Behavioral and molecular characterization of oxytocin's effect on alcohol consumption

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PROJECT SUMMARY: Despite the prevalence and devastating impact of alcohol use disorder (AUD), only three FDA approved pharmacotherapies exist and even fewer have proved efficacious. Thus, development of new pharmacotherapies is necessary. Of crucial importance in designing such therapies are the complex interactions of alcohol-related behaviors with the social environment, demonstrating the need for incorporating social paradigms in alcohol consumption studies. Our laboratory utilizes the unique Herdsman cage system to allow for precise, individualized measurements of both consumption and behavior in a truly social setting. Oxytocin (oxt), a hormone with crucial roles in a variety of social behaviors has drawn attention as a promising pharmacotherapy for AUD with its implicated role in mediating the processes associated with drug use, as well as its social effects, which may serve to bolster abstinence. Oxt has been shown to be effective in decreasing alcohol consumption in rodents and alcohol craving in humans. Our laboratory recently demonstrated robust effects of repeated oxt treatment in decreasing alcohol consumption in the prairie vole (Microtus ochrogaster) - a socially monogamous rodent species with demonstrated translational validity to humans through common mechanisms regulating social behaviors. Given the pharmacotherapeutic potential of oxt, it is essential to characterize the behavioral and molecular mechanisms of oxt's demonstrated ability to decrease alcohol consumption. We aim to characterize the behavioral mechanisms of oxt's effect using our Herdsman system to examine whether oxt's effects on alcohol consumption are direct or mediated by increased social interaction. We also seek to demonstrate, for the first time in prairie voles, expression patterns of the receptor for advanced glycation end products (RAGE) in the brain and transport of oxt across the blood brain barrier (BBB) facilitated by RAGE using a selective antagonist. Finally, we aim to identify through which receptor oxt is exerting its effect using selective Oxtr knock out (KO) prairie voles generated using CRISPR/Cas9. We aim to examine possible sex differences throughout our investigation. These experiments will explicate oxt's role in mediating the reward processes associated with drug use and social behavior, particularly within the context of alcohol, and serve to clarify whether oxt is a promising target for pharmacotherapy for AUD.