MECHANISM OF ACTION OF ANESTHETICS AND ETHANOL

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It is not known how volatile anesthetics or ethanol disrupt consciousness, nor is there agreement on the properties of their sites of action. Our long term goal is to understand which neurologic functions are disrupted by these agents. The phenomenon of "anesthesia" appears to be a very highly-conserved response by nervous systems of differing complexities to compounds with a variety of chemical structures. Susceptibility to the additive effects of ethanol may correlate to certain types of increased sensitivity to the drug. We plan to study genes controlling sensitivity to ethanol, using the simple nematode C. elegans as an animal model. Our studies in C. elegans suggest that there are multiple sites of action for volatile anesthetics, each primarily affected by different groups of anesthetics. We have found that ethanol appears to fit in one of these groups of anesthetics. We have isolated mutations which alter sensitivity to ethanol and are continuing to screen for others. These mutations will serve as probes for identifying the sites of action of ethanol in C.e. The specific aims of this proposal are to: CHARACTERIZE MUTATIONS CONFERRING ALTERING SENSITIVITY TO ETHANOL We plan to identify the genes that control ethanol sensitivity in C.e. We have isolated mutations in five genes that alter responses to the anesthetics enflurane and to ethanol. Altered sensitivity to ethanol appears to correlate with altered sensitivity to enflurane in C. elegans. We will continue to identify and map mutations which alter ethanol and sensitivity and the response of these mutations will be characterized. this will include making double mutations to determine the interaction of the identified mutations. We will attempt to construct a genetic pathway for the control of ethanol sensitivity in C. elegans. CLONE THE GENES WHICH CONTROL SENSITIVITY TO ETHANOL Three mutations, fc20, fc21 and fc34, strongly alter sensitivity to ethanol. We plan to clone one of these genes, fc34, to determine its gene products.