PROJECT SUMMARY Alcohol use disorder (AUD) persists as a costly public health problem that lacks widely effective medications and preventive strategies. The overarching premise of this Project, like others in the WF-TARC, is that the neural substrates that contribute to vulnerability and resilience to AUD are not fully understood. Studies using nonhuman primates (NHP) have advantages that make them a critical part of a comprehensive, translational approach to addressing this topic. This project continues and extends work accomplished in the ongoing funding cycle. Aim 1 will extend our characterization of 12 group-housed male cynomolgus monkeys who have been drinking ethanol (EtOH) for >2 years. We will assess brain structure, function and connectivity using MRI. In addition, in the current funding cycle we implemented home cage cognitive testing using touchscreen hardware and software that we developed. We will assess two clinically relevant characteristics: behavioral flexibility (with a stimulus discrimination and reversal task) and impulsive choice (with a delay discounting task). We will also characterize resistance to punishment by assessing the ability of the bitter tastant quinine to decrease EtOH consumption. We hypothesize that these measures will differ between heavy and light drinkers. Next, EtOH access will be discontinued, modeling abstinence, and Aim 2 will assess these same measures over the following year. We expect to observe increases in cognitive function, resistance to punishment, grey matter volumes, white matter integrity and functional connectivity in all monkeys but that this “recovery” will be slower and less complete in monkeys that had higher EtOH intakes prior to discontinuation. During this EtOH-free period we will also assess reactivity to EtOH-paired cues in a model of relapse. Finally, access to EtOH will be reinstated and Aim 3 will examine the efficacy of putative pharmacotherapies whose potential is suggested by other WF- TARC projects. Drugs will be administered chronically when monkeys have access to EtOH 6 hrs/day (modeling moderate drinking) and, later, 22 hrs/day (modeling heavy drinking). We hypothesize that putative medications will be more efficacious in light vs. heavy drinkers. When these data are combined with findings from other WF- TARC projects, specific candidates will emerge with a strong preclinical profile to suggest their utility in treating AUD. These NHP studies occupy a critical position in the translational structure of the WF-TARC, supporting forward and backward translation to inform and extend findings in rodent and human projects. Taken together, the results of the studies in this Project, particularly in combination with data generated in other components of the WF-TARC, will provide a comprehensive account of brain differences between populations that are resistant versus vulnerable to AUD. This knowledge will ultimately help practitioners direct preventive efforts to groups who will most benefit from them and will identify new targets for more effective medications that can be targeted to the most vulnerable populations.