Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice.

Alcohol use disorder (AUD) is a complex psychiatric disease characterized by periods of heavy drinking and periods of withdrawal. Chronic exposure to ethanol causes profound neuroadaptations in the extended amygdala, which cause allostatic changes promoting excessive drinking. The bed nucleus of the stria terminalis (BNST), a brain region involved in both excessive drinking and anxiety-like behavior, shows particularly high levels of pituitary adenylate cyclase activating polypeptide (PACAP), a key mediator of the stress response. Recently, a role for PACAP in withdrawal-induced alcohol drinking and anxiety-like behavior in alcohol-dependent rats has been proposed; whether the PACAP system of the BNST is also recruited in other models of alcohol addiction and whether it is of local or non-local origin is currently unknown. Here, we show that PACAP immunoreactivity is increased selectively in the BNST of C57Bl/6J mice exposed to a chronic, intermittent access to ethanol. While PAC1R expressing cells were unchanged by chronic alcohol, the levels of a peptide closely related to PACAP, the calcitonin gene related neuropeptide (CGRP), were found to also be increased in the BNST. Finally, using a retrograde chemogenetic approach in PACAP-ires-Cre mice, we found that the inhibition of PACAP neuronal afferents to the BNST reduced heavy ethanol drinking. Our data suggest that the PACAP system of the BNST is recruited by chronic, voluntary alcohol drinking in mice and that non-locally originating PACAP projections to the BNST regulate heavy alcohol intake, indicating that this system may represent a promising target for novel AUD therapies. Significance Statement Our results point at a key role for the neuropeptide PACAP specifically of the bed nucleus of the stria terminalis in mediating heavy alcohol drinking in mice. This system may, therefore, represent a novel target for the treatment of alcohol use disorders.