Selective D 2 and D 3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens.

The dopamine D ₃ receptor (D ₃ R) 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 D ₃ R'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 D ₃ R-targeted compounds often also interact with D ₂ receptors (D ₂ R). To resolve this issue, we set out to systematically characterize and compare the consequences of selective D ₂ R or D ₃ R 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 D ₂ R antagonist L-741,626 attenuated, while pretreatment with the selective D ₃ R 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 D ₃ R blockade uniquely facilitated dopamine-mediated excitation of D ₁ -expressing medium spiny neurons in the nucleus accumbens. Collectively, our results demonstrate that selective D ₃ R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D ₂ R antagonism or nonselective D ₂ -like receptor antagonists, and is likely mediated by facilitating D ₁ -mediated excitation in the nucleus accumbens. These findings provide novel insights into the neuropharmacological actions of D ₃ R antagonists on mesolimbic dopamine neurotransmission and their potential utility as pharmacotherapeutics.