MICRODIALYSIS STUDIES ON MDMA INDUCED NEUROTOXICITY

描述：（申请人摘要） 摇头丸和其他精神兴奋剂仍然是流行的滥用药物 尽管在啮齿类动物和非人类灵长类动物中有证据表明， 脑5-羟色胺（5-HT）及其主要代谢物的长期消耗， 5-羟基吲哚乙酸 然而，除了这一众所周知的发现， 这些药物产生5-HT神经毒性的机制仍不清楚。 有证据表明，大脑中5-HT的消耗依赖于， 部分，在延长和过量释放多巴胺引起的MDMA。 为研究提供基础的总体假设， 这种应用是MDMA诱导的脑5-HT消耗导致 来自a）MDMA诱导的细胞外浓度的增加， 多巴胺，B）多巴胺的酶促氧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 与其形成相关的氧化作用。 提供证据 支持MDMA诱导的5-HT神经毒性由以下因素引起的观点： 自由基产生后对神经元的氧化应激， 消耗内源性抗氧化剂，具体目标是利用 体内微透析和生物化学测定，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 2）MDMA诱导的羟基自由基形成 部分依赖于细胞外 浓度的多巴胺，3）MDMA诱导的游离羟基的形成， 自由基伴随着自由基介导的细胞毒性， 表现为脂质过氧化，维生素C的组织浓度降低 E和谷胱甘肽，和4）MDMA诱导的5-HT神经元的神经毒性，可以是 通过防止或抑制羟基自由基的形成而减弱， 用自由基清除剂处理或用铁螯合剂处理， 减少铁促进的多巴胺自氧化。 的理解 介导MDMA神经毒性作用的神经化学底物 最终将有助于确定对人类健康的风险， 与其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.