Mechanistic insights into epigenetic modulation of ethanol consumption

• Published in: Alcohol (Fayetteville, N.Y.) Vol. 60; pp. 95 - 101
• Main Authors: Ponomarev, Igor, Stelly, Claire E, Morikawa, Hitoshi, Blednov, Yuri A, Mayfield, R. Dayne, Harris, R. Adron
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2017; Elsevier Limited
• Subjects: 5-aza-2'-deoxycytidine; Addictive behaviors; Alcohol; Alcohol use; Alcoholism; Animal models; Behavior; Blood flow; Brain; Brain research; Cancer; Cerebral blood flow; Deoxyribonucleic acid; DNA; DNA methylation; Dopamine; Dopamine receptors; Drinking behavior; Drug abuse; Drug addiction; Drug dosages; Drug repurposing; Epigenetics; Ethanol; Experiments; Extracellular matrix; Gene expression; Histone deacetylase; Medical research; Molecular modelling; Neuromodulation; Neuronal activity; Neurosciences; Physiology; Psychiatry; Reinforcement; Ribonucleic acid; RNA; Transcriptome; Ventral tegmentum; Epigenetics; Drug repurposing; Alcohol; Neuronal activity; Behavior; Transcriptome
• ISSN: 0741-8329; 1873-6823
• DOI: 10.1016/j.alcohol.2017.01.016

Abstract There is growing evidence that small-molecule inhibitors of epigenetic modulators, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), can reduce voluntary ethanol consumption in animal models, but molecular and cellular processes underlying this behavioral effect are poorly understood. We used C57BL/6J male mice to investigate the effects of two FDA-approved drugs, decitabine (a DNMT inhibitor) and SAHA (an HDAC inhibitor), on ethanol consumption using two tests: binge-like drinking in the dark (DID) and chronic intermittent every other day (EOD) drinking. Decitabine but not SAHA reduced ethanol consumption in both tests. We further investigated decitabine's effects on the brain's reward pathway by gene expression profiling in the ventral tegmental area (VTA), using RNA sequencing and electrophysiological recordings from VTA dopaminergic neurons. Decitabine-induced decreases in EOD drinking were associated with global changes in gene expression, implicating regulation of cerebral blood flow, extracellular matrix organization, and neuroimmune functions in decitabine actions. In addition, an in vivo administration of decitabine shortened ethanol-induced excitation of VTA dopaminergic neurons in vitro , suggesting that decitabine reduces ethanol drinking via changes in the reward pathway. Taken together, our data suggest a contribution of both neuronal and non-neuronal mechanisms in the VTA in the regulation of ethanol consumption. Decitabine and other epigenetic compounds have been approved for cancer treatment, and understanding their mechanisms of actions in the brain may assist in repurposing these drugs and developing novel therapies for central disorders, including drug addiction.