Determinants and Consequences of MDMA Neurotoxicity

描述（由申请人提供）：安非他明类似物3，4-亚甲二氧基甲基安非他明（MDMA）仍然是一种流行的滥用药物，尽管在动物和人类中有证据表明该药物对5-羟色胺（5-HT）神经元产生长期毒性。 然而，除了这一明确的发现之外，MDMA产生5-HT神经毒性的机制仍然未知。 一些证据表明，氧化应激有助于MDMA诱导的5-HT毒性的过程。 本研究的目的是阐明的过程中，进行或后续的氧化应激的诱导，是MDMA诱导的5-HT神经毒性的决定因素。 本申请的一个中心焦点是以下假设：与纹状体相反，海马中的MDMA毒性部分是由于细胞外谷氨酸浓度过高所致。 具体而言，假设海马中MDMA产生的5-HT长期耗竭是由谷氨酸介导的一氧化氮形成增加和随后线粒体功能受损所致。 受损的线粒体功能提供了一种前馈机制，用于进一步产生自由基，并随后对5-HT末端造成结构损伤和5-HT耗竭。 该提案的具体目标是利用体内微透析、生物化学实验和免疫组织化学研究：1）评估谷氨酸对海马中MDMA毒性过程的贡献，并建立MDMA诱导的细胞外谷氨酸增加的潜在机制，2）评价MDMA增加一氧化氮形成的潜在机制，3）确定一氧化氮形成的增加是否有助于MDMA诱导的线粒体功能抑制，4）评估MDMA促进细胞骨架蛋白tau和血影蛋白裂解的程度和机制。 氧化损伤和线粒体损伤过程与MDMA对5-HT末端的长期影响之间的联系对药物诱导的神经变性和可能对人类健康造成的风险具有重要意义。

DESCRIPTION (provided by applicant): The amphetamine analog 3,4- methylenedioxymethamphetamine (MDMA) continues to be a popular drug of abuse despite evidence in animals and humans that this agent produces long-term toxicity to serotonin (5-HT) neurons. However, beyond this well-established finding, the mechanisms through which MDMA produces 5-HT neurotoxicity remain unknown. Several lines of evidence suggest that oxidative stress contributes to the process of MDMA-induced 5-HT toxicity. The intent of the present study is to elucidate the processes, proceeding or subsequent to, the induction of oxidative stress that are the determinants of MDMA-induced 5-HT neurotoxicity. A central focus of this application is the hypothesis that MDMA toxicity in the hippocampus, in contrast to the striatum, results, in part, from excessive extracellular concentrations of glutamate. Specifically, it is hypothesized that the long-term depletion of 5-HT produced by MDMA in the hippocampus results from a glutamate-mediated increase in nitric oxide formation and a subsequent impairment of mitochondrial function. Impaired mitochondrial function provides a feed forward mechanism for the further generation of free radicals and ensuing structural damage to 5-HT terminals and depletion of 5-HT. The specific aims of the proposal are to utilize in vivo microdialysis, biochemical experiments and immunohistochemical studies to: 1) assess the contribution of glutamate to the process of MDMA toxicity in the hippocampus and establish the mechanism underlying the MDMA-induced increase in extracellular glutamate, 2) evaluate potential mechanisms through which MDMA increases nitric oxide formation, 3) determine whether increased nitric oxide formation contributes to the MDMA-induced inhibition of mitochondrial function and 4) assess the extent and mechanism by which MDMA promotes the cleavage of the cytoskeletal proteins tau and spectrin. The linkage of the processes of oxidative damage and mitochondrial impairment to the long-term effects of MDMA on 5-HT terminals has significant implication for drug-induced neurodegeneration and risks this may pose to human health.