Serotonergic–dopaminergic mediation of MDMA's discriminative stimulus effects in a three-choice discrimination

Abstract

(±)3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”) is a common drug of abuse that is often described as both a psychostimulant and a hallucinogen. Two-choice drug discriminations (i.e. drug vs. nondrug) in nonhumans comparing the discriminative stimulus properties of MDMA to psychostimulants or hallucinogens have produced somewhat inconsistent findings. The relative contribution of serotonergic versus dopaminergic actions to MDMA's discriminative stimulus effects may depend on the training stimulus conditions employed. We have previously demonstrated that rats can learn to discriminate the effects of MDMA and d-amphetamine in a three-choice drug discrimination procedure, and that LSD produced nearly complete substitution for MDMA under these conditions, and fenfluramine fully substituted for MDMA. In the present study, 12 rats were trained to discriminate LSD (0.08 mg/kg) and MDMA (1.5 mg/kg) from saline in a three-choice drug discrimination procedure under a fixed-ratio (FR) 10 schedule of food reinforcement. d-Amphetamine produced only partial substitution for MDMA while fenfluramine produced complete stimulus generalization. Low doses of d-amphetamine and fenfluramine produced greater stimulus generalization when administered in combination than when given alone. The serontonin 2 antagonist MDL-100,907 only partially blocked the MDMA cue, but completely antagonized LSD discrimination. The dopamine antagonist haloperidol also failed to block MDMA discrimination. These results indicate that 5-HT release is a salient feature to MDMA's discriminative stimulus effects but that MDMA produces a compound discriminative stimulus.