Selective D₂ and D₃ receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic...

The dopamine D₃ receptor (D₃R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinson's disease, and substance use disorders. However, studies investigating the D₃R's precise role in dopamine neurotransmission or how it may be exploited to modulate responses to drugs of abuse have produced contrasting results, in part because most D₃R-targeted compounds often also interact with D₂ receptors (D₂R). To resolve this issue, we set out to systematically characterize and compare the consequences of selective D₂R or D₃R antagonists on the behavioral-stimulant properties of cocaine in mice, and to identify putative neurobiological mechanisms underlying their behavior-modifying effects. Pretreatment with the selective D₂R antagonist L-741,626 attenuated, while pretreatment with the selective D₃R antagonist PG01037 enhanced, the locomotor-activating effects of both acute cocaine administration as well as sensitization following repeated cocaine dosing. While both antagonists potentiated cocaine-induced increases in presynaptic dopamine release, we report for the first time that D₃R blockade uniquely facilitated dopamine-mediated excitation of D₁-expressing medium spiny neurons in the nucleus accumbens. Collectively, our results demonstrate that selective D₃R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D₂R antagonism or nonselective D₂-like receptor antagonists, and is likely mediated by facilitating D₁-mediated excitation in the nucleus accumbens. These findings provide novel insights into the neuropharmacological actions of D₃R antagonists on mesolimbic dopamine neurotransmission and their potential utility as pharmacotherapeutics.