Miller R T, Lau S S, Monks T J
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin 78712, USA.
Eur J Pharmacol. 1997 Apr 4;323(2-3):173-80. doi: 10.1016/s0014-2999(97)00044-7.
3,4-(+/-)-Methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) are serotonergic neurotoxicants. However, when injected directly into brain, MDA and MDMA are not neurotoxic, suggesting that systemic metabolism plays an important role in the development of neurotoxicity. The nature of the metabolite(s) responsible for MDA- and MDMA-mediated neurotoxicity is unclear. alpha-Methyldopamine is a major metabolite of MDA and is readily oxidized to the o-quinone, followed by conjugation with glutathione (GSH). Because the conjugation of quinones with GSH frequently results in preservation or enhancement of biological (re)activity, we have been investigating the role of quinone-thioethers in the acute and long-term neurochemical changes observed after administration of MDA. Although intracerebroventricular (i.c.v.) administration of 5-(glutathion-S-yl)-alpha-methyldopamine (4 x 720 nmol) and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine (1 x 7 nmol) to Sprague-Dawley rats produced overt behavioral changes similar to those seen following administration of MDA (93 mumol/kg, s.c.) they did not produce long-term decreases in brain serotonin (5-hydroxytryptamine, 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, hippocampus 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-methyldopamine 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 effects of MDA/MDMA.
3,4-(±)-亚甲二氧基苯丙胺（MDA）和3,4-(±)-亚甲二氧基甲基苯丙胺（MDMA）是血清素能神经毒素。然而，当直接注射到大脑中时，MDA和MDMA并无神经毒性，这表明全身代谢在神经毒性的发展中起重要作用。导致MDA和MDMA介导的神经毒性的代谢物的性质尚不清楚。α-甲基多巴胺是MDA的主要代谢物，很容易氧化为邻醌，然后与谷胱甘肽（GSH）结合。由于醌与GSH的结合经常导致生物（再）活性的保留或增强，我们一直在研究醌硫醚在MDA给药后观察到的急性和长期神经化学变化中的作用。虽然向Sprague-Dawley大鼠脑室内（i.c.v.）注射5-（谷胱甘肽-S-基）-α-甲基多巴胺（4×720 nmol）和5-（N-乙酰半胱氨酸-S-基）-α-甲基多巴胺（1×7 nmol）会产生与注射MDA（93 μmol/kg，皮下注射）后相似的明显行为变化，但它们并未导致脑内血清素（5-羟色胺，5-HT）浓度长期降低。相比之下，注射2,5-双（谷胱甘肽-S-基）-α-甲基多巴胺（4×475 nmol）7天后，纹状体、海马体和皮质中的5-HT水平分别降低了24%、65%和30%。纹状体、海马体和皮质对2,5-双（谷胱甘肽-S-基）-α-甲基多巴胺的相对敏感性与MDA观察到的相同；MDA的绝对效应更大。2,5-双（谷胱甘肽-S-基）-α-甲基多巴胺的作用对血清素能神经终末区域也具有选择性，即细胞体区域的5-HT水平未受影响。由于2,5-双（谷胱甘肽-S-基）-α-甲基多巴胺导致5-HT长期耗竭而未对多巴胺能系统产生不利影响，它也模拟了MDA/MDMA的选择性。这些数据表明醌硫醚在MDA/MDMA的神经行为和神经毒理学效应中可能起作用。
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