Determinants and Consequences of MDMA Neurotoxicity

描述（由申请人提供）：安非他明类似物3,4-亚甲基二氧甲基苯丙胺（MDMA）仍然是一种普遍滥用的药物，尽管在动物和人类中有证据表明这种药物对5-羟色胺（5-HT）神经元产生长期毒性。然而，除了这一公认的发现之外，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毒性过程。本研究的目的是阐明氧化应激诱导的过程，氧化应激是mdma诱导的5-HT神经毒性的决定因素。该应用的一个中心焦点是MDMA在海马体中的毒性，与纹状体相反，部分原因是细胞外谷氨酸浓度过高。具体来说，假设MDMA在海马中产生的5-HT的长期消耗是由谷氨酸介导的一氧化氮形成增加和随后的线粒体功能损伤引起的。线粒体功能受损为自由基的进一步产生和随后的5-HT末端结构损伤和5-HT消耗提供了前馈机制。该提案的具体目的是利用体内微透析，生化实验和免疫组织化学研究来：1)评估谷氨酸在海马MDMA毒性过程中的作用，并建立MDMA诱导细胞外谷氨酸增加的机制；2)评估MDMA增加一氧化氮形成的潜在机制；3)确定一氧化氮形成增加是否有助于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spectrin切割的程度和机制。氧化损伤和线粒体损伤过程与MDMA对5-羟色胺末端的长期影响之间的联系，对药物性神经变性及其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.