Locomotion, body temperature and drug lethality in single and group-housed mice was investigated with racemic, R-(-)-MDMA and S-(+)-MDMA. Aggregate toxicity was tested by housing mice 6 per cage and 12 per cage, and administering racemate at doses of 32, 56, 100 or 132 mg/kg, R-(-)-MDMA at 56, 100, 118 or 156 mg/kg, and S-(+)-MDMA at 32, 56, 100 or 132 mg/kg. In all conditions, mice were observed for a two-hour period after MDMA, and food and water were unavailable during experimental sessions. The 5HT2A/2C antagonist ketanserin, the 5HT2A antagonist MDL100907, the serotonin uptake inhibitor (SSRI) fluoxetine and a 4 deg C "cold room" environment were all tested as potential protection against MDMA-induced lethality. A second set of studies measured locomotion and core (body) temperature with a surgically implanted radiotelemetry probe. Singly housed mice were given 10, 32 or 56 mg/kg racemic MDMA, R-(-)-MDMA or S-(+)-MDMA, and temperature and locomotion were recorded at 5-minute intervals. Increasing cage density potentiated lethality for all three forms of MDMA (racemate, R-form, S-form), with racemic and S-(+)-MDMA equipotent in lethality and R-(-)-MDMA only half as lethal as the other two. Lethality was seen in the first 30 min post-drug, and all mice surviving after the first hour continued to survive for the whole experiment. Ketanserin completely blocked lethality for both racemic and S-(+)-MDMA in single or group-housed mice, but did not alter the lethality of R-(-)-MDMA in any housing condition (one, 6, or 12 mice per cage). MDL100907 only attenuated aggregate lethality after racemic MDMA without reducing lethality in singly-housed mice. Fluoxetine only reduced the lethality of racemic MDMA in singly-housed mice and did not affect lethality after R-(-)-MDMA or S-(+)-MDMA. Cold ambient temperature reduced lethality for singly-housed mice given racemic MDMA, but did not reduce lethality in singly-housed mice after receiving R-(-) or S-(+)-MDMA. However, in group-housed mice, cold ambient temperature completely abolished lethality for both racemic and S-(+)-MDMA without greatly altering lethality of R-(-)-MDMA. Racemic and S-(+)-MDMA both produced dose and time-dependent hyperthermia that lasted for 2 h. Hyperthermia, but not death, was produced at 32 mg/kg racemic or S-(+)-MDMA, whereas deaths occurred after 56 mg/kg S-(+)-MDMA only. R-(+)-MDMA never produced hyperthermia, even at doses that produced deaths. 5.6 mg/kg ketanserin, but not 1 mg/kg, attenuated S-(+)-MDMA induced hyperthermia. However, even 1 mg/kg ketanserin prevented hyperthermia after racemic MDMA. Hyperthermia after S-(+)-MDMA was not prevented by either MDL100907 or fluoxetine, but both drugs reduced hyperthermia after racemic MDMA. Racemic MDMA produced the greatest amount of locomotion, starting at 10 mg/kg and lasting 3.5 h, and S-(+)-MDMA was nearly equipotent in stimulating locomotion, producing slightly lower activity counts but having longer-lasting effects. R-(-)-MDMA was only one-tenth as effective in producing locomotor activity, with activity only appearing in the first 15 min after R-(-)-MDMA administration. Ketanserin (1 and 5.6 mg/kg), MDL100907 and fluoxetine all reduced locomotion after racemic MDMA while increasing intensity and duration of locomotion in S-(+)-MDMA treated animals. Study finding suggest that hyperthermia plays a role in aggregate toxicity after MDMA, and that activity at 5HT2 receptors might also play a role. Actions at 5HT2A receptors may have other effects unrelated to hyperthermia, since R-(-)-MDMA produced lethality without hyperthermia, and the 5HT2A antagonist MDL100907 reduced lethality from R-(-)-MDMA. Findings also suggest that racemic and S-(+)-MDMA produce hyperthermia for different reasons, with actions on the serotonin system involved in the first case, but not necessarily in the second. Furthermore, treatments that reduce locomotion in mice given racemic MDMA potentiate locomotion in S-(+)-MDMA-treated animals. Taken together, this research indicates that the effects of racemic MDMA result from synergistic actions of the two enantiomers rather than additive effects. It should be remembered that MDMA affects mice and rats differently. Nevertheless, the data presented here may still provide useful information about differences between MDMA enantiomers, and the relationship these differences play in aggregate toxicity. Study findings indicate that effects seen in research employing only one MDMA enantiomer (such as S-(+)-MDMA) are unlikely to generalize to human ecstasy users, since street ecstasy nearly always consists of racemic MDMA.