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Ponomarev I, Stelly CE, Morikawa H, Blednov YA, Mayfield RD, Harris RA

Waggoner Center for Alcohol and Addiction Research and The College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA

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, however, molecular and cellular processes underlying this behavioral effect are poorly understood. We showed that decitabine, a potent DNMT inhibitor, reduced ethanol consumption in mice in a chronic intermittent paradigm, and this reduction was associated with molecular and cellular alterations in VTA dopamine neurons. Specifically, an in vivo administration of decitabine reduced ethanol-induced excitation of dopamine neurons in vitro. In addition, the decitabine-induced reduction of ethanol consumption was associated with molecular changes in VTA measured using RNA sequencing. Taken together, our data suggest that decitabine reduces ethanol drinking via changes in the reward pathway. Supported by NIH NIAAA grant AA020683.