Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine

Abstract

The psychomotor effects of cocaine are mediated by dopamine (DA) through stimulation of striatal circuits. Gabaergic striatal medium spiny neurons (MSNs) are the only output of this pivotal structure in the control of movements. The majority of MSNs express either the DA D1 or D2 receptors (D1R, D2R). Studies have shown that the motor effect of cocaine depends on the DA-mediated stimulation of D1R-expressing MSNs (dMSNs), which is mirrored at the cellular level by stimulation of signaling pathways leading to phosphorylation of ERKs and induction of c-fos. Nevertheless, activation of dMSNs by cocaine is necessary but not sufficient, and D2R signaling is required for the behavioral and cellular effects of cocaine. Indeed, cocaine motor effects and activation of signaling in dMSNs are blunted in mice with the constitutive knockout of D2R (D2RKO). Using mouse lines with a cell-specific knockout of D2R either in MSNs (MSN-D2RKO) or in dopaminergic neurons (DA-D2RKO), we show that D2R signaling in MSNs is required and permissive for the motor stimulant effects of cocaine and the activation of signaling in dMSNs. MSN-D2RKO mice show the same phenotype as constitutive D2RKO mice both at the behavioral and cellular levels. Importantly, activation of signaling in dMSNs by cocaine is rescued by intrastriatal injection of the GABA antagonist, bicuculline. These results are in support of intrastriatal connections of D2R+-MSNs (iMSNs) with dMSNs and indicate that D2R signaling in MSNs is critical for the function of intrastriatal circuits.

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

“…The effects of D3R blockade are therefore in direct opposition to those reported previously for nonselective D2-like receptor antagonism (68,69,72) and for selective D2R antagonism in the present study, suggesting that the effect of nonselective D2-like receptor blockade on cocaineinduced locomotion is mediated predominantly by antagonism of the D2R in the NAc. This is supported by evidence that genetic deletion of the D2R subtype within striatal MSNs in mice diminishes the locomotor response to cocaine (73). Moreover, our present results with PG01037 are in agreement with the previous finding that administration of another highly-selective D3R antagonist, NGB 2904, potentiates amphetamine-induced locomotor activity in mice (51), as well as the reported hypersensitivity of various lines of D3R knockout mice to the behavioralstimulant effects of cocaine (52,74) and amphetamine (50,52).…”

Extracellular dopamine, acetylcholine, and activation of dopamine D1 and D2 receptors after selective breeding for cocaine self-administration in rats

“…Although cocaine induces c-Fos expression in striatal medium spiny neurons predominantly through D1 receptors, combined c-Fos and D2 receptor expression occurs in other cells that include cholinergic interneurons (Bertran-Gonzalez et al 2008). D2 receptor signaling in medium spiny neurons that make intra-striatal connections is required for full expression of cocaine-induced increases in locomotor activity (Kharkwal et al 2016). Activation of the D2 receptor observed in the present study likely reflects these other cell types.…”

Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders

“…; Kharkwal et al . ). In addition, these mice showed conditioned place preference for a low dose of cocaine that did not produce preference in littermate controls, indicating a heightened sensitivity to the rewarding properties of cocaine (Bello et al .…”

“…Selective deletion of D2Rs in iMSNs produces a robust and reliable decrease in locomotor activity (Anzalone et al 2012;Kharkwal et al 2016b;Lemos et al 2016). To test whether the motor deficit produced by downregulation of D2Rs in iMSNs was due to the increased GABAergic transmission within the striatum, a sub-threshold dose of the GABA-A antagonist picrotoxin was infused into the striatum.…”

“…Given the acute in vitro effects of cocaine on D2 autoreceptor function, both at somatodendritic and synaptic bouton compartments, it stands to reason that downregulation of D2 autoreceptors would have an effect on behavioral responses to cocaine. Mice lacking D2 autoreceptors (autoDrd2KO) have increased basal locomotion and are more sensitive to the acute locomotor stimulatory effect of cocaine (Anzalone et al 2012;Bello et al 2011;Kharkwal et al 2016b). In addition, these mice showed conditioned place preference for a low dose of cocaine that did not produce preference in littermate controls, indicating a heightened sensitivity to the rewarding properties of cocaine (Bello et al 2011).…”