Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors

In rats, MDMA caused a significant rise in body temperature (hyperthermia) that was competitively blocked by the selective 5-HT2 antagonist MDL 11,939. This antagonist also prevented MDMA-induced neurotoxicity, measured by reduced serotonin (5-HT) levels one week later. At higher MDMA doses, MDL 11,939 still fully protected against neurochemical deficits but only partially reduced hyperthermia, dissociating the two effects. Haloperidol did not affect MDMA-induced hyperthermia but did block long-term neurochemical effects. A selective serotonin reuptake inhibitor, MDL 27,777, did not alter hyperthermia from high-dose MDMA but completely prevented serotonin depletion. Preventing hyperthermia by lowering ambient temperature also blocked neurochemical changes. The results indicate that while the tested drugs do not counteract neurotoxicity by affecting temperature, hyperthermia may contribute to MDMA's long-term neurochemical effects.

Study at a glance

Abstract

Methylenedioxymethamphetamine (MDMA) produced a significant hyperthermia in rats which was antagonized in a competitive manner by the selective 5-HT2 antagonist, MDL 11,939. The 5-HT antagonist also blocked MDMA-induced neurotoxicity as assessed by the decline in regional 5-HT concentrations observed 1 week later. These two effects of MDL 11,939 were dissociated at higher doses of MDMA where the antagonist still provided virtually complete protection against the neurochemical deficits but only partially attenuated the hyperthermic response. In contrast to the effect of the 5-HT2 antagonist, haloperidol did not alter MDMA-induced hyperthermia but did antagonize its long-term neurochemical effects. Similarly, coadministration of the selective 5-HT uptake inhibitor, MDL 27,777, did not affect the hyperthermia produced by a high dose of MDMA but completely prevented the depletion of 5-HT. When the MDMA-induced hyperthermia was prevented by temporarily maintaining animals at reduced ambient temperature, the neurochemical changes normally observed 1 week later were also blocked. Although these results demonstrate that the drugs tested do not antagonize MDMA-induced neurotoxicity by interfering with its effect on body temperature, they do indicate that MDMA-induced hyperthermia may contribute to the development of the drug's long-term neurochemical effects.