The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking

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ABSTRACT Approximately 1 in 12 people in the USA abuse or are dependent on alcohol. Alcohol use disorder (AUD) is defined by persistent excessive alcohol intake, and compulsive drinking even in the face of adverse consequences. The neurobiological mechanisms underlying severe alcohol intake, as well as compulsive drinking, are not entirely understood. Increased glutamatergic signaling from prefrontal-striatal projection neurons has been implicated in the escalation of alcohol drinking and compulsive drinking behavior. This project will investigate these projection neurons from the prelimbic cortex (PrL) to the nucleus accumbens core (NAcc) in the context of a novel neuropeptide, Pituitary Adenylate Cyclase Activating Peptide (PACAP), and its receptor PAC1R. Reports in rodents and humans have begun to link the PACAP/PAC1R system to the actions of drugs of abuse, as well as the potentiation of glutamatergic signaling. Our preliminary data localizes this system to PrL to NAcc projection neurons, and suggests the involvement of the PACAP/PAC1R system in excessive drinking behavior. A major gap exists in the field in understanding the role of PACAP in AUD-related behaviors. Therefore, my long-term goal is to understand how this and other neuropeptidergic systems relate to excessive drinking, alcohol dependence, and AUD-related behaviors. The overarching hypothesis of this proposal is that hyperactivity of the PrLPACAP to NAcc neurons increases glutamatergic signaling within the NAcc and leads to excessive and compulsive drinking despite negative consequences. This hypothesis will be tested with an array of cutting-edge techniques including chemogenetic stimulation and inhibition, site-specific pharmacology (Aim 1), and calcium imaging in freely behaving animals (Aim 2). The results of this proposal will greatly add to the field of alcohol research and our understanding of excessive and compulsive drinking.