental group selection and alcohol consumption evaluation. The present paper aims at overcoming this key issue through a two-step approach. METHODS AND CONCLUSIONS: First, a literature review allows proposing an integrated BD conceptualization, distinguishing it from other subclinical alcohol consumption patterns. Six specific characteristics of BD are identified, namely, (1) the presence of physiological symptoms related to BD episodes, (2) the presence of psychological symptoms related to BD episodes, (3) the ratio of BD episodes compared to all alcohol drinking occasions, (4) the frequency of BD episodes, (5) the consumption speed and (6) the alternation between BD episodes and soberness periods. Second, capitalizing on this conceptual clarification, we propose an evaluation protocol jointly measuring these six BD characteristics. Finally, several research perspectives are presented to refine the proposed conceptualization.

Abstract 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 x c − 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.

Abstract It is important to assess drug abuse liability in ‘real life’ using different surveillance systems. Some are based on specific population surveys, such as individuals with drug abuse or dependence, or under opiate maintenance treatment, because this population is very familiar with drugs and is more likely to divert or abuse them. In France, an original surveillance system based on this specific population and called ‘Observation of illegal drugs and misuse of psychotropic medications ( OPPIDUM ) survey’ was set up in 1990 as the first of its kind. The aim of this article is to describe this precursor of French drug abuse surveillance using different examples, to demonstrate its ability to effectively give health authorities and physicians interesting data on drug abuse. OPPIDUM is an annual, cross‐sectional survey that anonymously collects information on abuse and dependence observed in patients recruited in specialized care centers dedicated to drug dependence. From 1990 to 2010, a total of 50 734 patients were included with descriptions of 102 631 psychoactive substance consumptions. These data have outlined emergent behaviors such as the misuse of buprenorphine by intravenous or nasal administration. It has contributed to assess abuse liability of emergent drugs such as clonazepam or methylphenidate. This surveillance system was also able to detect the decrease of flunitrazepam abuse following implementation of regulatory measures. OPPIDUM 's twenty years of experience clearly demonstrate that collection of valid and useful data on drug abuse is possible and can provide helpful information for physicians and health authorities.

Introduction: Gabapentinoid drugs (gabapentin and pregabalin) are widely used worldwide for epileptic and pain disorders. First signals of gabapentinoid abuse occurred in the last decade. This study aims to describe clinical characteristics of gabapentinoid use related disorders and health consequences in France. Materials and Methods: We designed a multisource investigation reviewing data reported to the French Addictovigilance Network (FAN) with pregabalin and gabapentin from 2010 to 2019. Information was obtained through the analysis of Spontaneous Reports (SRs) notified by health professionals and the pharmacoepidemiological surveys OSIAP (suspicious prescriptions forms indicators of potential abuse), OPPIDUM (observation of illicit drugs and misuse of psychotropic medications), DRAMES (death related to prescription drugs and other substances), and DTA (toxic deaths due to analgesics). Results: Over 2010–2019 period, were collected: (i) 265 SRs (258 pregabalin; 7 gabapentin); (ii) 816 forged prescription forms (805 pregabalin, 10 gabapentin, 1 involving both drugs); (iii) 145 cases of gabapentinoid use in people who use drugs (121 pregabalin; 24 gabapentin) and (iv) 31 cases of gabapentinoid-related deaths (25 pregabalin; 6 gabapentin). Risk factors of gabapentinoid abuse were opioid use disorders or psychiatric history, but cases of primary abuse in subjects without any substance abuse history were observed. Adverse outcomes concern almost exclusively pregabalin, with coma, dyspnea, convulsion, and conduction disorders. Treatment demands increased from 10.6% in 2018 to 23.1% in 2019, with pregabalin cited as the first substance leading to addictological care in the 2019 OPPIDUM survey. Gabapentinoid-related deaths increased over time. Pregabalin has become the first drug mentioned in forged prescriptions in 2019 (23.8% of OSIAP), while it ranked at the 15th position in 2017 (2.6%). Discussion: This study shows the importance of addictovigilance monitoring for gabapentinoids. Addictovigilance data helped to make visible the gabapentinoid-abuse related health harms (hospitalization for serious neurologic, psychiatric or cardiac effects, requests for addictological support and deaths) and to confirm the intrinsic abuse potential of pregabalin. These data highlight new points of vigilance considering observed primary abuse. At this point in France, the risk of abuse and related complications is very apparent with pregabalin. Still, it is identical to that observed elsewhere with gabapentin.

