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Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors
C J Schmidt1, C K Black, G M Abbate
1Merrell Dow Research Institute, Cincinnati, OH 45215.
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.
Insights
MDMA causes hyperthermia and neurotoxicity in rats. A 5-HT2 antagonist blocked both effects, suggesting hyperthermia may contribute to MDMA neurotoxicity.
Area of Science:
- Neuropharmacology
- Toxicology
- Psychopharmacology
Background:
- Methylenedioxymethamphetamine (MDMA) is known to cause hyperthermia and neurotoxicity.
- The precise mechanisms underlying MDMA-induced neurotoxicity are not fully understood.
- The role of hyperthermia in MDMA's long-term neurochemical effects requires further investigation.
Purpose of the Study:
- To investigate the relationship between MDMA-induced hyperthermia and neurotoxicity.
- To determine the involvement of 5-HT2 receptors in MDMA's hyperthermic and neurotoxic effects.
- To examine the potential contribution of hyperthermia to MDMA-induced neurochemical deficits.
Main Methods:
- Rats were administered MDMA and various antagonists or inhibitors, including MDL 11,939 (5-HT2 antagonist), haloperidol, and MDL 27,777 (5-HT uptake inhibitor).
- Hyperthermia was measured following MDMA administration.
- Neurotoxicity was assessed by measuring regional 5-HT concentrations 1 week after MDMA administration.
- In some experiments, MDMA-induced hyperthermia was prevented by maintaining animals at reduced ambient temperature.
Main Results:
- MDMA produced significant hyperthermia and neurotoxicity in rats.
- MDL 11,939 competitively antagonized both MDMA-induced hyperthermia and neurotoxicity.
- At higher MDMA doses, MDL 11,939 provided neuroprotection but only partially attenuated hyperthermia.
- Haloperidol did not affect MDMA hyperthermia but antagonized neurotoxicity.
- MDL 27,777 did not affect hyperthermia but prevented 5-HT depletion.
- Preventing MDMA-induced hyperthermia also blocked subsequent neurochemical changes.
Conclusions:
- MDMA-induced hyperthermia may play a role in the development of its long-term neurochemical effects.
- While 5-HT2 receptors are involved in both hyperthermia and neurotoxicity, these effects can be dissociated.
- The tested drugs do not antagonize MDMA-induced neurotoxicity solely by interfering with its hyperthermic effect.