Abstract
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.
Highlights
Binge drinking is a problematic pattern of behavior and often leads to the development of alcohol use disorders (AUD; https://niaaa.scienceblog.com/24/niaaa-scientists-provide-more-evidence-thatbinge-drinking-may-indicate-vulnerability-to-alcohol-use-disorder/; 02/15/20)
To identify the effect of manipulating nucleus accumbens (NAc) activity on binge-like ethanol drinking behavior, High Drinking in the Dark line 1 (HDID-1) mice were subjected to the drinking in the dark (DID) paradigm
We found that chronic binge-like drinking resulted in increased complexity of medium spiny neurons in the NAc of HDID-1 female mice, an effect that was ameliorated by chronic treatment with CNO
Summary
Binge drinking is a problematic pattern of behavior and often leads to the development of alcohol use disorders (AUD; https://niaaa.scienceblog.com/24/niaaa-scientists-provide-more-evidence-thatbinge-drinking-may-indicate-vulnerability-to-alcohol-use-disorder/; 02/15/20). Binge drinking is defined by the National Institute on Alcohol Abuse and Alcoholism as having 4 to 5 drinks within 2 h and/or achieving a blood alcohol level (BAL) >80 mg% Limited access ethanol drinking paradigms are used to model binge/intoxication in animal models (not all limited access paradigms and animal strains drink to intoxication). Brain Sci. 2020, 10, 109; doi:10.3390/brainsci10020109 www.mdpi.com/journal/brainsci. (DID) paradigm, mice are offered an ethanol solution early into the active period of their circadian cycle and can achieve BALs >80 mg%, suggesting they drink to intoxication [1]. C57BL/6J mice are typically reported as high drinking and can achieve BALs >80mg% in the DID paradigm; significant inbred strain differences have been observed suggesting there exists a genetic contribution to this phenotype [2,3]. The DID assay was used to independently create two lines of mice, HDID-1 and HDID-2, that were selectively bred (from genetically heterogeneous HS/Npt progenitors) for high
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