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

Abstract

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 behavioralstimulant 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.

Effects of the selective dopamine D3receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

“…One key question remaining is how pretreatment with PG01037 attenuates opioidinduced hyperactivity (present results) but potentiates cocaine-induced hyperactivity (Manvich et al, 2019). The enhancement of cocaine-induced locomotion by D3R antagonism occurs coincidentally with an increase in DA-induced excitability and activity of DA D1 receptorexpressing MSNs within the NAc (Manvich et al, 2019). However, it is unknown whether this or other modulations of MSN activity within the NAc underlie the inhibitory influence of D3R antagonism on opioid-induced hyperlocomotion.…”

“…It is possible that PG01037 potentiates drug-induced hyperactivity that is DA-dependent but attenuates drug-induced hyperactivity that is DAindependent. This hypothesis is further supported by findings that intra-NAc administration of a selective D3R antagonist potentiates the locomotor-activating effects of cocaine (Manvich et al, 2019) but attenuates the locomotor-activating effects of morphine (Liang et al, 2011).…”

“…), and placed back in the chamber for 120 min. The dose range for PG01037 was carefully selected for use based on our previous work showing that doses up to 10 mg/kg do not appreciably disrupt basal locomotion but significantly modulate the locomotor-activating effects of cocaine in C57BL/6J mice (Manvich et al, 2019). The 5.6 -56 mg/kg dose range of morphine was selected based on our own pilot studies showing that it captures both the ascending and descending limbs of the morphine dose-response curve.…”

“…Stimulation of locomotor activity in rodents is a useful behavioral measure with which to selectively interrogate NAc DA neurotransmission following systemic administration of drugs of abuse, including opioids and psychostimulants (Broekkamp et al, 1979;Delfs et al, 1990;Kalivas et al, 1983;Kelly and Iversen, 1976;Kelly et al, 1975). We recently reported that pretreatment with the highly-selective D3R antagonist PG01037 enhances cocaine-induced locomotor activity and locomotor sensitization, and that these potentiating effects of PG01037 are likely due to augmented DA-induced excitation of D1-expressing medium spiny neurons (MSNs) within the NAc (Manvich et al, 2019). Based on these findings, one might predict that PG01037 treatment, or perhaps D3R antagonism in general, would similarly enhance the locomotor-activating effects of other DA-increasing drugs of abuse such as opioids.…”

Exploring the structural basis and atomistic binding mechanistic of the selective antagonist blockade at D3 dopamine receptor over D2 dopamine receptor

“…25 Furthermore, the selective antagonism of D3DR has been shown to enhance the stimulant behavior effects of cocaine in mice, which is opposite to the effect produced by selective antagonism of D2DR or nonselective D 2 -like receptor antagonists. 26 Also, selective antagonist binding at the D 3 receptor has been shown to display promising results in reducing cocaine, and opioid reward and are highly effective in mitigating relapse to drug-seeking behavior in preclinical models. [27][28][29] Extensive medicinal chemistry research efforts had led to the development of D 3 dopamine receptor selective partial agonists and antagonists such as BP 897, NGB 2904, SB 277011A, and GSK598809.…”