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

The dopamine D3 receptor (D3 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 D3 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 D3 R-targeted compounds often also interact with D2 receptors (D2 R). To resolve this issue, we set out to systematically characterize and compare the consequences of selective D2 R or D3 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 D2 R antagonist L-741,626 attenuated, while pretreatment with the selective D3 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 D3 R blockade uniquely facilitated dopamine-mediated excitation of D1 -expressing medium spiny neurons in the nucleus accumbens. Collectively, our results demonstrate that selective D3 R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D2 R 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 D3 R antagonists on mesolimbic dopamine neurotransmission and their potential utility as pharmacotherapeutics.