Robins Meridith T, Chiang Terrance, Mores Kendall L, Alongkronrusmee Doungkamol, van Rijn Richard M
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States.
Purdue University Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, United States.
Front Psychiatry. 2018 Apr 5;9:112. doi: 10.3389/fpsyt.2018.00112. eCollection 2018.
The transition from non-dependent alcohol use to alcohol dependence involves increased activity of the dorsal striatum. Interestingly, the dorsal striatum expresses a large number of inhibitory G-protein-coupled receptors (GPCRs), which when activated may inhibit alcohol-induced increased activity and can decrease alcohol consumption. Here, we explore the hypothesis that dorsal striatal G-protein activation is sufficient to reduce voluntary alcohol intake. Using a voluntary, limited-access, two-bottle choice, drink-in-the-dark model of alcohol (10%) consumption, we validated the importance of G signaling in this region by locally expressing neuron-specific, adeno-associated-virus encoded G-coupled muscarinic M designer receptors exclusively activated by designer drugs (DREADD) in the dorsal striatum and observed a decrease in alcohol intake upon DREADD activation. We validated our findings by activating G-coupled delta-opioid receptors (DORs), which are natively expressed in the dorsal striatum, using either a G-protein biased agonist or a β-arrestin-biased agonist. Local infusion of TAN-67, an -determined G-protein biased DOR agonist, decreased voluntary alcohol intake in wild-type and β-arrestin-2 knockout (KO) mice. SNC80, a β-arrestin-2 biased DOR agonist, increased alcohol intake in wild-type mice; however, SNC80 decreased alcohol intake in β-arrestin-2 KO mice, thus resulting in a behavioral outcome generally observed for G-biased agonists and suggesting that β-arrestin recruitment is required for SNC80-increased alcohol intake. Overall, these results suggest that activation G-coupled GPCRs expressed in the dorsal striatum, such as the DOR, by G-protein biased agonists may be a potential strategy to decrease voluntary alcohol consumption and β-arrestin recruitment is to be avoided.
从非依赖性酒精使用到酒精依赖的转变涉及背侧纹状体活动增加。有趣的是，背侧纹状体表达大量抑制性G蛋白偶联受体（GPCR），这些受体激活后可能抑制酒精诱导的活动增加，并能减少酒精摄入。在此，我们探讨背侧纹状体G蛋白激活足以减少自愿性酒精摄入这一假说。利用自愿、有限接触、两瓶选择、暗处饮酒的酒精（10%）消费模型，我们通过在背侧纹状体局部表达由设计药物（DREADD）特异性激活的神经元特异性腺相关病毒编码的G偶联毒蕈碱M设计受体，验证了该区域G信号传导的重要性，并观察到DREADD激活后酒精摄入量减少。我们通过使用G蛋白偏向激动剂或β-抑制蛋白偏向激动剂激活背侧纹状体中天然表达的G偶联δ-阿片受体（DOR）来验证我们的发现。局部注射TAN-67（一种确定的G蛋白偏向DOR激动剂）可减少野生型和β-抑制蛋白-2基因敲除（KO）小鼠的自愿性酒精摄入。SNC80是一种β-抑制蛋白-2偏向的DOR激动剂，可增加野生型小鼠的酒精摄入量；然而，SNC80可减少β-抑制蛋白-2基因敲除小鼠的酒精摄入量，从而产生通常在G蛋白偏向激动剂中观察到的行为结果，这表明SNC80增加酒精摄入需要募集β-抑制蛋白。总体而言，这些结果表明，通过G蛋白偏向激动剂激活背侧纹状体中表达的G偶联GPCR（如DOR）可能是减少自愿性酒精消费的潜在策略，应避免募集β-抑制蛋白。
