Potentiation of 3,4-methylenedioxymethamphetamine-induced dopamine release and serotonin neurotoxicity by 5-HT2 receptor agonists.

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.

Study at a glance

Abstract

The effects of the 5-HT2 receptor agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on 3,4-methylenedioxymethamphetamine (MDMA)-induced dopamine release and 5-HT depletion in the striatum were studied. The MDMA-induced increase in the extracellular concentration of dopamine in the striatum was enhanced significantly in rats treated with either DOI (2 mg/kg, ip.) or 5-MeODMT (15 mg/kg, ip.), as assessed using in vivo microdialysis. Neither DOI nor 5-MeODMT alone altered the extracellular concentration of dopamine in the striatum. The striatal concentration of 5-HT was decreased, but not significantly, 7 days following a single administration of MDMA (10 mg/kg, sc.). However, 7 days following the concomitant treatment with DOI and MDMA the striatal concentration of 5-HT was significantly less than that in rats treated with MDMA alone or the vehicle-treated controls. It is concluded that activation of 5-HT2 receptors is an important determinant of the acute increase in extracellular dopamine and, consequently, the long-term depletion of brain 5-HT produced by MDMA.