Differential effects of intravenous R,S‐(±)‐3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)‐ and R(−)‐enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core

The stimulant drug MDMA (Ecstasy) increases dopamine transmission in the nucleus accumbens, a brain region involved in reward. This study in male rats examined how the two mirror-image forms (enantiomers) of MDMA—S(+)-MDMA and R(−)-MDMA—affect dopamine release and a downstream signaling molecule called phosphorylated ERK (pERK) in the shell and core of the nucleus accumbens. Racemic MDMA (the standard mixture) and S(+)-MDMA increased dopamine and pERK levels in a dose-related way, with S(+)-MDMA being more potent. R(−)-MDMA had no effect. Blocking D1 dopamine receptors prevented the pERK increase, while blocking D2/D3 receptors did not. The results indicate that the S(+) enantiomer drives MDMA's dopamine-stimulating effects, and pERK serves as a marker of D1-receptor-mediated dopamine signaling.

Study at a glance

Abstract

Abstract R,S(±)‐3,4‐methylenedioxymethamphetamine (R,S(±)‐MDMA, ‘Ecstasy’) is known to stimulate dopamine (DA) transmission in the nucleus accumbens (NAc). In order to investigate the post‐synaptic correlates of pre‐synaptic changes in DA transmission and their relationship with MDMA enantiomers, we studied the effects of R,S(±)‐MDMA, S(+)‐MDMA, and R(−)‐MDMA on extracellular DA and phosphorylated extracellular signal regulated kinase (pERK) in the NAc shell and core. Male Sprague–Dawley rats, implanted with a catheter in the femoral vein and vertical concentric dialysis probes in the NAc shell and core, were administered i.v. saline, R,S(±)‐MDMA, S(+)‐MDMA, or R(−)‐MDMA. Extracellular DA was monitored by in vivo microdialysis with HPLC. Intravenous R,S(±)‐MDMA (0.64, 1, and 2 mg/kg) increased dialysate DA, preferentially in the shell, in a dose‐related manner. S(+)‐MDMA exerted similar effects but at lower doses than R,S(±)‐MDMA, while R(−)‐MDMA (1 and 2 mg/kg) failed to affect dialysate DA. R,S(±)‐ and S(+)‐MDMA but not R(−)‐MDMA increased ERK phosphorylation (expressed as density/neuron and number of pERK‐positive neurons/area) in both subdivisions of the NAc. The administration of the D 1 receptor antagonist, SCH 39166, prevented the increase in pERK elicited by R,S(±)‐MDMA and S(+)‐MDMA, while the D 2/3 receptor antagonist, raclopride, increased pERK in the NAc core per se but failed to affect the R,S(±)‐MDMA‐elicited stimulation of pERK. The present results provide evidence that the DA stimulant effects of racemic MDMA are accounted for by the S(+)‐enantiomer and that pERK may represent a post‐synaptic correlate of the stimulant effect of R,S(±)‐MDMA on D 1 ‐dependent DA transmission.