MICRODIALYSIS STUDIES ON MDMA-INDUCED NEUROTOXICITY

MDMA 引起的神经毒性的微透析研究

• 批准号: 3214121
• 负责人: GARY GUDELSKY
• 金额: $ 10.59万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-15 至 1995-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3214121
• 关键词: 3,4 methylenedioxymethamphetamine; adduct; amphetamines; antioxidants; corpus striatum; dopamine; dopamine receptor; drug abuse; drug interactions; high performance liquid chromatography; laboratory rat; microdialysis; neural transmission; neuropharmacology; neurotoxins; serotonin; serotonin receptor; substantia nigra

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.

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、丙二醛等）是常见的滥用药物， 发现是血清素（5-HT）神经毒素。 单个或重复 对啮齿动物和非人类灵长类动物施用 MDMA 会导致 大脑 5-HT 轴突末端的长期损伤。 MDMA 的作用机制 而相关化合物产生的神经毒性作用尚不清楚。 这 拟议研究的目的是证明急性 MDMA 的施用会激活实体中的多巴胺 (DA) 神经元 黑质导致大脑中 DA 的长期过量释放 由黑质纹状体通路支配的区域。 假设 突触浓度过高的 DA 被 5-HT 轴突吸收 DA 可以被自动氧化的终端，从而产生高度 反应性醌会损坏轴突末端。 MDMA 的能力 增加细胞外 DA、5-HT 及其代谢物的浓度 将使用体内微透析进行研究。 MDMA 对人体的急性影响 载体和脉冲介导的 DA 和 5-HT 释放将在 黑质纹状体细胞体（黑质）和末端区域 （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端释放 DA，并且 (2) 在黑质中释放 5-HT，刺激 5-HT-2/1C 受体 导致纹状体中脉冲（囊泡）介导的 DA 释放。 它 假设重复使用 MDMA 会产生 DA 途径的致敏性，致敏的动物会更容易 易受 MDMA 的 5-HT 神经毒性作用影响。 此外，MDMA 是 预计会与安非他明交叉过敏。最后，假设 MDMA 会增加半胱氨酸-DA 加合物的形成，因为 DA 自氧化形成的醌之间的相互作用，以及 巯基位于轴突末端。 的急性影响 MDMA对DA和5-HT的释放会直接相关 通过测量该化合物的长期神经毒性作用的程度 大脑 5-HT 耗竭以及同一部位 5-HT 摄取位点的丧失 微透析研究后7天的动物。 总的来说，它是 预计这些研究将确定神经化学事件 服用 MDMA 后会产生 5-HT 神经毒性。 安非他明和 MDMA 之间的交叉致敏作用增强 神经毒性表明长期滥用兴奋剂的人可能更容易 即使模式不常见，也容易受到 MDMA 诱导的 5-HT 消耗的影响 的虐待。 最后，MDMA 产生的机制 神经毒性可以作为预测其他滥用药物是否 是潜在的 5-HT 神经毒素。