Role of hyperthermia in the protective action of clomethiazole against MDMA ('ecstasy')-induced neurodegeneration, comparison with the novel NMDA channel blocker AR-R15896AR.

1. The immediate effect of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on rectal temperature and the effect of putative neuroprotective agents on this change has been examined in rats. The influence of the temperature changes on the long term MDMA-induced neurodegeneration of cerebral 5-hydroxytryptamine (5-HT) nerve terminals was also examined. 2. The novel low affinity N-methyl-D-aspartate (NMDA) receptor channel blocker AR-R15896AR (20 mg kg(-1), i.p.) given 5 min before and 55 min after MDMA (15 mg kg(-1), i.p.) did not prevent the MDMA-induced hyperthermia and did not alter either the MDMA-induced neurodegenerative loss of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in cortex, striatum and hippocampus or loss of [3H]-paroxetine binding in cortex 7 days later. 3. The neuroprotective agent clomethiazole (50 mg kg(-1), i.p.) given 5 min before and 55 min after MDMA (15 mg kg(-1)) abolished the MDMA-induced hyperthermic response and markedly attenuated the loss of 5-HT, 5-HIAA and [3H]-paroxetine binding in the brain regions examined 7 days later. 4. When rats treated with MDMA plus clomethiazole were kept at high ambient temperature for 5 h post-MDMA, thereby keeping their body temperature elevated to near that seen in rats given MDMA alone, the MDMA-induced loss of 5-HT, 5-HIAA and [3H]-paroxetine was still attenuated. However, the protection (39%) afforded by the clomethiazole administration was less than seen in rats kept at normal ambient temperature (75%). 5. These data support the proposals of others that NMDA receptor antagonists are neuroprotective against MDMA-induced degeneration only if they induce hypothermia and further suggest that increased glutamate activity may not be involved in the neurotoxic action of MDMA. 6. These data further demonstrate that a proportion of the neuroprotective action of clomethiazole is due to an effect on body temperature but that, in addition, the compound protects against MDMA-induced damage by an unrelated mechanism.