Darvesh Altaf S, Gudelsky Gary A
College of Pharmacy, University of Cincinnati, 3223, Eden Ave., Cincinnati, OH 45267, USA.
Brain Res. 2005 Sep 21;1056(2):168-75. doi: 10.1016/j.brainres.2005.07.009.
Although the exact mechanism involved in the long-term depletion of brain serotonin (5-HT) produced by substituted amphetamines is not completely known, evidence suggests that oxidative and/or bioenergetic stress may contribute to 3,4-methylenedioxymethamphetamine (MDMA)-induced 5-HT toxicity. In the present study, the effect of supplementing energy substrates was examined on the long-term depletion of striatal 5-HT and dopamine produced by the local perfusion of MDMA (100 microM) and malonate (100 mM) and the depletion of striatal and hippocampal 5-HT concentrations produced by the systemic administration of MDMA (10 mg/kg i.p. x4). The effect of systemic administration of MDMA on ATP levels in the striatum and hippocampus also was examined. Reverse dialysis of MDMA and malonate directly into the striatum resulted in a 55-70% reduction in striatal concentrations of 5-HT and dopamine, and these reductions were significantly attenuated when MDMA and malonate were co-perfused with nicotinamide (1 mM). Perfusion of nicotinamide or ubiquinone (100 microM) also attenuated the depletion of 5-HT in the striatum and hippocampus produced by the systemic administration of MDMA. Finally, the systemic administration of MDMA produced a 30% decrease in the concentration of ATP in the striatum and hippocampus. These results support the conclusion that MDMA produces a dysregulation of energy metabolism which contributes to the mechanism of MDMA-induced 5-HT neurotoxicity.
虽然替代苯丙胺导致脑内5-羟色胺（5-HT）长期耗竭的确切机制尚不完全清楚，但有证据表明氧化应激和/或生物能量应激可能导致3,4-亚甲基二氧基甲基苯丙胺（摇头丸）诱导的5-HT毒性。在本研究中，研究了补充能量底物对局部灌注摇头丸（100微摩尔）和丙二酸（100毫摩尔）所致纹状体5-HT和多巴胺长期耗竭以及全身给予摇头丸（10毫克/千克腹腔注射×4次）所致纹状体和海马5-HT浓度降低的影响。还研究了全身给予摇头丸对纹状体和海马ATP水平的影响。将摇头丸和丙二酸直接逆向透析入纹状体导致纹状体5-HT和多巴胺浓度降低55%-70%，当摇头丸和丙二酸与烟酰胺（1毫摩尔）共同灌注时，这些降低显著减弱。灌注烟酰胺或泛醌（100微摩尔）也减弱了全身给予摇头丸所致纹状体和海马5-HT的耗竭。最后，全身给予摇头丸使纹状体和海马ATP浓度降低30%。这些结果支持以下结论：摇头丸导致能量代谢失调，这促成了摇头丸诱导的5-HT神经毒性机制。
