Assessment of the MDA and MDMA optical isomers in a stimulant-hallucinogen discrimination

The phenylisopropylamine derivatives 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) have been compared to both psychostimulants and hallucinogens in drug discrimination investigations. The stereoisomers of these compounds, in particular those of MDA, appear to produce differential effects. Previous studies have demonstrated that animals trained to discriminate amphetamine from vehicle generalize to the S(+)-isomers but not the R(-)-isomers of MDA and MDMA while animals trained to discriminate LSD from saline generalize to R(-)-MDA and neither isomer of MDMA. However, animals trained to discriminate mescaline from vehicle generalize to both stereoisomers of these phenylisopropylamine derivatives. The present study consisted of two experiments in which a three-choice drug discrimination procedure was employed to compare the stereoisomers of MDA and MDMA to both amphetamine and either mescaline (experiment one) or LSD (experiment two). Sixteen male Sprague-Dawley rats were trained to discriminate S(+)-amphetamine (1.0 mg/kg) and mescaline (12.5 mg/kg) and eight rats were trained to discriminate S(+)-amphetamine (1.0 mg/kg) and LSD (0.08 mg/kg) from saline in three-choice, food reinforced drug discrimination procedures. Substitution tests were administered with the isomers of MDA and MDMA. In the second experiment, substitution tests were also administered with lower doses of each training compound and with the stimulant cocaine and the hallucinogen 2,5-dimethoxy-4-methylphenylisopropylamine (DOM). In both experiments, all of the isomers produced very few responses on the S(+)-amphetamine lever. In the first experiment, R(-)-MDA and R(-)-MDMA produced nearly complete substitution for mescaline. The results of the second experiment revealed partial substitution for LSD with both isomers of MDMA and S(+)-MDA, and nearly complete substitution with R(-)MDA for LSD. The present findings do not support previous reports that S(+)-MDMA and S(+)-MDMA substitute for S(+)-amphetamine. The three-lever drug discrimination procedure may provide a more sensitive behavioral assay in which to examine the discriminative stimulus effects of drugs with compound stimulus properties.