The role of the neuropeptide PEN receptor, GPR83, in the reward pathway: Relationship to sex-differences.

GPR83, the receptor for the neuropeptide PEN, exhibits high expression in the nucleus accumbens of the human and rodent brain, suggesting that it plays a role in modulating the mesolimbic reward pathway. However, the cell-type specific expression of GPR83, its functional impact in the reward pathway, and in drug reward-learning has not been fully explored. Using GPR83/eGFP mice, we show high GPR83 expression on cholinergic interneurons in the nucleus accumbens and moderate expression on ventral tegmental area dopamine neurons. In GPR83 knockout mice, baseline dopamine release in the nucleus accumbens is enhanced which disrupts the ratio of tonic vs phasic release. Additionally, GPR83 knockout leads to changes in the expression of dopamine-related genes. Using the morphine conditioned place preference model, we identify sex differences in morphine reward-learning, show that GPR83 is upregulated in the nucleus accumbens following morphine conditioned place preference, and show that shRNA-mediated knockdown of GPR83 in the nucleus accumbens leads to attenuation morphine reward. Together, these findings detect GPR83 expression in the reward-pathway, and show its involvement in dopamine release and morphine reward-learning.