Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine ("ecstasy") and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice

Rationale: Few studies have directly compared the effects of methylenedioxymethamphetamine (MDMA, "ecstasy") and its enantiomers across measures. Objectives: To investigate the capacity of MDMA and its stereoisomers to produce aggregate toxicity in mice, the influence of 5-HT₂ receptors, 5-HT transporters, and ambient temperature on this effect, and to directly compare the racemate and its enantiomers in terms of their effects on core temperature and locomotor activity with and without various serotonergic pretreatments. Methods: Mice were injected with various doses of MDMA and its stereoisomers in various housing conditions, with and without pretreatments of serotonergic drugs, and at two distinct ambient temperatures; lethality was quantified 2 h after MDMA administration. For temperature/activity studies, mice were injected with various doses of MDMA and its enantiomers, with and without ketanserin, MDL100907, or fluoxetine pretreatments, and core temperature and locomotor activity data were collected for 24 h. Results: Racemic MDMA and its isomers produced aggregate toxicity in mice. The lethal effects of racemic MDMA and its enantiomers were differentially attenuated by the various serotonergic pretreatments and manipulation of the ambient temperature across housing conditions. Racemic and S(+)-MDMA produced hyperthermic effects in mice, while R(-)-MDMA did not. The pretreatment drugs attenuated the hyperthermic effects of racemic MDMA, but were less effective in blocking S(+)-MDMA-induced hyperthermia. Racemic MDMA and both enantiomers stimulated locomotor activity, although R(-)-MDMA was least effective. The pretreatments all reduced the locomotor stimulant effects of racemic MDMA but potentiated S(+)-MDMA-induced hyperlocomotion. Conclusions: The MDMA isomers have heterogeneous effects that can be demonstrated across a wide range of endpoints.