title: Chromatin remodeling--a novel strategy to control excessive alcohol drinking.
abstract: Harmful excessive use of alcohol has a severe impact on society and it remains one of the major causes of morbidity and mortality in the population. However, mechanisms that underlie excessive alcohol consumption are still poorly understood, and thus available medications for alcohol use disorders are limited. Here, we report that changing the level of chromatin condensation by affecting DNA methylation or histone acetylation limits excessive alcohol drinking and seeking behaviors in rodents. Specifically, we show that decreasing DNA methylation by inhibiting the activity of DNA methyltransferase (DNMT) with systemic administration of the FDA-approved drug, 5-azacitidine (5-AzaC) prevents excessive alcohol use in mice. Similarly, we find that increasing histone acetylation via systemic treatment with several histone deacetylase (HDAC) inhibitors reduces mice binge-like alcohol drinking. We further report that systemic administration of the FDA-approved HDAC inhibitor, SAHA, inhibits the motivation of rats to seek alcohol. Importantly, the actions of both DNMT and HDAC inhibitors are specific for alcohol, as no changes in saccharin or sucrose intake were observed. In line with these behavioral findings, we demonstrate that excessive alcohol drinking increases DNMT1 levels and reduces histone H4 acetylation in the nucleus accumbens (NAc) of rodents. Together, our findings illustrate that DNA methylation and histone acetylation control the level of excessive alcohol drinking and seeking behaviors in preclinical rodent models. Our study therefore highlights the possibility that DNMT and HDAC inhibitors can be used to treat harmful alcohol abuse.
authors: Department of Neurology, The Gallo Research Center, University of California, Emeryville, CA 94608, USA.
authors: V
authors: V
authors: Warnault
authors: E
authors: E
authors: Darcq
authors: A
authors: A
authors: Levine
authors: S
authors: S
authors: Barak
authors: D
authors: D
authors: Ron
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000437:Alcoholism / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006657:Histones / Q000187:drug effects; D006801:Humans; D051379:Mice; D051381:Rats
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C000619382:Dnmt1 protein, rat; D001374:Azacitidine