Dopamine D3 autoreceptor inhibition enhances cocaine potency at the dopamine transporter

Abstract

Cocaine is a commonly abused central nervous system stimulant that enhances dopamine (DA) neurotransmission through its ability to block dopamine transporters (DATs). Recent evidence suggests there may be an interaction between DATs and D2/D3 autoreceptors that modulates cocaine's effects. The purpose of this study was to explore how D2/D3 autoreceptors modulate the ability of cocaine to inhibit DA uptake through DATs on presynaptic DA terminals. Using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core from male and female C57BL/6J mice, we first sought to examine the effects of global autoreceptor blockade using the nonselective D2/D3 autoreceptor antagonist, raclopride. We found that the ability of cocaine to inhibit DA uptake was increased by raclopride and that this effect was consistent across sexes. Further, using D2 (L-741,626) or D3 (SB-277011-A) autoreceptor selective antagonists, we discovered that blockade of D3, but not D2, autoreceptors was responsible for the increased cocaine potency. Alterations in cocaine potency were attributable to alterations in uptake inhibition, rather than cocaine effects on vesicular DA release, suggesting that these results may be a product of a functional D3/DAT interaction apart from the canonical inhibitory actions of D3 autoreceptors on DA release. Additionally, application of D2 (sumanirole) and D3 (PD 128907) autoreceptor specific agonists had inverse effects, whereby D2 autoreceptor activation decreased cocaine potency and D3 autoreceptor activation had no effect. Together, these data show that dopamine autoreceptors dynamically regulate cocaine potency at the DAT, which is important for understanding cocaine's rewarding and addictive properties.

Dopaminergic control of anxiety in young and aged zebrafish

“…In striking contrast, cocaine-induced anxiety in young wild-type animals is further augmented by the inhibition of the D2/D3 receptors. This has also recently been shown by McGinnis et al (Mcginnis et al, 2016), who hypothesize that the enhancement of the effect of cocaine by D3 inhibition is due to increased potency at DAT. There is also prior work showing that D2 deficiency leads to increased sensitivity to cocaine.…”

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

“…However, when the dose of SCH23390 was increased ten-fold, the D3R antagonist was rendered ineffective, probably because the level of D1-like receptor signaling was no longer sufficient to increase locomotor output. Our electrophysiological and behavioral studies are uniformly consistent with the hypothesis that D3R antagonism renders NAc D1-MSNs hyperresponsive to DA-induced excitation, and also provide mechanistic evidence as to how D3R antagonism functionally enhances the behavioral, cellular, and neurochemical effects of cocaine observed herein and previously by others (38,41,44,74,89,90).…”

“…In support of this hypothesis, we found that application of PG01037 enhanced cocaine-induced increases in DA release and also significantly facilitated cocaine's inhibitory action on DA clearance. The effects we observed with PG01037 in our FSCV experiments are similar to those produced by another highly-selective D3R antagonist, SB-277011-A, (41,44), and mirror the facilitation of stimulant-induced increases in extracellular DA following systemic D3R antagonism (43). Together, these studies and our present results indicate that presynaptic D3R antagonism potentiates stimulant-induced increases in NAc DA levels, even in the absence of any effects on basal DA concentrations.…”

“…Together, these studies and our present results indicate that presynaptic D3R antagonism potentiates stimulant-induced increases in NAc DA levels, even in the absence of any effects on basal DA concentrations. The exact mechanisms by which D3R antagonists exert these effects on DA release and clearance and why they only do so under conditions of increased DA levels remain to be determined, but possible explanations include disinhibition of the presynaptic terminal via autoreceptor blockade (8,26,27) and/or modulation of the structure and/or function of the dopamine transporter itself (41,82). Regardless, these actions are unlikely to wholly explain the facilitatory effects of D3R antagonism on cocaine-induced locomotion because application of L-741,626 to NAc slices produced effects similar to, and not opposite from, those produced by PG01037.…”

Regulator of G Protein Signaling-12 (RGS12) in dopaminergic and kappa opioid receptor-dependent signaling and behavior

“…1), these mice may consequently display lower rates of DA reuptake than expected (relative to observed synaptosomal [ 3 H]DA-uptake rates) simply due to the considerably lower levels of extracellular DA present during the experiment. Unlike in brain-slice FSCV (Phillips et al, 2002;McGinnis et al, 2016), in vitro synaptosomal [ 3 H]DA-uptake experiments employ high levels of both [ 3 H]-labeled and unlabeled DA to achieve DAT saturation (e.g., refs. (Bermingham and Blakely, 2016;).…”