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Binge drinking is the most common pattern of excessive alcohol consumption and is a significant contributor to the development of Alcohol Use Disorder and dependence. Previous studies demonstrated involvement of kappa opioid receptors (KOR) in binge-like drinking in mice using the Drinking-in-the-Dark model. The current studies examined the role of KOR specifically in the bed nucleus of the stria terminals (BNST) in binge-like alcohol consumption in male and female mice. Direct administration of the long lasting KOR antagonist, nor-BNI, into the BNST decreased binge-like alcohol consumption and blood alcohol concentrations in male and female C57BL/6J mice. Similarly, direct nor-BNI administration into the BNST modestly reduced sucrose consumption and the suppression of fluid intake was not related to reduced locomotor activity. To further determine the role of KOR within the BNST on binge-like alcohol consumption, the KOR agonist U50,488 was administered systemically which resulted in a robust increase in alcohol intake. Microinjection of nor-BNI into the BNST blocked the high level of alcohol intake after systemic U50,488 challenge reducing intake and resultant blood alcohol concentrations. Together, these data suggest that KOR activity in the BNST contributes to binge-like alcohol consumption in both male and female mice. This article is part of the special issue on 'Neuropeptides'., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Although previous research has demonstrated a role for kappa opioid receptor-mediated signaling in escalated alcohol consumption associated with dependence and stress exposure, involvement of the dynorphin/kappa opioid receptor (DYN/KOR) system in binge-like drinking has not been fully explored. Here we used pharmacological and chemogenetic approaches to examine the influence of DYN/KOR signaling on alcohol consumption in the drinking-in-the-dark (DID) model of binge-like drinking. Systemic administration of the KOR agonist U50,488 increased binge-like drinking (Experiment 1) while, conversely, systemic administration of the KOR antagonist nor-BNI reduced drinking in the DID model (Experiment 2). These effects of systemic KOR manipulation were selective for alcohol as neither drug influenced consumption of sucrose in the DID paradigm (Experiment 3). In Experiment 4, administration of the long-acting KOR antagonist nor-BNI into the central nucleus of the amygdala (CeA) decreased alcohol intake. Next, targeted "silencing" of DYN+ neurons in the CeA was accomplished using a chemogenetic strategy. Cre-dependent viral expression in DYN+ neurons was confirmed in CeA of Pdyn-IRES-Cre mice and functionality of an inhibitory (hM4Di) DREADD was validated (Experiment 5). Activating the inhibitory DREADD by CNO injection reduced binge-like alcohol drinking, but CNO injection did not alter alcohol intake in mice that were treated with control virus (Experiment 6). Collectively, these results demonstrate that DYN/KOR signaling in the CeA contributes to excessive alcohol consumption in a binge-drinking model.