ETHANOL EFFECTS ON C-FOS GENE EXPRESSION IN THE CNS

乙醇对 CNS 中 C-FOS 基因表达的影响

• 批准号: 6362184
• 负责人: LEONARD M EISENMAN
• 金额: $ 9.29万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362184
• 关键词: alcoholic beverage consumption; behavioral /social science research tag; behavioral genetics; biological signal transduction; cerebellum; chemosensitizing agent; dosage; drug administration rate /duration; ethanol; fos protein; gene expression; genetic strain; intraperitoneal injections; ketamine; laboratory mouse; pentobarbital; pons; psychomotor function; regulatory gene; serotonin; substance abuse related behavior; tube feeding

Alcoholism and acute alcohol intoxication are serious societal problems which jeopardize the lives of many individuals each year. Understand the mechanisms of action of alcohol during acute intoxication may lead to treatments that would reduce these risks to society. This exploratory development grant application is proposed by a senior investigator interested in conducting studies on the sites and mechanisms of ethanol's effects in the cerebellum and related structure. These structures were chosen for analysis because many of the behavioral abnormalities that result from acute alcohol intoxication are concerned with compromised motor behaviors. These studies represent a new area of investigation for this P.I. The studies involve the determination of changes in neuronal activity subsequent to acute ethanol intoxication as measured by the detection of the protein product, Fos, for the immediately-early gene c-fos. The expression of the c-fos gene has been used very successfully and reliably as a indication of stimulus-induced changes in neuronal activity. This marker system is particularly appropriate for analyzing the effects of ethanol on neurons, since these effects are heterogeneous. As such changes in c-fox expression provides a mechanism to determine the specific subsets of neurons whose excitability is altered by ethanol intoxication. Identification of these neuronal targets of ethanol would permit a focused examination of the afferent and receptor characteristics of neurons which mediate their ethanol sensitivity. In addition, it would provide a morphological basis upon which to analyze the behavioral sequelae of ethanol intoxication in strains of mice that exhibit varied behavioral responses to ethanol. Our initial preliminary studies suggest that different groups of cerebellar granule cells and subdivisions of the inferior olive are differentially affected by ethanol. The proposed exploratory studies are designed to further delineate these heterogeneous effects on c-fox expression in different strains of mice and consequent to different doses of ethanol and at different time periods after ethanol administration and to correlates these changes with measures of behavioral activity. In addition, studies are proposed to begin to analyze transmitter and receptor systems that are responsible for neuronal sensitivity to ethanol. By understanding the neuronal targets for ethanol and its mechanisms of action during acute alcohol intoxication it may be possible to ameliorate ethanol's effects on the CNS and the abnormal behaviors which result.

酒精中毒和急性酒精中毒是严重的社会问题，每年危害许多人的生命。了解酒精在急性中毒过程中的作用机制可能会导致治疗，减少这些风险的社会。这项探索性开发补助金申请是由一位高级研究人员提出的，他对研究乙醇在小脑和相关结构中的作用部位和机制感兴趣。选择这些结构进行分析是因为许多由急性酒精中毒引起的行为异常与受损的运动行为有关。这些研究代表了该P.I.的一个新的研究领域。这些研究涉及确定急性乙醇中毒后神经元活动的变化，通过检测即刻早期基因c-fos的蛋白产物Fos来测量。c-fos基因的表达已被非常成功和可靠地用作刺激诱导的神经元活动变化的指示。该标记系统特别适合于分析乙醇对神经元的影响，因为这些影响是异质的。因此，c-fox表达的变化提供了一种机制，以确定其兴奋性被乙醇中毒改变的神经元的特定子集。这些神经元的乙醇目标的识别将允许一个集中的检查传入和受体的神经元介导的乙醇敏感性的特点。此外，它将提供一个形态学的基础上，分析酒精中毒的行为后遗症的小鼠品系，表现出不同的行为反应，乙醇。我们最初的初步研究表明，不同群体的小脑颗粒细胞和亚部的下橄榄是不同的影响乙醇。拟定的探索性研究旨在进一步描述不同品系小鼠中c-fox表达的这些异质性效应，以及不同剂量乙醇和乙醇给药后不同时间段的效应，并将这些变化与行为活动的测量相关联。此外，研究建议开始分析负责神经元对乙醇敏感性的递质和受体系统。通过了解乙醇的神经靶点及其在急性酒精中毒过程中的作用机制，有可能改善乙醇对CNS的影响及其导致的异常行为。