Alcoholism and alcohol dependence are important contributors to health problems facing US veterans. Alcoholism is a multigenic and polygenic disease: that is, many genes contribute modest effects to enhance risk or protection. Together, genetic factors appear to contribute approximately half of an individual's total risk, with the other half coming from environmental factors, such as socioeconomic, family, and peer attributes. We can now only predict that an individual may be at an increased statistical risk based on his or her genetic relationships to alcoholics. One important goal is to be able to predict actual individual differences in risk, base on knowledge about specific genes. There is currently no animal model that captures the full range of alcohol withdrawal symptoms. During 34 years of continuous funding, this Merit Review Program has established and studied a number of genetic animal models for aspects of alcohol (ethanol) dependence, and has contributed to the identification of the first gene influencing a drug-dependence related behavioral trait, Mpdz, influencing ethanol withdrawal seizures. Because of the high degree of mouse/human genetic homology (approx. 85%), genes mapped in mice are able to predict human gene locations. However, to date, nearly all gene mapping efforts for ethanol dependence by any group have focused on either withdrawal seizures or alcohol preference drinking. Beginning in 1999, we began studies in several behavioral domains (motor impairment, anxiety, activity, increased drinking after withdrawal) to start mapping the landscape of withdrawal more broadly. An important goal is to identify the genes responsible for increased risk for and protection against additional symptoms of alcohol dependence. In filling this gap, this project will (1) develop more comprehensive assessment assays to describe ethanol withdrawal effects across multiple behaviors, including pain sensitivity, anhedonia/depression, learning & memory /cognitive impairment, thermal disruption, and reinforcement; (2) elucidate the time course of each of these withdrawal effects; (3) use brain microinjection to test whether a specific neural circuit underlies one withdrawal behavior, exacerbated drinking; (4) sequence the exomes of the most widely used genetic animal model for ethanol dependence syndromes, the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mouse lines and their Controls (WSC), to identify potentially informative sequence variants (SNVs); (5) using generational strategies, including an F2 cross of WSP x WSR, identify SNVs that segregate with various withdrawal symptoms; and (6) continue to support the WSP, WSR, WSC, and inbred iWSP and iWSR mouse lines. These studies, through identification of gene targets that are affected by alcohol dependence and withdrawal symptoms, will ultimately directly suggest possible pharmacotherapies for the problems underlying alcoholism.