Project 2: Mechanisms underlying vulnerability to ethanol self-administration: behavioral and brain imaging studies in group-housed monkeys

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PROJECT SUMMARY Alcohol use disorder (AUD) persists as a costly public health problem that lacks widely effective medications and strategies for prevention. The overarching scientific premise of this Project, like the others of the Wake Forest Translational Alcohol Research Center (WF-TARC), is that the neural substrates that contribute to vulnerability and resilience to AUD are not fully understood. Studies using nonhuman primate (NHP) subjects have specific advantages that make them a critical part of a comprehensive, translational approach to addressing this topic, including the possibility of experimental control not possible in human subjects and a greater similarity to humans' neurobiology compared to rodents. Group-housed monkeys form linear social hierarchies; social rank has been shown to influence sensitivity to abuse drugs, with subordinates showing vulnerability to the abuse-related effects of stimulants and ethanol (EtOH). Project 2 of the WF-TARC will exploit this differential sensitivity across social ranks to determine the behavioral and brain mechanisms that underlie vulnerability to develop AUD. Behavioral studies will characterize rank-related differences in induction of EtOH drinking, EtOH consumption over one year of 22 hours-per-day access and EtOH seeking behavior during abstinence using an extremely well-characterized NHP EtOH self-administration model of long-term drinking in humans. We will also determine whether dominant and subordinate monkeys differ in sensitivity to chronic treatment potential medications for AUD. In parallel to these experiments, brain imaging studies using magnetic resonance imaging will characterize the structural and functional differences between dominants and subordinates, and determine the specific changes that occur in grey and white matter integrity, cerebral blood flow and functional connectivity during long-term EtOH drinking and subsequent abstinence. Importantly, these NHP studies occupy a critical position in the translational structure of the WF-TARC, supporting forward and backwards translation to inform and extend findings in rodent and human projects. NHP imaging studies will focus on the same brain regions and nodes that will be imaged in human subjects and studied and manipulated in rodents. Secondary analyses on imaging data will expand this focus to the entire brain. 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 targeted to the most vulnerable populations.