Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA)

In rats trained to distinguish either the (+)- or (-)-isomer of MDMA from saline, both isomers of MDMA and MDA fully substituted for the training drugs. Stimulants like amphetamine and cocaine did not substitute. Hallucinogens such as DOM, LSD, and mescaline did not fully substitute for (+)-MDMA; LSD substituted for (-)-MDMA only at a specific dose. The serotonin-releasing agents fenfluramine and p-chloroamphetamine substituted partially or fully for both isomers. Serotonin receptor antagonists pirenpirone and metergoline did not consistently block MDMA's effects. The findings suggest that serotonin release, but not action at 5-HT(2) receptors, is important for the discriminative stimulus effects of MDMA isomers.

Study at a glance

Abstract

The discriminative stimulus effects of the stereoisomers of 3,4-methylenedioxymethamphetamine (MDMA) were studied in rats trained to discriminate 1.25mg/kg of (+)-MDMA or 3.5mg/kg of (-)-MDMA from saline, in a two lever, water-reinforced, drug discrimination situation. The isomers of MDMA and 3,4-methylenedioxyamphetamine (MDA) substituted completely for both training drugs. The stimulants amphetamine and cocaine did not substitute for either MDMA isomer. The hallucinogens (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-lysergic acid diethylamide (LSD), and mescaline failed to substitute completely for (+)-MDMA. Similarly, DOM and mescaline did not substitute for (-)-MDMA; however, LSD did substitute for this isomer at a dose of 0.06mg/kg but not at higher doses. Substitution tests with 5-HT-releasing agents revealed that fenfluramine substituted partially for (+)-MDMA and completely for (-)-MDMA, while p-chloroamphetamine substituted completely for both isomers of MDMA. When given in combination with (+)-or (-)-MDMA, neither the 5-HT(2) antagonist pirenpirone nor the less selective 5-HT antagonist metergoline consistently blocked drug-appropriate responding. These results indicate that the stereoisomers of MDMA and MDA have similar discriminative stimulus properties. More importantly, the present findings suggest that 5-HT release may be important for the discriminative stimulus effects of (+)-and (-)-MDMA. Actions at 5-HT(2) receptors, however, do not appear to be critical.