Targeting GPR3 as a novel approach for nicotine cessation therapeutic development.

Tobacco use remains the leading cause of preventable death worldwide. Unfortunately, currently available cessation aids have limited long-term efficacy. GPR3 is a Gαs coupled receptor expressed in discrete brain regions, with notably high expression in cholinergic neurons of the medial habenula. Here, we investigated whether modulation of GPR3 could be a viable target for therapeutic development to promote nicotine cessation. We first examined whether our recently developed GPR3 receptor agonist, RTI-19318-32, could induce effects on intravenous nicotine self-administration at low, moderate or high nicotine doses in mice. We found that in both males and females, RTI-19318-32 significantly reduced nicotine intake at all self-administered nicotine doses, thereby supporting the validity of this therapeutic approach for individuals using varying levels of daily nicotine. RTI-19318-32 was further validated as being selective for GPR3, as it did not alter nicotine intake in GPR3 knockout mice, nor did it exert effects on anxiety-associated behavior or locomotion. While the higher RTI-19318-32 dose attenuated food-related reinforcement behavior, it was ineffective in altering baseline food consumption. Moreover, the lower RTI-19318-32 dose did not alter food reinforcement behavior, indicating selectivity in mediating nicotine intake. Finally, GPR3 expression co-localized with multiple nAChR subunits in the medial habenula, thereby supporting our proposed targeted approach for circuit engagement intentionally directed at modulating the drive to consume nicotine. Taken together, these data reveal the functional significance of agonist-inducted activation of the GPR3 receptor and establish the validity of focusing on therapeutic development of GPR3 ligands for nicotine cessation.