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The current study was performed to establish the actions of nanomolar concentrations of cocaine, not blocking the dopamine transporter, on dopamine D2 receptor (D 2 R)-sigma 1 receptor (δ1R) heteroreceptor complexes and the D 2 R protomer recognition, signaling and internalization in cellular models. We report the existence of D 2 R-δ1R heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum, with different distribution patterns using the in situ proximity ligation assay. Also, through BRET, these heteromers were demonstrated in HEK293 cells. Furthermore, saturation binding assay demonstrated that in membrane preparations of HEK293 cells coexpressing D 2 R and δ1R, cocaine (1 nM) significantly increased the D 2 R B max values over cells singly expressing D 2 R. CREB reporter luc-gene assay indicated that coexpressed δ1R significantly reduced the potency of the D 2 R-like agonist quinpirole to inhibit via D 2 R activation the forskolin induced increase of the CREB signal. In contrast, the addition of 100 nM cocaine was found to markedly increase the quinpirole potency to inhibit the forskolin-induced increase of the CREB signal in the D 2 R-δ1R cells. These events were associated with a marked reduction of cocaine-induced internalization of D 2 R protomers in D 2 R-δ1R heteromer-containing cells vs D 2 R singly expressing cells as studied by means of confocal analysis of D 2 R-δ1R trafficking and internalization. Overall, the formation of D 2 R-δ1R heteromers enhanced the ability of cocaine to increase the D 2 R protomer function associated with a marked reduction of its internalization. The existence of D 2 R-δ1R heteromers opens up a new understanding of the acute actions of cocaine.

Acute Cocaine Enhances Dopamine D2R Recognition and Signaling and Counteracts D2R Internalization in Sigma1R-D2R Heteroreceptor Complexes