Roles of metabotropic signaling of nicotine receptors in the development and maintenance of nicotine reward through regulation of dopamine D₃ receptor expression

The α4β2 nicotinic acetylcholine receptor (nAChR), an ionophore, has been suggested to signal through metabotropic pathways and interact with other receptor families, such as dopamine receptors. In this study, the interaction between α4β2 nAChR and dopamine receptors was investigated through in vivo and in vitro studies. Nicotine exposure in adolescent rats is known to induce a sustained increase in nicotine's rewarding effects which was assessed by conditioned place preference (CPP) assay. The expression levels of α4β2 nAChR and dopamine D₂/D₃ receptors (D₂R, D₃R) increased after nicotine treatment. To determine which of these two dopamine receptors was increased by nicotine treatment, a newly developed ligand with high selectivity for D₃R was used in the radioligand binding assay. Although the expression of both α4β2 nAChR and D₃R was enhanced by nicotine exposure during adolescence, only the elevated level of D₃R persisted into adulthood. In experiments conducted on mice, D₃R knockout mice showed significantly lower CPP scores in adulthood compared to wild-type mice. Cellular studies showed that an increase in D₃R expression was attributed to enhanced D₃R promoter activity, regulated by a signaling cascade composed of Src, Syk, PKC, and NF-κB. These results demonstrate that the metabotropic signaling pathway is involved in the interaction between α4β2 nAChR and D₃R, and also suggest how nicotine reward initiated in adolescence could relapse after a long abstinence period. Given the significance of adolescent nicotine exposure on nicotine addiction, this study is thought to offer a novel mechanistic perspective for understanding nicotine reward and relapse.