title: The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals.
abstract: 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.
authors.affiliation: UFR de Pharmacie, INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Université de Picardie Jules Verne, Amiens, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Simon-O'Brien
authors.affiliation: UFR de Pharmacie, INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Université de Picardie Jules Verne, Amiens, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Alaux-Cantin
authors.affiliation: UFR de Pharmacie, INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Université de Picardie Jules Verne, Amiens, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Warnault
authors.affiliation: UFR de Pharmacie, INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Université de Picardie Jules Verne, Amiens, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Buttolo
authors.affiliation: UFR de Pharmacie, INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Université de Picardie Jules Verne, Amiens, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Naassila
authors.affiliation: UFR de Pharmacie, INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Université de Picardie Jules Verne, Amiens, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilpoux
mesh_terms: D000107:Acetylation; D000437:Alcoholism / Q000235:genetics / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D020148:Butyric Acid / Q000008:administration & dosage / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003216:Conditioning, Operant; D044127:Epigenesis, Genetic / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012008:Recurrence; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage
chemical_list: D001549:Benzamides; D002492:Central Nervous System Depressants; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011725:Pyridines; D013549:Sweetening Agents; D020148:Butyric Acid; C118739:entinostat; D000431:Ethanol; D013395:Sucrose
keywords: Addiction; HDAC inhibitor; alcohol; epigenetics; histone acetylation; operant self-administration; relapse; sodium butyrate