2,5-BIS-(GLUTATHIONE-S-YL)-ALPHA-METHYLDOPAMINE, A PUTATIVE METABOLITE OF (+ -)-3,4-METHYLENEDIOXYAMPHETAMINE, DECREASES BRAIN-SEROTONIN CONCENTRATIONS/

3,4-(+/-)-Methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxy methamphetamine (MDMA) are serotonergic neurotoxicants. However, when injected directly into brain, MDA and MDMA are not neurotoxic, suggest ing that systemic metabolism plays an important role in the developmen t of neurotoxicity. The nature of the metabolite(s) responsible for MD A- and MDMA-mediated neurotoxicity is unclear. alpha-Methyldopamine is a major metabolite of MDA and is readily oxidized to the omicron-quin one, followed by conjugation with glutathione (GSH). Because the conju gation of quinones with GSH frequently results in preservation or enha ncement of biological (re)activity, we have been investigating the rol e of quinone-thioethers in the acute and long-term neurochemical chang es observed after administration of MDA. Although intracerebroventricu lar (i.c.v.) administration of 5-(glutathion-S-yl)-alpha-methyldopamin e (4 x 720 nmol) and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine (1 x 7 nmol) to Sprague-Dawley rats produced overt behavioral changes sim ilar to those seen following administration of MDA (93 mu mol/kg, s.c. ) they did not produce lone-term decreases in brain serotonin (5-hydro xytryptamine, 5-HT) concentrations. In contrast, 2,5-bis-(glutathion-S -yl)-alpha-methyldopamine (4 x 475 nmol) decreased 5-HT levels by 24%, 65% and 30% in the striatum, hippocampus and cortex, respectively, 7 days after injection. The relative sensitivity of the striatum, hippoc ampus and cortex to 2,5-bis-(glutathion S-yl)-alpha-methyldopamine was the same as that observed for MDA; the absolute effects were greater with MDA. The effects of 2,5-bis-(glutathion-S-yl)-alpha-methyldopamin e were also selective for serotonergic nerve terminal fields, in that 5-HT levels were unaffected in regions of the cell bodies. Because 2,5 -bis-(glutathion-S-yl)-alpha-methyldopamine caused long-term depletion in 5-HT without adversely affecting the dopaminergic system, it also mimics the selectivity of MDA/MDMA. The data imply a possible role for quinone-thioethers in the neurobehavioral and neurotoxicological effe cts of MDA/MDMA. (C) 1997 Elsevier Science B.V.