PROJECT SUMMARY Women progress more rapidly than men from social to problematic alcohol drinking. We propose that this difference may be due in part to a difference in how they respond to abstinence. In laboratory animals, short- term abstinence increases alcohol consumption, with repeated deprivations leading to disordered drinking. . We hypothesize that a similar phenomenon exists in humans, and that women are more sensitive to it. We have recently developed a novel translational paradigm to measure response to abstinence in humans. In this experiment, we found that after abstinence women, on average, increased, while men decreased their alcohol seeking. The objectives of this application are to characterize the human post abstinence response in the lab as well as community and understand its underlying mechanisms in moderate-heavy drinkers. We will complement our existing dataset with free-access self-administration, use identical alcohol exposures to study the mechanisms underlying our identified sex differences, and relate our findings to community drinking with examination of sex differences in how self-reported abstinence intervals influence drinking over a one-year follow-up. Our long-term goal is to inform alcohol use disorder treatment selection and to design and test novel interventions using our novel human laboratory measure of post-abstinence response. There is a critical unfilled need to understand accelerated disease progression among women and our lab-based assessment coupled to longitudinal follow-up provides the rigorous experimental design to begin to meet that need. This project will increase our scientific knowledge by advancing the translation between preclinical and clinical models, eventually informing sex-specific intervention and prevention strategies for problematic drinking and establishing a model to test those interventions.