The role of PACAP of the extended amygdala in heavy alcohol drinking

About This Grant

ABSTRACT Alcohol use disorder (AUD) is a highly prevalent, chronic, relapsing disorder for which pharmacological treatments remain few. People affected by AUD show heavy, compulsive alcohol drinking, a negative emotional state when abstaining from alcohol, and an inability to reduce or stop intake. Key neuroadaptations induced by chronic alcohol include the recruitment of stress neurotransmitter systems in the bed nucleus of the stria terminalis (BNST). The BNST is a brain region that plays a key role in both excessive drinking and anxiety-like behavior. This project concerns pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide particularly abundant in the BNST, which has recently emerged as a master regulator of the stress response. The central hypothesis of this application is that the central PACAP system is a key mediator of heavy alcohol drinking and associated anxiety-like behavior and heightened pain sensitivity. Furthermore, we hypothesize that PACAP acts in the BNST via the stimulation of corticotropin-releasing factor (CRF) neurons. Finally, we hypothesize that PACAP projections from the lateral parabrachial nucleus to the BNST are those mediating the effects. These hypotheses will be tested using well-established animal models of heavy alcohol drinking and affective behavior, combined with state of the art pharmacological, molecular, and viral approaches. This highly translational and mechanistic research will shed light on the role of a key neuropeptide system in heavy drinking and anxiety-like behavior. A deeper understanding of the molecular mechanisms underlying heavy drinking and the neuroadaptations occurring in the extended amygdala neurocircuitry may lead to the discovery of novel therapeutic agents for AUD.