Department of Cell Biology and Anatomy, LSU Health Sciences Center New Orleans, New Orleans, LA, USA.
Neuroscience Center of Excellence, LSU Health Sciences Center New Orleans, New Orleans, LA, USA.
Transl Psychiatry. 2021 Mar 17;11(1):178. doi: 10.1038/s41398-021-01285-y.
Adolescent alcohol use is one of the strongest predictors for the development of an alcohol use disorder (AUD). Notably, this period of risk coincides with the development of affective disorders, which disproportionately impact and drive problematic drinking behavior in women. Stress is a particularly salient factor that drives relapse during periods of abstinence. Previous work in our lab has shown that adolescent intermittent ethanol vapor (AIE) produces sex-dependent changes in glutamatergic activity in the bed nucleus of the stria terminalis (BNST) and behavioral outcomes following acute restraint stress in adulthood. In females, AIE disrupts group 1 metabotropic glutamate (mGlu1/5) receptor activity and enhances anhedonia-like behavior. The current study site-specifically knocked down mGlu5 receptors in the BNST of male and female Grm5 mice, exposed them to AIE, and observed the interaction of AIE and stress on negative affect-like behaviors in adulthood. These negative affect-like behaviors included the novelty-induced hypophagia task following acute restraint stress, open field activity, and contextual fear conditioning. Overall, we replicated our previous findings that AIE enhanced anhedonia-like activity in the novelty-induced hypophagia task in females and fear acquisition in males. The primary effect of BNST-mGlu5 receptor knockdown was that it independently enhanced anhedonia-like activity in females. Correlation analyses revealed that behavior in these paradigms showed poor interdependence. These results indicate that preclinical models of negative affective-like states encompass distinct features that may have independent, clinically relevant mechanisms. Further, modulating mGlu5 receptors is a prospective treatment target for females experiencing anhedonic-like states that make them susceptible to alcohol relapse.
青少年饮酒是发展酒精使用障碍（AUD）的最强预测因素之一。值得注意的是，这段风险期恰逢情感障碍的发展，这对女性的问题性饮酒行为产生了不成比例的影响和推动。压力是导致禁欲期间复发的一个特别突出的因素。我们实验室之前的工作表明，青少年间歇性乙醇蒸气（AIE）会导致终纹床核（BNST）中的谷氨酸能活动产生性别依赖性变化，并在成年期急性束缚应激后产生行为结果。在女性中，AIE 会破坏代谢型谷氨酸受体 1/5（mGlu1/5）受体活性，并增强快感缺失样行为。本研究特异性敲低了雄性和雌性 Grm5 小鼠 BNST 中的 mGlu5 受体，使它们暴露于 AIE 中，并观察 AIE 和应激对成年期负性情感样行为的相互作用。这些负性情感样行为包括急性束缚应激后的新异诱发摄食减少任务、旷场活动和情境恐惧条件反射。总的来说，我们复制了之前的发现，即 AIE 增强了女性新异诱发摄食减少任务中的快感缺失样活动和男性的恐惧获得。BNST-mGlu5 受体敲低的主要作用是独立增强了女性的快感缺失样活动。相关分析表明，这些范式中的行为表现出较差的相互依赖性。这些结果表明，负性情感样状态的临床前模型包含独立的、具有临床相关性的机制的独特特征。此外，调节 mGlu5 受体可能是对经历快感缺失样状态的女性的一种有前景的治疗靶点，这种状态使她们容易酒精复发。
