Pleiotropic Pituitary Adenylate Cyclase-activating Polypeptide (PACAP): Novel Insights into the Role of PACAP in Eating and Drug Intake

Pituitary adenylate cyclase-activating polypeptide (PACAP) was discovered thirty years ago, but its role in eating and drug use disorders has only recently begun to be investigated. The present review develops the hypothesis that, although PACAP normally functions to tightly regulate intake, inhibiting it through negative feedback, this relationship can become dysregulated with the development of dependence, such that PACAP instead acts through positive feedback to promote excessive intake. We propose that repeated exposure to palatable food and drugs of abuse can alter the downstream responses of specific populations of neurons to stimulation by PACAP, leading to the perpetuation of the addiction cycle. Thus, this review will first describe published literature on homeostatic food intake, which shows that PACAP suppresses food intake, while its levels are themselves increased by overfeeding. Next, it will present literature on palatable food, cocaine, alcohol, and nicotine, which overall demonstrates that PACAP in specific limbic brain regions can promote their seeking and intake and itself is stimulated by their intake. Then, it will present literature on affective behavior, which shows that chronic stress increases levels of PACAP, which then promotes anxiety and depression, factors that can trigger substance seeking. Finally, the review will address mechanisms through which chronic substance exposure may dysregulate the PACAP system, proposing that it alters expression of PACAP receptor splice variants. While many questions remain to be addressed, the current evidence suggests that PACAP could be a viable medication target for the treatment of binge eating and drug and alcohol use disorders.