Pathways to Alcohol Tolerance

酒精耐受性的途径

• 批准号: 6533694
• 负责人: BORIS TABAKOFF
• 金额: $ 25.84万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533694
• 关键词: adenylate cyclase; alcoholism /alcohol abuse; amygdala; behavioral /social science research tag; cAMP response element binding protein; cooperative study; cyclic AMP; drug tolerance; ethanol; functional /structural genomics; gene expression; genetically modified animals; in situ hybridization; laboratory mouse; microarray technology; mitogen activated protein kinase; molecular biology information system; pharmacogenetics; protein kinase A; psychopharmacology; substance abuse related behavior

This proposal is directed at determining the molecular mechanisms by which tolerance develops to anxiolytic actions of ethanol. The understanding of the mechanisms of tolerance development will provide information that should assist in the understanding of the motivation driving increased ingestion of alcohol. Our research design will utilize genetically-modified animals which carry a modification in an enzyme in their brains through which alcohol can exert its action (i.e., adenylyl cyclase). The transgenic mice and their "wild-type" littermates will be treated acutely and chronically with ethanol. We will study the effect of drug administration on the animals' levels of anxiety and changes in drug response over a period of chronic drug administration. We will also monitor environmental influences on drug response after chronic ethanol treatment. Simultaneously, we will monitor the function and changes in function of intraneuronal signalling systems that control gene transcription. Finally, we will use gene- expression arrays to monitor which genes are modulated in the short- term and long-term by ethanol administration and which genes are related to tolerance development. In all, our studies should provide an excellent foundation for understanding the neuroadaptive processes leading to ethanol tolerance in reference to the anxiolytic action of this drug.

该提案旨在确定对乙醇抗焦虑作用产生耐受性的分子机制。对耐受性发展机制的理解将提供有助于理解导致酒精摄入增加的动机的信息。我们的研究设计将利用转基因动物，这些动物的大脑中携带一种酶，酒精可以通过这种酶发挥作用（即腺苷酸环化酶）。转基因小鼠及其“野生型”同窝小鼠将接受乙醇的急性和长期治疗。我们将研究长期给药期间给药对动物焦虑水平和药物反应变化的影响。我们还将监测长期乙醇治疗后环境对药物反应的影响。同时，我们将监测控制基因转录的神经元内信号系统的功能和功能变化。最后，我们将使用基因表达阵列来监测哪些基因受到乙醇施用的短期和长期调节以及哪些基因与耐受性发展相关。总而言之，我们的研究应该为理解导致乙醇耐受的神经适应过程（参考该药物的抗焦虑作用）提供良好的基础。