Effects of dopamine D₁- or D₂-like receptor antagonists on the hypermotive and discriminative stimulus effects of (+)-MDMA

Rationale: Both dopamine (DA) and serotonin (5-HT) release are evoked by (+)-MDMA; however, little is known of the contribution of DA D₁- and D₂-like receptors (D₁R and D₂R, respectively) in the behavioral effects of (+)-MDMA. Objectives: To test the hypothesis that a D₁R or D₂R antagonist would attenuate the hypermotive or discriminative stimulus effects of (+)-MDMA. Methods: Male Sprague-Dawley rats (n=164) were pretreated with the D₁R antagonist SCH 23390 (3.125-50 μg/kg, SC) or the D₂R antagonist eticlopride (12.5-50 μg/kg, SC) prior to treatment with (+)-MDMA (3 mg/kg, SC) and locomotor activity was recorded using photobeam monitors. Twelve additional rats trained to discriminate (+)-MDMA (1 mg/kg, IP) from saline in a two-lever water-reinforced FR20 task were administered SCH 23390 (6.25 μg/kg, IP) or eticlopride (12.5 μg/kg, IP) prior to (+)-MDMA (0.375-1.0 mg/kg, IP). Rats were then placed in the drug discrimination chambers and the percent (+)-MDMA appropriate responding and response rate were measured. Results: Both SCH 23390 and eticlopride blocked (+)-MDMA-evoked hyperactivity in a dose-related manner; the highest doses of the antagonists also effectively suppressed basal locomotor activity. In rats trained to discriminate (+)-MDMA from saline, SCH 23390 (6.25 μg/kg), but not eticlopride (12.5 μg/ kg), blocked the stimulus effects of (+)-MDMA without altering response rate. Conclusion: These data indicate that DA released indirectly by (+)-MDMA administration results in stimulation of D₁R and D₂R to enhance locomotor activity. Furthermore, the D ₁R appears to play a more prominent role than the D₂R in the discriminative stimulus properties of (+)-MDMA.