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Open AccessArticle

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

1
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA
2
Research & Development, VA Portland Health Care System, Portland, OR 97239, USA
3
Chemistry Department, Portland State University, Portland, OR 97207, USA
4
College of Natural Sciences, Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin TX 78712, USA
*
Author to whom correspondence should be addressed.
Brain Sci. 2020, 10(2), 109; https://doi.org/10.3390/brainsci10020109
Received: 17 December 2019 / Revised: 11 February 2020 / Accepted: 17 February 2020 / Published: 18 February 2020
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 effects 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. View Full-Text
Keywords: binge drinking; genes; signaling pathways; DREADDs or chemogenetics; high drinking in the dark mice binge drinking; genes; signaling pathways; DREADDs or chemogenetics; high drinking in the dark mice
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Pozhidayeva, D.Y.; Farris, S.P.; Goeke, C.M.; Firsick, E.J.; Townsley, K.G.; Guizzetti, M.; Ozburn, A.R. Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes. Brain Sci. 2020, 10, 109.

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