SKF-81297

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.

LRRK2 G2019S is associated with familial and sporadic Parkinson's disease and G2019S knock-in mice represent a valuable model to study early changes of basal ganglia transmission associated with Parkinson's disease. Here, we performed behavioral, biochemical and neurochemical analysis in 3-month-old and 12-month-old G2019S knock-in (KI) mice to investigate whether the G2019S mutation is associated with changes of D1 transmission during ageing. Behavioral analysis revealed no difference across genotypes at 3 months but elevated grooming activity in 12-month-old G2019S KI mice compared to wild-type and LRRK2 kinase-dead mice. Immunoblotting revealed a two-fold increase of the levels of phosphorylated GluA1 subunit of the AMPA receptor in 12-month-old G2019S KI mice challenged with the D1 receptor agonist SKF-81297 (5 mg/Kg), compared to wild-type mice. In vivo dual probe microdialysis revealed elevations of basal striatal and nigral extracellular glutamate levels and reduction of nigral GABA levels in 12-month-old G2019S KI mice. Systemic administration of the D1 receptor agonist SKF-81297 did not affect neurotransmitter release whereas reverse dialysis of the D1 receptor antagonist SCH-23390 (10-1000 nM) elevated striatal GABA release in 12-month-old G2019S KI but not wild-type mice. Intrastriatal SCH-233390 was also associated with a prolonged reduction of glutamate release in the substantia nigra reticulata in both genotypes. Finally, 12-month-old G2019S KI mice showed a more prolonged hypokinetic response to intraperitoneal administration of SCH-23390 (1 mg/Kg) compared to wild-type mice. We conclude that the LRRK2 G2019S mutation is associated with age-dependent enhancement of D1 dopaminergic responses, possibly due to elevated endogenous D1 transmission in striatum, that might be instrumental to sustain motor and cognitive function over ageing and help explain the slower and more benign course of G2019S-associated Parkinson's disease.