The highly selective 5-HT2 receptor antagonist MDL 100,907 blocked MDMA-stimulated dopamine synthesis in vivo without affecting basal synthesis. It also prevented long-term deficits in serotonin concentrations believed to result from MDMA-induced dopamine release. Microdialysis showed that MDL 100,907 attenuated MDMA-induced increases in extracellular striatal dopamine. However, MDL 100,907 did not alter dopamine synthesis stimulated by haloperidol or reserpine, nor dopamine release produced by haloperidol. The results suggest a permissive role for 5-HT2 receptors in activating the dopamine system during states of high serotonergic activity or elevated dopamine efflux with high D2 receptor occupancy.
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.