NARRATIVE Abuse and dependence on alcohol and other sedative-hypnotic drugs continue to be substantial mental health problems that face United States veterans. There are a host of biological (genetic) and environmental factors interacting in a complex manner throughout the addictive process to influence alcohol and drug use/abuse and relapse. We recently identified a chromosomal region with a large effect on alcohol physical dependence and associated withdrawal in a preclinical model, and identified a network of genes involved in oxidative stress that plausibly underlies its mechanism of action on withdrawal behaviors. The focus and overall objective of this renewal application is to utilize robust mouse models of alcohol withdrawal to rigorously test the hypothesis that genotype-dependent differences in oxidative stress and mitochondrial respiratory function contribute to genetic susceptibility for severe alcohol physical dependence and associated withdrawal, as well as genetically correlated behaviors (i.e., ethanol preference drinking, and withdrawal from other abused sedative-hypnotic drugs). The animal models developed for the proposed work will provide a powerful foundation for translational research in which gene networks important in determining liability for development of physical dependence and withdrawal in humans are studied, and for developing gene and drug therapies to enhance treatment and prevention.