MICRODIALYSIS STUDIES ON MDMA INDUCED NEUROTOXICITY

描述：(申请人摘要) MDMA和其他精神刺激剂仍然是受欢迎的滥用药物 尽管在啮齿动物和非人类灵长类动物中有证据表明，这些毒剂产生 大脑5-羟色胺(5-羟色胺)及其主要代谢物的长期枯竭， 5-羟基吲哚乙酸。然而，除了这一众所周知的发现之外， 这些药物产生5-羟色胺神经毒性的机制尚不清楚。 有证据表明，大脑中5-羟色胺的耗竭是依赖的，在 部分是由于MDMA引起的多巴胺的长期和过度释放。 中提出的研究的基础的总体假设 本应用是MDMA引起的脑组织5-羟色胺耗竭的结果 来自a)MDMA诱导的胞外浓度增加 多巴胺，b)多巴胺的酶催化或自氧化以及随后的 羟基自由基的形成和c)细胞损伤(例如，脂质 过氧化)与它们的形成有关。在…中提供证据 支持MDMA诱导的5-羟色胺神经毒性是由 自由基的产生和神经元的氧化应激 消耗内源性抗氧化剂，其具体目标是在 活体微渗析和生化分析以确定1)MDMA产生 羟基自由基形成的剂量和时间依赖性增加 大脑中的自由基，2)MDMA诱导的羟基自由基的形成 在一定程度上依赖于细胞外的持续增加 多巴胺浓度，3)MDMA诱导的羟基自由基形成 自由基伴随着自由基介导的细胞毒性，如 证明是脂质过氧化，组织中维生素的浓度降低 E和谷胱甘肽，以及4)MDMA引起的5-羟色胺神经元的神经毒性 通过防止或抑制羟基自由基的形成而减弱的， 用自由基清除剂治疗或用铁络合剂治疗 减少铁促进的多巴胺自氧化作用。对这一概念的理解 介导MDMA神经毒性作用的神经化学底物 最终将有助于确定相关的人类健康风险 它的滥用和预测其他滥用的神经毒性后果 物质。

DESCRIPTION: (Applicant's Abstract) MDMA and other psychostimulants continue to be popular drugs of abuse despite evidence in rodents and non-human primates that these agents produce a long-lasting depletion of brain serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid. However, beyond this well-known finding, the mechanisms by which these agents produce 5-HT neurotoxicity remains unknown. There is evidence that the depletion of 5-HT in the brain is dependent, in part, upon the prolonged and excessive release of dopamine elicited by MDMA. The overall hypothesis that provides the basis for the studies proposed in this application is that the MDMA-induced depletion of brain 5-HT results from a) a MDMA-induced increase in the extracellular concentration of dopamine, b) the enzymatic or autoxidation of dopamine and the subsequent formation of hydroxyl-free radicals and c) the cellular damage (e.g., lipid peroxidation) associated with their formation. To provide evidence in support of the view that MDMA-induced 5-HT neurotoxicity results from oxidative stress to neurons following the generation of free radicals and depletion of endogenous antioxidants, the specific aims are to utilize in vivo microdialysis and biochemical assays to establish that 1) MDMA produces a dose- and time-dependent increase in the formation of hydroxyl free radicals in the brain, 2) MDMA-induced formation of hydroxyl free radicals is dependent, in part, upon the sustained increase in the extracellular concentration of dopamine, 3) MDMA-induced formation of hydroxyl free radicals is accompanied by free radical-mediated cellular toxicity, as evidenced by lipid peroxidation, decreased tissue concentrations of vitamin E and glutathione, and 4) MDMA-induced neurotoxicity of 5-HT neurons can be attenuated by prevention or inhibition of hydroxyl radical formation, treatment with free radical scavengers or treatment with iron chelators that diminish iron-facilitated autoxidation of dopamine. An understanding of the neurochemical substrates that mediate the neurotoxic effects of MDMA ultimately will assist in determining the risk to human health associated with its abuse and predicting neurotoxic consequences of other abused substances.