Binge drinking is associated with impaired cognitive functioning, but the relationship of cognitive impairments and white matter integrity is less known. We used diffusion tensor imaging (DTI) to investigate the relationships of binge drinking, whole brain white matter integrity and cognitive performance during young adulthood (18 to 25 years), a period of continued brain development in two sessions 1 year apart. Binge drinkers (n = 20) and non-binge drinkers (n = 20) underwent DTI and completed measures of spatial working memory and motor impulsivity. Fractional anisotropy (FA), a measure derived from DTI, was estimated from whole brain and from five segments of the corpus callosum (CC): prefrontal, premotor/supplementary motor, motor, (SMA) sensory and parietal/temporal/occipital (PTO). FA was lower for binge than for non-binge men but not women at Session 1 and 2 for all measurements except for FA in the motor segment, which was significantly increased from Session 1 to Session 2. Lower FA in the prefrontal and PTO CC segments was associated with higher binge score, whereas lower FA in all five segments was associated with greater drug use in men and worse spatial working memory both in men and women. These findings extend the literature by showing that in early adulthood, binge drinking and drug use are linked with degradations in neural white matter and that compromised white matter at this period of brain development is linked with impaired cognitive functioning.

A major cause of alcohol toxicity is the production of reactive oxygen species generated during ethanol metabolism. The aim of this study was to compare the effect of binge drinking-like alcohol exposure on a panel of genes implicated in oxidative mechanisms in adolescent and adult mice. In adolescent animals, alcohol decreased the expression of genes involved in the repair and protection of oxidative DNA damage such as atr, gpx7, or nudt15 and increased the expression of proapoptotic genes such as casp3. In contrast, in the adult brain, genes activated by alcohol were mainly associated with protective mechanisms that prevent cells from oxidative damage. Whatever the age, iterative binge-like episodes provoked the same deleterious effects as those observed after a single binge episode. In adolescent mice, multiple binge ethanol exposure substantially reduced neurogenesis in the dentate gyrus and impaired short-term memory in the novel object and passive avoidance tests. Taken together, our results indicate that alcohol causes deleterious effects in the adolescent brain which are distinct from those observed in adults. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity. The effects of alcohol exposure were investigated on genes involved in oxidative mechanisms. In adolescent animals, alcohol decreased the expression of genes involved in DNA repair, a potential cause of the observed decrease of neurogenesis. In contrast, in the adult brain, alcohol increased the expression of genes associated with antioxidant mechanisms. Apoptosis was increase in all groups and converged with other biochemical alterations to enhance short-term memory impairment in the adolescent brain. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity.

Background Cannabidiol (CBD) is a natural compound of cannabis, which exerts complex and widespread immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Many experimental data suggest that CBD could have several types of application in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver. Aim To provide a rationale for using CBD in human subjects with AUD, based on the findings of the experimental studies. Methods Narrative review of the studies pertaining to the assessment of CBD for reducing drinking, or improving any aspect of alcohol-related toxicity in AUD. Results Experimental studies converge to find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, and by decreasing anxiety and impulsivity. Moreover, CBD has been shown to reduce alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and inducing death of activated hepatic stellate cells. Last, CBD has been found to reduce alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties. Conclusions CBD could directly reduce alcohol drinking in subjects with AUD. But other original applications warrant human trials in this population. By reducing alcohol-related processes of steatosis in the liver, and brain alcohol-related damage, CBD could improve both the hepatic and neurocognitive outcomes of subjects with AUD, regardless of the individual drinking trajectories. This might pave the way for testing new harm reduction approaches in AUD, i.e., for protecting the organs of subjects with an ongoing AUD.

