POTENTIATION OF 3,4-METHYLENEDIOXYMETHAMPHETAMINE-INDUCED DOPAMINE RELEASE AND SEROTONIN NEUROTOXICITY BY 5-HT2 RECEPTOR AGONISTS

The effects of the 5-HT2 receptor agonists 1-(2,5-dimethoxy-4-iodophen yl)-2-aminoproane (DOI) and 5-methoxy-N,N-dimethyrtryptamine (5-MeODMT ) on 3,4-methylenedioxymethamphetamine (MDMA)-induced dopamine release and 5-HT depletion in the striatum were studied. The MDMA-induced inc rease in the extracellular concentration of dopamine in the striatum w as enhanced significantly in rats treated with either DOI (2 mg/kg, ip .) or 5-MeODMT (15 mg/kg, ip.), as assessed using in vivo microdialysi s. Neither DOI nor 5-MeODMT alone altered the extracellular concentrat ion of dopamine in the striatum. The striatal concentration of 5-HT wa s decreased, but not significantly, 7 days following a single administ ration of MDMA (10 mg/kg, sc.). However, 7 days following the concomit ant treatment with DOI and MDMA the striatal concentration of 5-HT was significantly less than that in rats treated with MDMA alone or the v ehicle-treated controls. It is concluded that activation of 5-HT2 rece ptors is an important determinant of the acute increase in extracellul ar dopamine and, consequently, the long-term depletion of brain 5-HT p roduced by MDMA.