Disruption of a dopamine receptor complex amplifies the actions of cocaine

Cocaine-induced increases in dopamine signaling in nucleus accumbens (NAc) play a significant role in cocaine seeking behavior. The majority of cocaine addiction research has focused on neuroanatomically segregated dopamine D1 and D2 receptor-expressing neurons, yet an involvement for those NAc neurons coexpressing D1 and D2 receptors in cocaine addiction has never been explored. In situ proximity ligation assay, confocal fluorescence resonance energy transfer and coimmunoprecipitation were used to show native D1 and D2 receptors formed a heteromeric complex in D1/D2 receptor-coexpressing neurons in rat and non-human primate NAc. D1-D2 heteromer expression was lower in NAc of adolescent rats compared to their adult counterparts. Functional disruption of the dopamine D1-D2 receptor heteromer, using a peptide targeting the site of interaction between the D1 and D2 receptor, induced conditioned place preference and increased NAc expression of ∆FosB. D1-D2 heteromer disruption also resulted in the promotion, exacerbation and acceleration of the locomotor activating and incentive motivational effects of cocaine in the self-administration paradigm. These findings support a model for tonic inhibition of basal and cocaine-induced reward processes by the D1-D2 heteromer thus highlighting its potential value as a novel target for drug discovery in cocaine addiction. Given that adolescents show increased drug abuse susceptibility, an involvement for reduced D1-D2 heteromer function in the heightened sensitivity to the rewarding effects of cocaine in adolescence is also implicated.