BACKGROUND: Binge drinking is common in adolescents, but the impact of only a few binges on learning and memory appears underestimated. Many studies have tested the effects of long and intermittent ethanol exposure on long-term synaptic potentiation, and whether long-term synaptic depression is affected remains unknown. METHODS: We studied the effects of one (3 g/kg, i.p.; blood ethanol content of 197.5±19 mg/dL) or 2 alcohol intoxications (given 9 hours apart) on adolescent rat's memory and synaptic plasticity in hippocampus slice after different delay. RESULTS: Animals treated with 2 ethanol intoxications 48 hours before training phase in the novel object recognition task failed during test phase. As learning is related to NMDA-dependent mechanisms, we tested ketamine and found the same effect as ethanol, whereas D-serine prevented learning deficit. In hippocampus slice, NMDA-dependent long-term synaptic depression was abolished 48 hours after ethanol or ketamine but prevented after D-serine or in a low-Mg(2+) recording medium. Long-term synaptic depression abolition was not observed 8 days after treatment. An i.p. treatment with MK-801, tetrahydroisoxazolopyridine, or muscimol was ineffective, and long-term synaptic potentiation, intrinsic excitability, and glutamate release remained unaffected. The input/ouput curve for NMDA-fEPSPs was shifted to the left 48 hours after the binges with a stronger contribution of GluN2B subunit, leading to a leftward shift of the Bienenstock-Cooper-Munro relationship. Interestingly, there were no cellular effects after only one ethanol injection. CONCLUSION: Two ethanol "binges" in adolescent rats are sufficient to reversibly abolish long-term synaptic depression and to evoke cognitive deficits via a short-lasting, repeated blockade of NMDA receptors only, inducing a change in the receptor subunit composition. Furthermore, ethanol effects developed over a 48-hour period of abstinence, indicating an important role of intermittence during a repeated long-duration binge behavior.

BACKGROUND: Behavioral sensitization induced by repeated ethanol (EtOH) exposure may play a critical role in the development of alcohol dependence. Because recent data demonstrate that histone deacetylase inhibitor (HDACi) may be of interest in the treatment of addiction, we explored the effect of the HDACi sodium butyrate (NaB) on EtOH-induced behavioral sensitization (EIBS) in DBA/2J mice. We also investigated gene regulations in the striatum of sensitized mice using epigenetic- and signal transduction-related PCR arrays. METHODS: Mice were injected with saline or EtOH (0.5 to 2.5 g/kg) once a day for 10 days. Mice received NaB (200 to 600 mg/kg) 30 minutes before each injection (prevention protocol) or once daily between days 11 and 16 (reversal protocol). At day 17, brains were removed 30 minutes after a saline or EtOH challenge to assess gene and proteins levels. RESULTS: Only the intermediate EtOH doses (1.0 and 2.0 g/kg) were effective in inducing EIBS, and both doses were associated with specific gene regulations in the striatum. The induction of sensitization by 1.0 g/kg (but not 2.0 g/kg) EtOH was dose-dependently prevented or reversed by NaB. Among the 168 studied genes, EIBS blockade was associated with specific gene regulations (bcl-2, bdnf, hdac4, pak1, penk, tacr1, vip…) and changes in brain-derived neurotrophic factor in both striatum and prefrontal cortex. CONCLUSIONS: These results indicate that EIBS is associated with specific gene regulations in the striatum depending on the EtOH dose and that NaB can be useful in blocking some long-lasting neuro-adaptations to repeated EtOH administrations.

