Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

The dopamine D-3 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 D-2 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 D-1-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 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 D3R antagonists on mesolimbic dopamine neurotransmission and their potential utility as pharmacotherapeutics.