GABA-A Receptors, Ethanol, and Stress in Monkey Amygdala

猴子杏仁核中的 GABA-A 受体、乙醇和压力

• 批准号: 7046949
• 负责人: BRIAN A MCCOOL
• 金额: $ 13.14万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046949
• 关键词: GABA receptor; Macaca mulatta; alcoholic beverage consumption; alcoholism /alcohol abuse; amygdala; animal data; animal developmental psychology; animal tissue; anxiety; behavioral /social science research tag; biological models; ethanol; gene environment interaction; immature animal; mature animal; neurobiology; neuropharmacology; neurophysiology; protein structure; protein structure function; psychobiology; self medication; single cell analysis; stress; substance abuse related behavior; voltage /patch clamp

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.

描述（由申请人提供）：众所周知，急性乙醇消耗可以减轻焦虑，而从慢性乙醇暴露中退出会增加焦虑。 此外，在恢复酗酒和实验动物模型中，可以通过暴露于焦虑/压力来调节自愿性乙醇的消耗。啮齿动物模型对于理解压力/焦虑和慢性酒精摄入的细胞和分子适应尤其重要。但是，啮齿动物模型中模仿人类酗酒者的发现的程度尚不清楚。因此，长期乙醇自我管理的灵长类动物模型可能会为压力/焦虑与酗酒之间的关系提供宝贵的见解，这可能与人类状况更加相关。焦虑和对压力的行为反应的调节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，是控制此类行为的关键脑区域。我们实验室的初步研究利用了来自对照巨麦卡筋膜猴的急性分离的杏仁核神经元，以及从具有自我管理乙醇的猴子进行了18个月。这些研究的结果表明，长期的乙醇自我给药会导致杏仁核GABA（A）受体功能和药理学的改变，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中焦虑/压力与慢性乙醇之间的相互作用，我们将利用孤立的杏仁核神经元中的全细胞贴剂电生理学来表征GABA受体（A）受体（A）受体的细胞适应性，以对近原质应激和长期的乙醇自我给药，Macaca Mulatta。这些研究将通过实时RTPCR和对猴杏仁核组织的西方分析进行补充，以鉴定依靠的分子机制改变了GABA（a）受体功能。最终，我们提出的研究将有助于更好地理解灵长类动物中乙醇的焦虑/压力相互作用。