Role of the Prefronto‐Striatal PACAP System in Excessive Drinking

The neural adaptations mediating the propensity to consume high amounts of alcohol are still poorly understood. Dysfunctions of prefronto‐striatal projections have been proposed to play a critical role in the pathological drive to drink excessively. This series of experiment concerns the pituitary adenylate cyclase‐activating polypeptide (PACAP) and its receptor PAC1R; the hypothesis was that hyperactivation of the PACAP/PAC1R system in the Prelimbic Cortex–Nucleus Accumbens Core (PrL‐NAcc Core) pathway mediates excessive and compulsive drinking and the long‐lasting neuroplastic changes observed in alcohol addiction. We found that, in PrL, PACAP is expressed in layers 2/3 and 5 and predominantly with the glutamatergic marker vGluT2, while in virtually no cells labeled by the GABAergic marker GAD, suggesting that PACAP may predominantly modulate long‐range glutamatergic transmission; in addition, PrL‐PACAP neurons were confirmed to project to the NAcc Core. Chronic intermittent drinking in mice increased the activation of PrL PACAP neurons, and the function of PrL‐PACAP neurons in alcohol drinking was then assessed. Notably, PAC1R levels of the NAcc Core were found to be increased in alcohol‐preferring rats, suggesting that high levels of PAC1R may result in an excessive motivation to drink. Both intracerebroventricular and intra‐NAcc Core administration of a PAC1R antagonist significantly reduced alcohol intake in both models, as did the viral vector‐mediated PAC1R knockdown in the NAcc Core, suggesting a functional relevance of the molecular changes. These data suggest a key role of PACAP neurons and PAC1R of the PrL‐NAcc Core pathway in alcohol addiction.