The authors gratefully acknowledge their research funding. To ARO: U.S. Department of Veterans Affairs Awards - IK2BX002488, NIH – AA013519, AA10760, and AA026997, Andrews Genomics Fund, NARSAD Young Investigator Award, Collins Medical Trust. To DP and KT: Build EXITO program Grant 5TL4GM118965; To DP: Ronald E. McNair Scholar Program. To SPF: NIH AA020926 and AA024836. To CG: AA024950. To MG: NIH – AA021468 and AA022948, VA Merit Review Award I01BX001819.
Binge Drinking -- Metabolism
Binge drinking is a dangerous pattern of behavior. We tested whether chronically manipulating nucleus accumbens (NAc) activity (via clozapine-N-oxide (CNO) and Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) could produce lasting eects on ethanol binge-like drinking in mice selectively bred to drink to intoxication. We found chronically increasing NAc activity (4 weeks, via CNO and the excitatory DREADD, hM3Dq) decreased binge-like drinking, but did not observe CNO-induced changes in drinking with the inhibitory DREADD, hM4Di. The CNO/hM3Dq-induced reduction in ethanol drinking persisted for at least one week, suggesting adaptive neuroplasticity via transcriptional and epigenetic mechanisms. Therefore, we defined this plasticity at the morphological and transcriptomic levels. We found that chronic binge drinking (6 weeks) altered neuronal morphology in the NAc, an effect that was ameliorated with CNO/hM3Dq. Moreover, we detected significant changes in expression of several plasticity-related genes with binge drinking that were ameliorated with CNO treatment (e.g., Hdac4). Lastly, we found that LMK235, an HDAC4/5 inhibitor, reduced binge-like drinking. Thus, we were able to target specific molecular pathways using pharmacology to mimic the behavioral effects of DREADDs.
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Pozhidayeva, D. Y. Y., Farris, S. P., Goeke, C. M., Firsick, E. J., Townsley, K. G., Guizzetti, M., & Ozburn, A. R. (2020). Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes. Brain Sciences, 10(2), 109.