GABA-A Receptors, Ethanol, and Stress in Amygdala

描述（由申请人提供）：众所周知，急性乙醇消费可以减少焦虑，而从慢性乙醇暴露中退出会增加焦虑。

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.