MICRODIALYSIS STUDIES ON MDMA-INDUCED NEUROTOXICITY

MDMA（3，4-亚甲二氧基甲基苯丙胺）和相关苯乙胺（即 甲基苯丙胺、MDA等）是一种流行的滥用药物， 5-羟色胺（5-HT）神经毒素。 单次或重复 对啮齿类动物和非人灵长类动物施用MDMA导致 长期损害脑5-HT轴突终末。 MDMA的作用机制 和相关化合物产生其神经毒性作用是未知的。 的 拟议研究的目的是证明急性 MDMA的给药激活了脑实质中的多巴胺（DA）神经元 黑质导致大脑中DA的长期和过度释放 由黑质纹状体通路支配的区域。 它是假设 过量的DA突触浓度被5-HT轴突吸收 DA可以被自动氧化的终端，导致产生高度 能损伤轴突末梢的活性醌类。 MDMA的能力， 增加细胞外DA、5-HT及其代谢产物的浓度 将使用体内微透析进行研究。 MDMA的急性效应 载体和冲动介导的DA和5-HT释放将在 黑质纹状体细胞体（黑质）和终末区 （纹状体）。 根据初步研究，假设 MDMA通过2种机制增加多巴胺能神经传递：（1）直接 通过载体介导的交换从轴突末梢释放DA，以及（2） 在黑质释放5-HT，刺激5-HT-2/1C受体 导致纹状体中DA的冲动（囊泡）介导的释放。 它 假设MDMA的重复给药会产生 DA途径的致敏作用，致敏动物将更多 对MDMA的5-HT神经毒性作用敏感。 此外，MDMA是 会和安非他明交叉致敏最后，假设 MDMA会增加半胱氨酸-DA加合物的形成， DA自氧化形成的醌类与 位于轴突末端的巯基。 的急性效应 MDMA对DA和5-HT的释放有直接关系 通过测量这种化合物的长期神经毒性作用的程度， 脑5-HT消耗以及相同脑内5-HT摄取位点的丧失， 微透析研究后7天的动物。 总的来说， 预计这些研究将建立神经化学事件， 其在施用MDMA后产生5-HT神经毒性。 安非他明和二亚甲基双氧安非他明之间的交叉致敏作用， 神经毒性表明，慢性兴奋剂滥用者可能更多 对MDMA诱导的5-HT耗竭敏感，即使是罕见的模式 虐待 最后，MDMA产生的机制 神经毒性可以作为一个模型来预测是否其他滥用药物 是潜在的5-HT神经毒素。

MDMA (3,4-methylenedioxymethamphetamine) and related phenethylamines (i.e. methamphetamine, MDA, etc.) are popular drugs of abuse which have been found to be serotonin (5-HT) neurotoxins. Single or repeated administration of MDMA to rodents as well as nonhuman primates results in long term damage to brain 5-HT axon terminals. The mechanism by which MDMA and related compounds produce their neurotoxic effect is unknown. The objective of the proposed studies is to demonstrate that acute administration of MDMA activates dopamine (DA) neurons in the substantia nigra resulting in the prolonged and excessive release of DA in brain regions innervated by nigrostriatal pathways. It is hypothesized that excessive synaptic concentrations of DA are taken up into 5-HT axon terminals where DA can be autoxidized resulting in the production of highly reactive quinones which can damage axon terminals. The ability of MDMA to increase the extracellular concentrations of DA, 5-HT and their metabolites will by studied using in vivo microdialysis. The acute effect of MDMA on carrier and impulse-mediated DA and 5-HT release will be determined in the nigrostriatal cell bodies (substantia nigra) and terminal regions (striatum). On the basis of preliminary studies, it is hypothesized that MDMA increases dopaminergic neurotransmission by 2 mechanisms: (1) direct release of DA from axon terminals via a carrier-mediated exchange and (2) releasing 5-HT in the substantia nigra which stimulates 5-HT-2/1C receptors resulting in impulse (vesicle) mediated release of DA in the striatum. It is hypothesized that repeated administration of MDMA will produce a sensitization of DA pathways and that sensitized animals will be more susceptible to the 5-HT neurotoxic effect of MDMA. In addition, MDMA is expected to cross-sensitize with amphetamine. Finally, it is hypothesized that MDMA will increase the formation of cysteine-DA adducts as a result of the interaction between quinones, formed from DA autoxidation, and sulfydryl groups located within the axon terminal. The acute effects of MDMA on the release of DA and 5-HT will be directly related to the long-term neurotoxic effects of this compound by measuring the extent of brain 5-HT depletion as well as the loss of 5-HT uptake sites in the same animal 7 days following the microdialysis studies. Collectively, it is anticipated that these studies will establish the neurochemical events which produce 5-HT neurotoxicity following the administration of MDMA. Cross-sensitization between amphetamine and MDMA resulting in enhanced neurotoxicity is suggestive that chronic stimulant abusers may be more susceptible to MDMA-induced 5-HT depletion, even with infrequent patterns of abuse. Finally, the mechanism(s) by which MDMA produces it neurotoxicity may serve as a model to predict whether other abused drugs are potential 5-HT neurotoxins.