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ETHANOL EFFECTS ON C-FOS GENE EXPRESSION IN THE CNS

乙醇对 CNS 中 C-FOS 基因表达的影响

基本信息

批准号：
6440131
负责人：
LEONARD M EISENMAN
金额：
$ 0.66万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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减少这些社会风险的治疗。这项探索性开发拨款申请是由一位资深研究员提出的，他对乙醇在小脑及其相关结构中的作用部位和机制进行了研究。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受损的运动行为有关。这些研究代表了这一P.I.的一个新的研究领域。这些研究涉及通过检测即刻早期基因c-fos的蛋白产物Fos来确定急性乙醇中毒后神经元活动的变化。C-fos基因的表达已经非常成功和可靠地被用来指示刺激诱导的神经元活动的变化。这个标记系统特别适合于分析乙醇对神经元的影响，因为这些影响是不同的。因此，c-fox表达的变化提供了一种机制来确定其兴奋性因乙醇中毒而改变的神经元的特定亚群。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，这些特征介导了它们对酒精的敏感性。此外，它还将为分析对乙醇表现出不同行为反应的小鼠品系的酒精中毒行为后遗症提供一个形态学基础。我们的初步研究表明，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。拟议的探索性研究旨在进一步描述不同品系的小鼠以及不同剂量的乙醇和酒精注射后不同时间段对c-fox表达的异质性影响，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。通过了解酒精的神经元靶点及其在急性酒精中毒中的作用机制，有可能改善酒精对中枢神经系统的影响以及由此导致的异常行为。