Alcoholism and tobacco addiction are significant problems in modern society that are highly correlated with one another. One possible reason for their correlation may be that common genes regulate an individual's sensitivity to the two drugs. In humans, low initial sensitivity to ethanol has been a reliable predictor of future alcoholism, and recent quantitative trait loci studies have significantly correlated such behavior to a locus on chromosome 20 that is nearly identical to that of the alpha4 subunit of the nicotinic acetylcholine receptor. In vitro studies suggest that ethanol can induce a gain of function in some nicotinic receptors. Our laboratory has identified a polymorphism in the alpha4 subunit of the mouse that is highly correlated with differential effects in alcohol- and nicotine-related behavioral assays, nicotinic receptor function, and nicotine stimulated neurotransmitter release. However, the action of ethanol on in vivo alpha4-containing nicotinic receptors is uncertain, nor is it known how the alpha4 polymorphism is involved with the direct effects of ethanol at these receptors. To answer these questions we propose to: (1) ascertain the role of the alpha4 polymorphism in alcohol- and nicotine-related behaviors using classical genetic methods merged with null-mutation approaches; and (2) assess the effects of ethanol on naturally occurring neuronal nicotinic receptors that contain the alpha4 subunit with direct (86Rb+ efflux) and indirect ([3H]dopamine release) neurochemical measures of receptor function.