Neuronal DNA-methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.

Monday, September 22, 2014 — Poster Session I
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NIAAA	NEURO-2

Authors

• E Barbier
• J.D. Tapocik
• N Juergens
• C Pitcairn
• A Borich
• J.C. Hanson
• J.R. Schank
• H Sui
• A Thorsell
• K Schuebel
• Z Zhou
• Q Yuan
• M Emmert-Buck
• D Goldman
• M Heilig

Abstract

Recent studies suggest an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined DNA methyltransferase 1 (DNMT1) and the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent neuroadaptations, we studied the role of DNA methylation and DNMT1 activity for medial prefrontal cortex gene expression and for alcohol self-administration in rats 3 weeks into abstinence following alcohol dependence. Post-dependent (PD) rats showed escalated alcohol intake, which was associated with increased DNMT1 expression and decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNMT1 inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced down-regulation of 4 transcripts modified in PD rats. DNMT1 treatment directly reversed the down-regulation of syt2 which was caused by alcohol-induced hypermethylation. Lentiviral inhibition of syt2 expression in the mPFC increased aversion-resistant alcohol drinking,supporting a mechanistic role of syt2 in alcohol seeking. Our findings show a functional role of DNMT1 in persistent alcohol induced behaviors, and identify a gene network that may mediate its effects. These data provide evidence for DNMT1 as a potential therapeutic target for alcoholism.

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