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Citation |
Ponomarev I, Stelly CE, Morikawa H, Blednov YA, Mayfield RD, Harris RA. Alcohol 2017; 60: 95-101. |
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Affiliation |
Waggoner Center for Alcohol and Addiction Research, USA; The College of Pharmacy, The University of Texas at Austin, 2500 Speedway A4800, Austin, TX, 78712, USA. |
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Copyright |
(Copyright © 2017, Elsevier Publishing) |
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DOI |
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PMID |
28433417 |
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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. Language: en |
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Keywords |
Alcohol; Behavior; Drug repurposing; Epigenetics; Neuronal activity; Transcriptome |