ETHANOL EFFECTS ON C-FOS GENE EXPRESSION IN THE CNS

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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.