Pituitary adenylate cyclase-activating polypeptide regulates excessive alcohol consumption

Abstract

Alcoholism results from an interaction between genetic and environmental factors. However, the neurobiological mechanisms mediating the propensity to consume excessive amounts of alcohol are still not well understood. Using genetically selected alcohol-preferring rats, a well-established animal model of alcoholism, we demonstrate that central administration of a peptide antagonist for the pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1), the cognate receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), blocks excessive alcohol drinking as well as motivation to drink. On the other hand, the PAC1 antagonist does not significantly affect water intake, saccharin intake, or responding for ethanol in non-selected outbred Wistar rats. In addition, the antagonist significantly reduced responding maintained by alcohol-associated incentive stimuli (alcohol seeking behavior). Using immunohistochemistry, a significant reduction in the number of PAC1 positive cells was observed selectively in the Nucleus Accumbens (NAcc) Core of alcohol-preferring compared to Wistar rats. Proving the functional relevance of these changes, excessive drinking in alcohol-preferring rats was markedly reduced following microinfusion of the PAC1 antagonist into the Core, but not the Shell, of the NAcc. Finally, using retrograde tracing techniques coupled with immunofluorescence, we show that the dopaminergic neurons of the VTA which project to the NAcc core co-express PACAP. Altogether, our findings demonstrate that the dysregulation of the PACAP/PAC1R system, specifically in the NAcc core, promotes excessive drinking and alcohol-seeking behavior, indicating that blockade of the PACAP/PAC1R system may represent a novel target for alcohol addiction.