GABA-A Receptors, Ethanol, and Stress in Amygdala

描述(由申请者提供)：众所周知，急性饮酒可以降低焦虑，而停止长期接触酒精会增加焦虑。 此外，在戒酒者和实验动物模型中，自愿的酒精消耗可以通过暴露于焦虑/压力中来调节。啮齿动物模型对于了解细胞和分子对压力/焦虑和慢性酒精摄入的适应尤为重要。然而，在啮齿动物模型中的发现在多大程度上模仿了人类酗酒者的发现还没有被很好地理解。因此，长期酒精自我给药的灵长类动物模型可能会为了解压力/焦虑和酒精滥用之间的关系提供有价值的见解，这可能与人类的状况更相关。焦虑的调节和对压力的行为反应涉及许多大脑区域之间的复杂相互作用。杏仁核是一个边缘前脑区域，是控制这种行为的关键脑区。我们实验室的初步研究利用了从对照猕猴和自我注射酒精18个月的猴子身上急性分离的杏仁核神经元。这些研究的结果表明，长期的酒精自我给药会导致杏仁核GABA(A)受体功能和药理的改变，这与某些啮齿动物模型中发现的不同。为了更好地了解灵长类动物焦虑/应激与慢性酒精之间的相互作用，我们将利用分离的杏仁核神经元的全细胞膜片钳电生理学来研究近缘物种猕猴的GABA(A)受体对围产期应激和长期酒精自我注射的细胞适应。这些研究将得到实时RT-PCR和对猴子杏仁核组织的Western分析的补充，以确定潜在的GABA(A)受体功能变化的分子机制。最终，我们提出的研究将有助于更好地理解灵长类动物中酒精-焦虑/压力的相互作用。

DESCRIPTION (provided by applicant): It is well established that acute ethanol consumption can decrease anxiety and that withdrawal from chronic ethanol exposure can increase anxiety. Furthermore, voluntary ethanol consumption can be regulated by exposure to anxiety/stress in both recovering alcoholics and experimental animal models. Rodent models have been especially important for understanding cellular and molecular adaptations to stress/anxiety and chronic alcohol ingestion. However, the extent to which findings in rodent models mimic those in human alcoholics is not well understood. Primate models of long-term ethanol self-administration may therefore provide valuable insight into the relationship between stress/anxiety and alcohol abuse that is potentially more relevant to the human condition. The regulation of anxiety and behavioral responses to stress involve complex interactions between numerous brain regions. The amygdala, a limbic forebrain area, is a pivotal brain region controlling such behaviors. Preliminary studies in our laboratory have utilized acutely isolated amygdala neurons from control Macaca fascicularis monkeys and from monkeys that have self-administered ethanol for 18 months. Results from these studies indicate that long-term ethanol self-administration causes alterations in amygdala GABA(A) receptor function and pharmacology that are distinct from those found in some rodent models. To better understand the interactions between anxiety/stress and chronic ethanol in primates, we will utilize whole-cell patch clamp electrophysiology in isolated amygdala neurons to characterize cellular adaptations of the GABA(A) receptor to peri-natal stress and long-term ethanol self administration in a related species, Macaca mulatta. These studies will be complemented by real-time RTPCR and western analysis of monkey amygdala tissue to identify molecular mechanisms underlying changes GABA(A) receptor function. Ultimately, our proposed studies will help lead to a better understanding of the ethanol-anxiety/stress interaction in primates.