Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Neurochem Int. 2011 Jan;58(1):92-101. doi: 10.1016/j.neuint.2010.11.001. Epub 2010 Nov 11.
The neurotoxicity of MDMA or "Ecstasy" in rats is selectively serotonergic, while in mice it is both dopaminergic and serotonergic. MDMA metabolism may play a key role in this neurotoxicity. The function of serotonin and dopamine transporter and the effect of MDMA and its metabolites on them are essential to understand MDMA neurotoxicity. The aim of the present study was to investigate and compare the effects of MDMA and its metabolite alpha-methyldopamine (MeDA) on several molecular targets, mainly the dopamine and serotonin transporter functionality, to provide evidence for the role of this metabolite in the neurotoxicity of MDMA in rodents. MeDA had no affinity for the serotonin transporter but competed with serotonin for its uptake. It had no persistent effects on the functionalism of the serotonin transporter, in contrast to the effect of MDMA. Moreover, MeDA inhibited the uptake of dopamine into the serotonergic terminal and also MAO(B) activity. MeDA inhibited dopamine uptake with a lower IC(50) value than MDMA. After drug washout, the inhibition by MeDA persisted while that of MDMA was significantly reduced. The effect of MDMA on the dopamine transporter is related with dopamine release from vesicular stores, as this inhibition disappeared in reserpine-treated animals. However, the effect of MeDA seems to be a persistent conformational change of this transporter. Moreover, in contrast with MDMA, MeDA did not show affinity for nicotinic receptors, so no effects of MeDA derived from these interactions can be expected. The metabolite reduced cell viability at lower concentrations than MDMA. Apoptosis plays a key role in MDMA induced cellular toxicity but necrosis is the major process involved in MeDA cytotoxicity. We conclude that MeDA could protect against the serotonergic lesion induced by MDMA but potentiate the dopaminergic lesion as a result of the persistent blockade of the dopamine transporter induced this metabolite.
MDMA 或“摇头丸”对大鼠的神经毒性具有选择性 5-羟色胺能，而对小鼠则具有多巴胺能和 5-羟色胺能。MDMA 的代谢可能在这种神经毒性中起关键作用。5-羟色胺和多巴胺转运体的功能以及 MDMA 及其代谢物对它们的影响对于理解 MDMA 的神经毒性至关重要。本研究的目的是研究和比较 MDMA 和其代谢物 α-甲基多巴胺（MeDA）对几个分子靶点的影响，主要是多巴胺和 5-羟色胺转运体的功能，为该代谢物在啮齿动物 MDMA 神经毒性中的作用提供证据。MeDA 对 5-羟色胺转运体没有亲和力，但可以与 5-羟色胺竞争摄取。与 MDMA 不同，它对 5-羟色胺转运体的功能没有持久影响。此外，MeDA 抑制多巴胺进入 5-羟色胺能末梢的摄取，也抑制 MAO（B）活性。MeDA 抑制多巴胺摄取的 IC（50）值低于 MDMA。药物洗脱后，MeDA 的抑制作用持续存在，而 MDMA 的抑制作用明显降低。MeDA 对多巴胺转运体的作用与多巴胺从囊泡储存中的释放有关，因为这种抑制在利血平处理的动物中消失了。然而，MeDA 的作用似乎是对该转运体的持久构象改变。此外，与 MDMA 不同，MeDA 对烟碱受体没有亲和力，因此不能期望 MeDA 产生源自这些相互作用的任何影响。与 MDMA 相比，较低浓度的 MeDA 降低细胞活力。细胞凋亡在 MDMA 诱导的细胞毒性中起着关键作用，但坏死是 MeDA 细胞毒性中涉及的主要过程。我们得出结论，MeDA 可以保护 MDMA 诱导的 5-羟色胺能损伤，但由于这种代谢物持续阻断多巴胺转运体，会增强多巴胺能损伤。
