Estimating the relative reinforcing strength of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine

Rationale ()3,4-Methylenedioxymethamphetamine (MDMA) is an analog of methamphetamine (MA) and a drug of abuse. MA, MDMA, and its isomers release monoamine neurotransmitters with varying selectivities and would, therefore, be predicted to vary in their relative strength as reinforcers. Objectives This study compared self-administration of MA, MDMA, and its isomers using a progressive-ratio schedule in rhesus monkeys. Methods Rhesus monkeys [n=6, MA and MDMA; n=5, (+)-MDMA and (-)-MDMA] were prepared with chronic i.v. catheters and allowed to self-administer cocaine or saline in daily baseline sessions. When responding was stable, MA (0.006-0.1 mg/kg per injection), MDMA (0.025-0.8 mg/kg injection), (+)-MDMA (0.025-0.8 mg/kg per injection), or (-)-MDMA (0.05-0.8 mg/kg per injection) was made available in test sessions. Results MA, MDMA, and (+)-MDMA functioned as positive reinforcers in all monkeys with a potency relationship of MA >(+)-MDMA >(+/-)-MDMA. Two of five monkeys took (-)-MDMA above saline levels. Dose-response relationships were biphasic for MA and (+/-)-MDMA, and asymptotic for (+)-MDMA. In terms of maximum number of injection per session, a measure of relative reinforcing strength, the order was MA >(+)-MDMA=(+/-)-MDMA >(-)-MDMA. Conclusions MDMA and (+)-MDMA were consistent positive reinforcers, but weaker than MA, whereas (-)-MDMA was, at best, a weak reinforcer in some monkeys. The reinforcing strength of MDMA appears to derive primarily from (+)-MDMA. Because MDMA and its isomers have been shown to have relatively higher serotonin to dopamine releasing potency, these data support the hypothesis that increasing 5-HT releasing potency relative to DA is associated with weaker reinforcing effects.