Pati Dipanwita, Lee Sophia I, Conley Sara Y, Sides Tori, Boyt Kristen M, Hunker Avery C, Zweifel Larry S, Kash Thomas L
Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Curriculum of Neuroscience, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
bioRxiv. 2023 Jun 14:2023.06.13.544820. doi: 10.1101/2023.06.13.544820.
Dysregulation of the dopamine (DA) system is a hallmark of substance abuse disorders, including alcohol use disorder (AUD). Of the DA receptor subtypes, the DA D2 receptors (D2Rs) play a key role in the reinforcing effects of alcohol. D2Rs are expressed in numerous brain regions associated with the regulation of appetitive behaviors. One such region is the bed nucleus of the stria terminalis (BNST), which has been linked to the development and maintenance of AUD. Recently, we identified alcohol withdrawal-related neuroadaptations in the periaqueductal gray/dorsal raphe to BNST DA circuit in male mice. However, the role of D2R-expressing BNST neurons in voluntary alcohol consumption is not well characterized. In this study, we used a CRISPR-Cas9-based viral approach, to selectively reduce the expression of D2Rs in BNST VGAT neurons and interrogated the impact of BNST D2Rs in alcohol-related behaviors. In male mice, reduced D2R expression potentiated the stimulatory effects of alcohol and increased voluntary consumption of 20% w/v alcohol in a two-bottle choice intermittent access paradigm. This effect was not specific to alcohol, as D2R deletion also increased sucrose intake in male mice. Interestingly, cell-specific deletion of BNST D2Rs in female mice did not alter alcohol-related behaviors but lowered the threshold for mechanical pain sensitivity. Collectively, our findings suggest a role for postsynaptic BNST D2Rs in the modulation of sex-specific behavioral responses to alcohol and sucrose.
多巴胺（DA）系统失调是包括酒精使用障碍（AUD）在内的物质使用障碍的一个标志。在DA受体亚型中，DA D2受体（D2Rs）在酒精的强化作用中起关键作用。D2Rs在许多与调节食欲行为相关的脑区表达。终纹床核（BNST）就是这样一个区域，它与AUD的发生和维持有关。最近，我们在雄性小鼠中发现了中脑导水管周围灰质/背侧中缝核至BNST DA回路中与酒精戒断相关的神经适应性变化。然而，表达D2R的BNST神经元在自愿饮酒中的作用尚未得到充分表征。在本研究中，我们使用基于CRISPR-Cas9的病毒方法，选择性降低BNST VGAT神经元中D2Rs的表达，并研究BNST D2Rs对酒精相关行为的影响。在雄性小鼠中，D2R表达降低增强了酒精的刺激作用，并在双瓶选择间歇性接触范式中增加了20% w/v酒精的自愿摄入量。这种效应并非酒精所特有，因为D2R缺失也增加了雄性小鼠的蔗糖摄入量。有趣的是，雌性小鼠中BNST D2Rs的细胞特异性缺失并未改变酒精相关行为，但降低了机械性疼痛敏感性阈值。总的来说，我们的研究结果表明突触后BNST D2Rs在调节对酒精和蔗糖的性别特异性行为反应中发挥作用。