BACKGROUND: New strategies for the treatment of alcohol dependence are a pressing need, and recent evidence suggests that targeting enzymes involved in epigenetic mechanisms seems to have great potential. Among these mechanisms, alteration of histone acetylation by histone deacetylases is of great importance for gene expression and has also been implicated in addiction. Here, we examined whether intra-cerebroventricular administration of MS-275, a class I-specific histone deacetylase inhibitor, could alter ethanol self-administration, motivation to consume ethanol, and relapse in heavy drinking rats. METHODS: Male Long Evans rats trained to self-administer high levels of ethanol received intra-cerebroventricular micro-infusions of MS-275 (250 µM, 500 µM, and 1000 µM) 3 hours prior to the self-administration sessions. RESULTS: First, we demonstrated that intra-cerebroventricular infusion of MS-275 increases acetylation of Histone 4 within the nucleus accumbens nucleus accumbens and the dorsolateral striatum. Second, we observed that MS-275 decreases ethanol self-administration by about 75%. We found that 2 consecutive daily injections are necessary to decrease ethanol self-administration. Additionally, the dose-response curve test indicated that MS-275 has a U-shape effect on ethanol self-administration with the dose of 500 µM as the most efficient dose. Furthermore, we showed that MS-275 also diminished the motivation to consume ethanol (25% decrease), and finally, we demonstrated that MS-275 reduced relapse (by about 50%) and postponed reacquisition even when the treatment was stopped. CONCLUSIONS: Our study confirms the potential therapeutic interest of targeting epigenetic mechanisms in excessive alcohol drinking and strengthens the interest of focusing on specific isoforms of histone deacetylases.

The French system of evaluation of dependence has been defined in the French Public Health Code by decree 99-249 of 31 March 1999. It was created by health authorities 10 years earlier and concerns dependence and abuse, which were previously just submitted to control under the designation of non-conforming use and misuse. The consultative function of the narcotics and psychotropics commission has been reinforced and its mission extended to include evaluation. Cooperation with different actors has been organized. This is based on the complexity of the methods of evaluation and the impact of decisions concerning control and/or information. The same principles organize the cooperation of this system at the European and international levels.

BACKGROUND: Binge eating disorder (BED) is very frequently observed in patients considered for weight loss surgery and seems to influence their outcome critically. Literature highlights a global emotional overload in individuals with BED, but little is known on the mechanisms involved. The present study aimed to focus on emotion regulation, impulsivity, depression, and anxiety in people with and without BED and fulfilling inclusion criteria for bariatric surgery. Doing so, we sought to individualize factors related to BED. Then, we examined the contribution of depression, anxiety, emotion regulation difficulties, and impulsivity to inappropriate eating behaviors observed in patients with BED. METHODS: ± 7.55) seeking bariatric surgery were recruited at the Champagne Ardenne Specialized Center in Obesity in Reims, France from November 2017 to October 2018. They were stratified as with or without BED according to the binge eating scale. Characteristics identified in univariate analyses as differentiating the two groups were then included in multivariable analyses. RESULTS: Multivariable analyses showed that limited access to emotional regulation strategies was significantly associated with BED. Furthermore, inappropriate eating behaviors were independently associated with age, depression severity, anxiety, emotional dysregulation, and impulsivity in BED group. CONCLUSIONS: The present findings are indicative of an association between emotion deficit and BED in obese patients seeking bariatric surgery. Patients with BED could benefit from the addition of an emotion regulation intervention.

Schizophrenia is a mental disorder characterized by a series of positive, negative or cognitive symptoms but with also the particularity of exhibiting a high rate of co-morbid use of drugs of abuse. While more than 80% of schizophrenics are smokers, the second most consumed drug is alcohol, with dramatic consequences on frequency and intensity of psychotic episodes and on life expectancy. Here we investigated the impact of light alcohol intake during adolescence on the subsequent occurrence of alcohol addiction-like behavior in neonatal ventral hippocampal lesion (NVHL) rats, a neurodevelopmental model of schizophrenia. Our findings demonstrated an increased liability to addictive behaviors in adult NVHL rats after voluntary alcohol intake during adolescence. NVHL rats displayed several signs of alcohol use disorder such as a loss of control over alcohol intake and high motivation to consume alcohol, associated with a higher resistance to extinction. In addition, once NVHL rats relapsed, they maintained higher drinking levels than controls. We finally showed that the anti-addictive drug naltrexone is efficient in reducing excessive alcohol intake in NVHL rats. Our results are in accordance with epidemiological studies underlying the particular vulnerability to alcohol addiction after adolescent exposure to alcohol and highlight the fact that schizophrenic subjects may be particularly at risk even after light alcohol consumption. Based on these results, it seems particularly relevant to prevent early onset of alcohol use in at-risk subjects and thus to reduce the incidence of co-morbid alcohol abuse in psychotic patients.