PACAP Signalling Network in the Nucleus Accumbens Core Regulates Reinstatement Behaviour in Rat

Cocaine use disorder (CUD) lacks FDA-approved treatments, partly due to the difficulty of creating therapeutics that target behaviour-related neural circuits without disrupting signalling throughout the brain. One promising candidate for circuit-selective neuromodulation is pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with pleiotropic behavioural actions whose signalling network spans the gut-brain axis. Here, we investigated the potential existence and function of an endogenous PACAP signalling network within the nucleus accumbens core (NAcc), which is a structure that integrates emotional, cognitive and reward processes underlying behaviour. We found that PACAP and its cognate receptor, PAC1R, are endogenously expressed in the rat NAcc and that PACAP mRNA is present in medial prefrontal cortical projections to the NAcc. Behaviourally, intra-NAcc infusions of PACAP_1-38 (450 ng/500 nL) did not induce seeking behaviour. Instead, it blocked cocaine-primed reinstatement (10 mg/kg, intraperitoneal [ip]). Intra-NAcc PACAP_1-38 (450 ng/500 nL) also blocked reinstatement driven by coinfusion of the D1-like dopamine receptor agonist (SKF81297, 3 μg/500 nL) but not the D2-like dopamine receptor agonist (sumanirole, 100 ng/500 nL). These findings are notable because previous studies have shown D1-like and D2-like dopamine receptors in the NAcc regulate distinct processes and circuits. Collectively, these studies provide novel insights into the behaviour-modulating actions of central PACAP signalling within the NAcc. Taken together with prior findings, the results underscore the need for additional research to reveal the precise behavioural processes and mechanisms that can be regulated by the full PACAP signalling network, which may reveal how to target this system to develop targeted therapeutics.