PHARMACOGENETIC ANALYSIS OF LOW-DOSE ETHANOL EFFECTS

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The research outlined in this proposal examines genetic influences on behavioral responses to low doses of ethanol and neurochemical events which underlie low-dose ethanol sensitivity. Recombinant inbred strains and selected lines of mice which evince widely differential behavioral responses to low doses of ethanol will be used to generate genetic correlational analyses among behaviors and between behavioral and neurochemical measures. The behaviors of interest include locomotor activity, exploration and indices of anxiety, i.e., thigmotaxis and plus- maze performance. Specific neurochemical mechanisms of interest in low- dose ethanol behavioral response include dopamine metabolism and neurotensin levels in discrete areas of the fore and midbrain. Specific structures include the nucleus accumbens, ventral tegmentum, caudate- putamen and frontal cortex. Specific dopamine receptor agonists and antagonists [both D1 and D2] will be applied centrally, concomitantly with i.p. administration of doses of ethanol which maximally differentiate strain/line-related behavioral response to low doses of ethanol. The long- term goal of this research is to define genetically based neurochemical mechanisms mediating effects of low doses of ethanol. Ultimately these studies will have general heuristic value in understanding alcohol-seeking behavior and alcoholism.