Role of the serotonin 5-HT_2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethamphetamine

Rationale: Contradictory evidence exists regarding the role of the 5-HT_2A receptor (5-HT_2AR) in hyperactivity and hyperthermia elicited by the substituted amphetamine (+)-3,4- methylenedioxymethamphetamine. Objectives: The present studies examined the ability of the selective 5-HT_2AR antagonist M100907 to block hyperactivity and hyperthermia produced across the (+)-MDMA dose-effect curve. Methods: Male rats were pretreated with M100907 (0, 0.25, 0.5, 1, and 2 mg/kg) followed by treatment with (+)-MDMA (0-12 mg/kg); activity was recorded for 90 min followed by determination of rectal temperature. Additionally, we investigated the ability of M100907 (0 and 0.5 mg/kg) to reverse hyperthermia elicited by (+)-MDMA (12 mg/kg). Results: The first study demonstrated that M100907 attenuated hyperactivity in the periphery of the monitor and eliminated rearing induced by (+)-MDMA (3 mg/kg) with no effect on basal activity. In two subsequent studies, (+)-MDMA (0-12 mg/kg) dose-dependently increased peripheral activity and rearing and produced hyperthermia. Pretreatment with M100907 decreased peripheral activity evoked by (+)-MDMA, right-shifted the dose-effect curve for rearing, and blocked (+)-MDMA-induced hyperthermia, while having no effect when administered alone. A final study demonstrated the ability of M100907 (0.5 mg/kg) to reverse hyperthermia produced by (+)-MDMA (12 mg/kg). Conclusions: These results suggest that the 5-HT_2AR contributes to the generation of peripheral hyperactivity and rearing and, especially, the hyperthermia evoked by (+)-MDMA and that 5-HT_2AR antagonists should be further investigated as treatments for the psychological and hyperthermic effects of (±)-MDMA.