This project examines the effects of genetic background and past experience with alcohol on voluntary alcohol intake using an innovative animal (mouse) model of Intragastric Alcohol Consumption (IGAC). Recent research with this model has shown that intermittent passive exposure to alcohol (but not water) produces a large increase in subsequent alcohol intake in several mouse genotypes, including genotypes that normally avoid alcohol in drinking procedures. Our aims are designed to test the general hypothesis that individual differences in vulnerability to excessive alcohol intake are jointly determined by environmental and genetic influences on alcohol-induced neuroadaptations that contribute importantly to the development of alcoholism in humans (i.e., tolerance, dependence, withdrawal and learning). Aim 1 will assess possible pharmacological and behavioral mechanisms of enhanced voluntary intake after passive ethanol exposure in two well-studied inbred mouse strains, the C57BL/6J (B6) and DBA/2J (D2). Studies will examine the specificity and persistence of dependence-enhanced alcohol intake, stress levels, dispositional tolerance, the decay of functional tolerance (to both alcohol hypothermia and alcohol-induced conditioned taste aversion) as well as alcohol's ability to condition preference to a paired flavor when mice self-infuse alcohol during the acute phase of withdrawal. Aim 2 will provide new information on genetic mechanisms involved in dependence-enhanced alcohol intake in mouse lines selectively bred for differences in alcohol drinking preference (HAP3/LAP3) or alcohol withdrawal severity (WSP/WSR) by testing the hypothesis that common genes influence alcohol drinking, IGAC and withdrawal severity. Aim 3 will identify brain systems that mediate dependence-enhanced alcohol intake in alcohol-dependent D2 mice by disrupting three candidate brain areas thought to play important roles in dependence-induced increases in voluntary alcohol intake (amygdala, caudolateral substantia nigra, nucleus accumbens). Initial studies will use temporary inactivation of these candidate areas during acute withdrawal to identify target areas for follow-up studies that will assess the roles played by specific neuropharmacological systems using receptor-specific drug pretreatments during acute withdrawal. Aim 3 will also provide new information on the time course of negative reinforcement produced by withdrawal relief during the first day of acute withdrawal. The long-term goal of this project is to understand the environmental, genetic and neurobiological processes underlying the excessive drinking that contributes to alcoholism in humans. By improving our understanding of these processes, we can identify more effective treatment and prevention strategies. PUBLIC HEALTH RELEVANCE: Our long-term goal is to understand the environmental, genetic and brain mechanisms that underlie excessive alcohol intake in human alcoholics. This project uses an innovative animal model to study basic processes related to alcohol reinforcement (positive and negative), tolerance, dependence and withdrawal, all of which are thought to affect the development of alcoholism as well as relapse after abstinence. Information obtained from this research could be especially useful in the future identification of pharmacological and other interventions to reduce alcoholic drinking behavior.