DOPAMINE OXIDATION IN METHAMPHETAMINE--INDUCED TOXICITY

描述：（申请人摘要） 纹状体多巴胺终末的丢失对高剂量的 甲基苯丙胺已经被很好地确立。 虽然毒性已经被证明 依赖于甲基苯丙胺诱导的多巴胺释放， 细胞外空间，多巴胺诱导的确切机制 毒性仍不清楚。 一个经常被提出的机制是多巴胺可以 氧化形成活性代谢物，如自由基和DA醌 可能攻击细胞成分导致毒性。 尽管一些 有证据支持这一理论，即氧化 多巴胺和药物诱导的毒性尚未直接检测。 因此，在本发明中， 这项研究的目的是严格检验多巴胺 氧化在甲基苯丙胺诱导的机制中起作用 神经毒性 该提案旨在研究多巴胺的具体措施 接触甲基苯丙胺期间和之后的氧化： 游离和蛋白质结合的半胱氨酰-邻苯二酚，以及水杨酸盐捕获 羟基自由基 多巴胺合成的药理学操作和 代谢将被用来关联多巴胺氧化与结果 毒性 组织和细胞外液中的抗氧化剂水平也将 在接触甲基苯丙胺期间进行监测。 药理学操作 增加或减少大脑中抗氧化剂的水平， 研究大脑抗氧化状态对多巴胺氧化的影响， 导致毒性。 最后，假设多巴胺诱导的氧化 压力可以影响细胞外潜在毒性的水平， 神经递质通过破坏多巴胺和/或谷氨酸 运输商将接受检查。 研究结果可能表明， 滥用安非他明的人有可能造成永久性损害 到CNS。 抗氧化剂形式的治疗干预 可能需要补充以防止对CNS的永久性损伤， 以减少这些人的潜在易感性， 帕金森病的发展在以后的生活中。

DESCRIPTION: (Applicant's Abstract) The loss of dopamine terminals in the striatum in response to high doses of methamphetamine has been well established. Although toxicity has been shown to be dependent upon the methamphetamine-induced release of dopamine into the extracellular space, the exact mechanism by which dopamine induces toxicity remains unclear. One mechanism often proposed is that dopamine can oxidize to form reactive metabolites such as free radicals and DA quinones that may attack cellular components resulting in toxicity. Although some evidence exists to support this theory, the relation between the oxidation of dopamine and drug-induced toxicity has not been examined directly. Thus, the goal of this study is to rigorously test the hypothesis that dopamine oxidation plays a role in the mechanism of methamphetamine-induced neurotoxicity. The proposal aims to examine specific measures of dopamine oxidation during and after exposure to methamphetamine: the formation of free and protein-bound cysteinyl-catechols, and salicylate trapping of hydroxyl radicals. Pharmacological manipulations of dopamine synthesis and metabolism will be used to correlate dopamine oxidation with the resulting toxicity. Antioxidant levels in tissue and extracellular fluid also will be monitored during exposure to methamphetamine. Pharmacological manipulations that increase or decrease brain levels of antioxidants will be used to examine the effect of brain antioxidant status on dopamine oxidation and the resulting toxicity. Finally, the hypothesis that dopamine-induced oxidative stress can influence extracellular levels of potentially toxic neurotransmitters via disruption of the dopamine and/or glutamate transporters will be examined. The findings may suggest that individuals who abuse amphetamines are at risk for the development of permanent damage to the CNS. Therapeutic intervention in the form of antioxidant supplementation may be warranted to prevent permanent-damage to the CNS and to reduce the potential predisposition of these individuals for the development of Parkinson's disease later in life.