Involvement of neuropeptide systems in excessive alcohol drinking

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ABSTRACT Approximately 18 million people (1 in every 12 adults) in the USA abuse or are dependent on alcohol. The etiology of alcohol use disorders is complex; heritable susceptibility factors interact with environmental factors to produce and maintain the disease state. One goal of current neuroscience research is, therefore, to identify the neuroadaptations mediating the propensity to consume high amounts of alcohol, of either innate or environmental origin. In particular, dysfunctions of prefronto-striatal projections have been proposed to play a critical role in alcohol addiction. This project concerns pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved 38 amino acid neuropeptide, and its receptor PAC1R. Studies in flies, rodents and humans have started to reveal a crucial role for the PACAP/PAC1R system in motivated behaviors and in the actions of drugs of abuse. The lack of studies exploring its role in alcohol addiction constitutes a barrier to the advancement of the field. Our preliminary data strongly suggest that neuroadaptions in the PACAP/PAC1R system of the nucleus accumbens core (NAcc Core) mediate the susceptibility to drink excessively. Our long-term goal is to unravel the molecular mechanisms underlying the genetic propensity to drink excessively and the transition to alcohol dependence. The overarching hypothesis of this proposal is that hyperactivation of the PACAP/PAC1 system in the medial prefrontal cortex -NAcc Core pathway mediates excessive drinking and the long-lasting neuroplastic changes observed in alcohol dependence. We will test our hypotheses using a multidisciplinary approach which includes the use of chemogenetic, pharmacological, neurochemical, and molecular techniques. The results of the proposed experiments will provide key insights into the neuroadaptive changes responsible for excessive drinking.