MICRODIALYSIS STUDIES ON MDMA-INDUCED NEUROTOXICITY

MDMA(3，4-亚甲基二氧基甲基苯丙胺)和相关的苯乙胺(即 甲基苯丙胺、丙二醛等)是流行的滥用药物，已经被 发现是5-羟色胺(5-羟色胺)神经毒素。单一或重复 给啮齿动物和非人灵长类动物注射MDMA会导致 对大脑5-羟色胺轴突终末的长期损害。MDMA的机制 而相关化合物产生的神经毒性作用尚不清楚。这个 拟议研究的目标是证明急性 给予MDMA可激活脑实质中的多巴胺(DA)神经元 黑质导致脑内DA长时间过度释放 黑质纹状体通路支配的区域。据推测， 突触中过量的DA被5-羟色胺轴突吸收 DA可被自动氧化的终端，导致高度 可损害轴突终末的反应性苯二酚。MDMA的能力 提高多巴胺、5-羟色胺及其代谢产物的胞外浓度 采用体内微透析法进行研究。MDMA对人类健康的严重影响 携带者和脉冲介导的多巴胺和5-羟色胺释放将在 黑质纹状体细胞体(黑质)和终末区域 (纹状体)。在初步研究的基础上，假设 MDMA通过两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终末释放DA和(2) 黑质释放5-羟色胺刺激5-羟色胺-2/1C受体 导致纹状体DA释放的脉冲(囊泡)介导。它 假设重复服用MDMA会产生 DA通路的致敏和致敏的动物将更多 易受MDMA的5-羟色胺神经毒性影响。此外，MDMA是 预计会与安非他明交叉致敏。最后，对其进行了假设 MDMA将增加半胱氨酸-DA加合物的形成 DA自氧化形成的苯二酚与苯二酚之间的相互作用 位于轴突末端的巯基。病毒的严重影响 MDMA对多巴胺和5-羟色胺的释放将直接相关 通过测量该化合物的长期神经毒性作用的程度 脑内5-羟色胺的耗竭以及5-羟色胺摄取部位的丢失 动物在微透析研究后7天。总而言之，它是 预计这些研究将确定神经化学事件 在服用MDMA后会产生5-羟色胺的神经毒性。 苯丙胺和MDMA之间的交叉敏化导致增强 神经毒性提示慢性兴奋剂滥用者可能比 易受MDMA诱导的5-羟色胺耗竭的影响，即使是罕见的模式 滥用职权。最后，MDMA生产它的机制(S) 神经毒性可作为预测其他滥用药物是否 是潜在的5-羟色胺神经毒素。

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.