title: DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.
abstract: Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism.
authors: Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden, estelle.barbier@liu.se.
authors: Estelle
authors: http://orcid.org/0000-0001-6924-1855
authors: E
authors: Barbier
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.
authors: Jenica D
authors: JD
authors: Tapocik
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.
authors: Nathan
authors: N
authors: Juergens
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.
authors: Caleb
authors: C
authors: Pitcairn
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.
authors: Abbey
authors: A
authors: Borich
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.
authors: Jesse R
authors: JR
authors: Schank
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.
authors: Hui
authors: H
authors: Sun
authors: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, and.
authors: Kornel
authors: K
authors: Schuebel
authors: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, and.
authors: Zhifeng
authors: Z
authors: Zhou
authors: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, and.
authors: Qiaoping
authors: http://orcid.org/0000-0002-5880-8702
authors: Q
authors: Yuan
authors: Integrative Neuroscience Research Branch, National Institute of Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
authors: Leandro F
authors: http://orcid.org/0000-0002-8829-8627
authors: LF
authors: Vendruscolo
authors: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, and.
authors: David
authors: D
authors: Goldman
authors: Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.
authors: Markus
authors: http://orcid.org/0000-0003-2706-2482
authors: M
authors: Heilig
mesh_terms: D000437:Alcoholism / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D002755:Choice Behavior; D003216:Conditioning, Operant; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage; D020869:Gene Expression Profiling; D008297:Male; D008780:Methyltransferases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D010797:Phthalimides / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D018709:Statistics, Nonparametric; D050861:Synaptotagmin II / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010797:Phthalimides; C503639:RG108; D050861:Synaptotagmin II; C494264:Syt2 protein, rat; D000431:Ethanol; D014364:Tryptophan; D008780:Methyltransferases
keywords: DNA methylation; DNMT; alcoholism; epigenetics; neurotransmitter release; plasticity