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: 6039727
• 负责人: LEONARD M EISENMAN
• 金额: $ 10.32万
• 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 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6039727
• 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.

酗酒和急性酒精中毒是严重的社会问题，每年危及许多人的生命。了解酒精在急性中毒期间的作用机制可能会导致治疗，从而减少这些对社会的风险。这项探索性发展拨款申请是由一位高级研究员提出的，他对乙醇在小脑和相关结构中的作用的位置和机制有兴趣。之所以选择这些结构进行分析，是因为急性酒精中毒导致的许多行为异常与运动行为受损有关。这些研究代表了这个P.I.的一个新的研究领域，这些研究包括通过检测早期基因c-fos的蛋白质产物Fos来测定急性乙醇中毒后神经元活动的变化。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。这种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。由于c-fox表达的这种变化提供了一种机制，可以确定乙醇中毒导致兴奋性改变的特定神经元亚群。识别这些乙醇的神经元靶点将允许集中检查神经元的传入和受体特征，介导其乙醇敏感性。此外，它将为分析对乙醇表现出不同行为反应的小鼠品系的乙醇中毒行为后遗症提供形态学基础。我们最初的初步研究表明，乙醇对不同组的小脑颗粒细胞和下橄榄的细分有不同的影响。所提出的探索性研究旨在进一步描述不同品系小鼠中c-fox表达的异质性影响，以及不同剂量乙醇和乙醇给药后不同时间段的影响，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。通过了解急性酒精中毒时乙醇对神经系统的作用及其机制，有可能改善乙醇对中枢神经系统的影响以及由此导致的异常行为。