Biased Signaling Agonists of Dopamine D3 Receptor Differentially Regulate the Effects of Cocaine On Dopamine Transporter Function.

Cocaine use disorder is a major healthcare issue with no effective FDA-approved treatments. Cocaine exerts its effects - in part - by blocking dopamine transporters (DAT) and subsequently dysregulating DAT function. Several molecular targets have been identified as key regulators of DAT function and expression including dopamine D3 receptors (D3R) that are highly expressed in the mesolimbic dopamine pathway. Although D3R partial agonists and antagonists have been shown to influence cocaine seeking in rodents, effects have been inconsistent with studies reporting varying outcomes on cocaine-associated behavior. In this study, we tested the effects of SK609, a novel G-protein biased D3R agonist, and pramipexole, an unbiased agonist of D3R, on DAT expression and function and cocaine-seeking behavior. Results indicated that SK609 reduced phosphorylation of DATs following cocaine and the uptake inhibition effects of cocaine on dopamine transmission in in vitro and ex vivo studies, respectively. By comparison, pramipexole augmented the effects of cocaine on DAT phosphorylation, enhanced dopamine levels, and increased cocaine seeking in rats. These results suggest that unbiased D3R activation promotes the effects of cocaine and that limiting D3R agonists to G-protein signaling pathways may have the potential to reduce these effects.