GPR6: A Circuit-Level Druggable Target in Cocaine Use Disorder

Cocaine use disorder (CUD) remains a significant threat to the health and welfare of millions of affected individuals. Despite advances in understanding the neurobiology of CUD, the impact of chronic cocaine use on the brain and the neuronal mechanisms underlying associated behavioral deficits are not fully understood, representing untapped opportunities for therapeutic intervention. Cocaine induces potent rewarding effects primarily through rapid dopamine (DA) release, with medium spiny neurons (MSNs) in the nucleus accumbens (NAc) being particularly responsive to this DA surge. Using a bioinformatics-informed approach, we identified high and selective expression of the G protein-coupled receptor (GPCR) GPR6 in MSNs. GPR6 is an orphan GPCR which lacks verified endogenous agonist(s) and exhibit high constitutive activation of G?s signaling which is proposed to regulate reward-specific behaviors.