Dynorphin-kappa opioid receptor activity in the central amygdala modulates binge-like alcohol drinking in mice.,Neuropsychopharmacology

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Dynorphin-kappa opioid receptor activity in the central amygdala modulates binge-like alcohol drinking in mice.
Neuropsychopharmacology ( IF 6.6 ) Pub Date : 2018-12-11 , DOI: 10.1038/s41386-018-0294-3
Rachel I Anderson ₁ , Marcelo F Lopez ₁ , William C Griffin ₁ , Harold L Haun ₂ , Daniel W Bloodgood _{3,

4} , Dipanwita Pati ₄ , Kristen M Boyt ₄ , Thomas L Kash _{3,

4} , Howard C Becker _{1,

2,

5}

Affiliation

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.

中文翻译：

在中央杏仁核中的强啡肽-阿片受体活性调节小鼠中的暴饮暴食性饮酒。

尽管先前的研究已经证明了κ阿片受体介导的信号传导在与依赖性和压力暴露相关的酒精消费增加中的作用，但尚未充分探索强啡肽/κ阿片受体系统（DYN / KOR）在暴饮暴食中的作用。在这里，我们使用药理学和化学发生学的方法来检查DYN / KOR信号对暴饮暴饮的“暗饮”（DID）模型中酒精消耗的影响。全身性施用KOR激动剂U50,488可以增加暴饮样的饮酒（实验1），相反，全身性施用KOR拮抗剂nor-BNI可以减少DID模型中的饮酒（实验2）。全身性KOR操纵的这些作用对酒精具有选择性，因为这两种药物均未影响DID范式中蔗糖的消耗（实验3）。在实验4中，将长效KOR拮抗剂nor-BNI施用到杏仁核（CeA）的中央核中会减少酒精摄入量。接下来，使用化学生成策略实现了CeA中DYN +神经元的靶向“沉默”。在Pdyn-IRES-Cre小鼠的CeA中证实了DYN +神经元中Cre依赖的病毒表达，并验证了抑制性（hM4Di）DREADD的功能（实验5）。通过CNO注射激活抑制性DREADD可以减少暴饮酒般的饮酒，但是CNO注射不会改变用对照病毒治疗的小鼠的酒精摄入（实验6）。总的来说，

更新日期：2019-01-26

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