Activating 5-HT2 receptors with DOI or 5-MeODMT significantly enhanced the acute increase in extracellular dopamine in the rat striatum caused by MDMA, as measured by in vivo microdialysis. Neither drug alone altered dopamine levels. Seven days after a single MDMA dose (10 mg/kg), striatal serotonin (5-HT) was decreased but not significantly. However, combined treatment with DOI and MDMA led to a significantly greater depletion of striatal 5-HT than MDMA alone or vehicle. The findings suggest that 5-HT2 receptor activation is an important determinant of MDMA-induced acute dopamine release and subsequent long-term serotonin depletion.
Repeated administration of 5-MeODMT (3 mg/kg, twice daily for 14 days) in animals reduced the hypothermia and corticosterone secretion caused by an acute challenge with the 5-HT1A agonist 8-OH-DPAT, compared to vehicle-treated animals. Chronic 5-MeODMT did not affect hyperthermia or corticosterone secretion from the 5-HT2 agonist MK-212. Repeated administration of DOI (1 mg/kg daily for 7 days) reduced corticosterone but not body temperature increases from MK-212, and did not alter responses to 8-OH-DPAT. These results suggest that chronic 5-MeODMT selectively reduces 5-HT1A receptor-mediated responses, while chronic DOI selectively reduces 5-HT2 receptor-mediated corticosterone secretion without affecting thermoregulatory responses, supporting the independence of these receptor systems.