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1 The pharmacology of the acute hyperthermia that follows 3,4-methylenedioxymethamphetamine (MDMA,`ecstasy') administration to rats has been investigated. 2 MDMA (12.5 mg kg 71 i.p.) produced acute hyperthermia (measured rectally). The tail skin temperature did not increase, suggesting that MDMA may impair heat dissipation.

1 Administration of 3,4-methylenedioxymethamphetamine (MDMA,`ecstasy') to mice produces acute hyperthermia and long-term degeneration of striatal dopamine nerve terminals. Attenuation of the hyperthermia decreases the neurodegeneration. We have investigated the mechanisms involved in producing the neurotoxic loss of striatal dopamine. 2 MDMA produced a dose-dependent loss in striatal dopamine concentration 7 days later with 3 doses of 25 mg kg 71 (3 h apart) producing a 70% loss. ) increased 2,3-dihydroxybenzoic acid formation from salicylic acid perfused through a microdialysis tube implanted in the striatum, indicating increased free radical formation. This increase was prevented by AR-R17477AR administration. Since AR-R17477AR was also found to have no radical trapping activity this result suggests that MDMA-induced neurotoxicity results from MDMA or dopamine metabolites producing radicals that combine with NO to form tissuedamaging peroxynitrites.

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MDMA administration to rats housed at 30 degrees C produces a more severe hyperthermic response than that seen in rats housed at 19 degrees C. A prior neurotoxic dose enhances the response further in animals housed at 30 degrees C. Binge dosing produces a higher final peak response than a similar non-divided dose. This effect is more marked in animals housed at high room temperature. These data may have implications for recreational users of MDMA in hot environments, particularly those who may have damaged serotoninergic neurones because of prior heavy or frequent use of the drug.

1 3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') administration to rats produces hyperthermia if they are housed in normal or warm ambient room temperature (T a ) conditions (X201C), but hypothermia when in cool conditions (T a p171C). We have now investigated some of the mechanisms involved. 2 MDMA (5 mg kg À1 i.p.) produced a rapid decrease in rectal temperature in rats at T a 151C. This response was blocked by pretreatment with the dopamine D 2 receptor antagonist remoxipride (10 mg kg À1 i.p.), but unaltered by pretreatment with the D 1 antagonist SCH23390 (1.1 mg kg À1 i.p.). 3 MDMA (5 mg kg À1 ) did not alter the tail temperature of rats at T a 151C, but decreased the tail temperature of rats at T a 301C. 4 A neurotoxic dose of MDMA (three doses of 5 mg kg À1 given 3 h apart) decreased cortical and hippocampal 5-HT content by approximately 30% 7 days later. This lesion did not influence the rise in tail temperature when rats were moved from T a 201C to 301C compared to nonlesioned controls, but did result in a lower tail temperature than that of controls when they were returned to T a 241C. 5 Acute administration of MDMA (5 mg kg À1) to MDMA-lesioned rats produced a sustained decrease in tail temperature in rats housed at T a 301C compared to nonlesioned controls. 6 These data suggest that the thermoregulatory problems previously observed in MDMA-lesioned rats housed at T a 301C result, partially, from their inability to lose heat by vasodilation of the tail, a major heat-loss organ in this species.

The behavioural consequences of a single neurotoxic dose of MDMA can be demonstrated over 2 months after administration of the compound, thereby indicating that long-term adaptive changes occur within the brain following the neurodegeneration of 5-HT neurones produced by this recreationally used drug.