Determinants and Consequences of MDMA Neurotoxicity

MDMA 神经毒性的决定因素和后果

• 批准号: 7276785
• 负责人: GARY GUDELSKY
• 金额: $ 30.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276785
• 关键词: Accounting; Acetylcholine; Amphetamines; Animals; Attention; Biochemical; Bioenergetics; Biological Markers; Brain; Brain region; Corpus striatum structure; Cytoskeletal Proteins; Dopamine; Failure; Free Radical Formation; Free Radicals; Generations; Glutamates; Goals; Health; Hippocampus (Brain); Human; Impairment; Long-Term Effects; Mediating; Microdialysis; Mitochondria; Nerve Degeneration; Neurons; Nitric Oxide; Oxidative Stress; Oxidative Stress Induction; Pharmaceutical Preparations; Process; Proteolysis; Reactive Nitrogen Species; Risk; Role; Serotonin; Spectrin; Stress; Synapses; Toxic effect; Tryptophan 5-monooxygenase; analog; base; carbene; dopaminergic neuron; drug of abuse; ecstasy; extracellular; feeding; in vivo; neurotoxicity; novel; oxidation; psychostimulant; research study; tau Proteins

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.

描述（由申请人提供）：苯丙胺类似物3,4-甲基二甲基甲基苯丙胺（MDMA）仍然是一种流行的滥用药物，尽管动物和人类的证据表明该药物对5-羟色胺（5-HT）神经元产生了长期毒性。 但是，除了这一良好的发现之外，MDMA产生5-HT神经毒性的机制仍然未知。 几条证据表明，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氧化应激的诱导过程，这些过程是MDMA诱导的5-HT神经毒性的决定因素。 该应用的一个主要重点是假设是，与纹状体相比，海马中的MDMA毒性部分是由于细胞外谷氨酸的过度浓度而导致的。 具体而言，假设MDMA在海马中产生的5-HT的长期耗竭是由一氧化氮形成的增加以及随后的线粒体功能损害引起的。 线粒体功能受损为进一步的自由基生成饲料前向机制，并随后对5-HT终端造成结构性损害和5-HT的耗竭。 该提案的具体目的是在体内微透析，生化实验和免疫组织化学研究中使用：1）评估谷氨酸对海马中MDMA毒性过程的贡献形成，3）确定一氧化氮的形成是否有助于MDMA诱导的线粒体功能抑制作用，4）评估MDMA促进细胞骨架蛋白Tau和Spectrin的裂解的程度和机制。 氧化损伤和线粒体损害与MDMA对5-HT终端的长期影响的过程的联系对药物诱导的神经变性具有重要意义，并且这可能对人类健康构成可能构成人类健康。