NEUROTOXICITY OF PSYCHOTROPIC DRUGS

临床处方和非法精神药物的使用和滥用 会导致非治疗性的心理和生理变化 中枢神经系统。三维旋转介导的重组 由特定区域的单细胞悬液形成的组织培养 胚胎小鼠的大脑可以用来系统地评估已知的 或潜在的神经毒性作用和此类药物的作用机制。 此应用程序建议对以下几个因素的影响进行调查 临床上可归类为结构相关的精神药物 有用(醋酸甲酯、芬氟拉明)、神经毒性(甲基苯丙胺、 1-甲基-4-苯基-1，2，3，6-四氢吡啶)和潜在的神经毒性 (3，4-亚甲二氧基甲基苯丙胺)。具体目标包括 通过检测1)剂量反应和2)神经毒性 这些药物对水平影响的时程和可逆性 多巴胺、5-羟色胺、3，4-二羟基苯乙酸，5 羟基吲哚乳酸和γ-氨基丁酸对DA蓄积的影响 以及在含有来自大脑的神经元的聚集体中DA细胞的数量 胚胎吻部、中脑被盖和纹状体。第三 这项应用的目的是研究一种已提出的毒性机制。 对于这些涉及形成反应性自由基代谢的物质 中间体和/或氧还原为活性氧 中间体，如超氧化物、羟基和过氧化氢自由基。这 假说将首先在未经处理和药物处理的聚集体中进行检验 通过测量超氧化物歧化酶的活性和/或水平， 过氧化氢酶、谷胱甘肽过氧化物酶和氧化还原谷胱甘肽 作为活性分子的内源性失活剂。第二， 外源性自由基清除剂对大鼠脑内多巴胺和多巴胺水平的影响 DA细胞编号将被评估为间接确认 氧的活性物种的参与以及识别潜力 防范剂。第三，自由基或产物的实际存在 他们的反应将使用硫代巴比妥酸测试和 H202产量的测量。这些研究将证明 三维重组组织培养作为筛选的一般用途 关于新的和/或未经测试的精神药物的潜在神经毒性作用 探员们。此外，这些研究可能会导致预防性和 旨在预防和/或逆转毒性的治疗方法。这些 研究还可能提出新的和/或未经测试的毒性机制 代理，也用作自然发生的建模的一种手段 衰老过程中的退行性疾病过程或正常细胞死亡 类似的机制。

The use and abuse of clinically prescribed and illicit psychotropic drugs can cause non-therapeutic psychological and physiological changes in the central nervous system. Three dimensional rotation-mediated reaggregate tissue cultures formed from single cell suspensions of specific areas of the embryonic mouse brain can be used to systematically evaluate the known or potential neurotoxic effects and mechanisms of action of such drugs. This application proposes an investigation of the effects of several structurally related psychotropic agents which can be grouped as clinically useful (methylphenidate, fenfluramine), neurotoxic (methamphetamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and potentially neurotoxic (3,4-methylenedioxy-methamphetamine). The specific aims include an assessment of neurotoxicity by examining 1) the dose-response and 2) the time-course and reversibility of the effects of these agents on the levels of dopamine (DA), serotonin, 3,4-dihydroxyphenylacetic acid, 5 hydroxyindoleactic acid, and gamma-aminobutyric acid, on DA accumulation and on the number of DA cells in reaggregates containing neurons from the embryonic rostral mesencephalic tegmentum and corpus striatum. The third aim of this application is to investigate a proposed mechanism of toxicity for these agents involving the formation of reactive free radical metabolic intermediates and/or the reduction of oxygen to activated oxygen intermediates such as superoxide, hydroxyl and peroxide radicals. This hypothesis will be tested in untreated and drug treated reaggregates first by measuring the activities and/or levels of superoxide dismutase, catalase, glutathione peroxidase and oxidized and reduced glutathione which function as endogenous inactivators of reactive molecules. Second, the effects of exogenous free radical scavenging agents on the levels of DA and on DA cell numbers will be assessed as an indirect means of confirming the involvement of active species of oxygen as well as identifying potential preventive agents. Third, the actual presence of free radicals or products of their reactions will be measured using the thiobarbituric acid test and measurements of H202 production. These studies will demonstrate the general utility of three-dimensional reaggregate tissue culture as a screen for the potential neurotoxic effects of new and/or untested psychotropic agents. In addition, these studies may lead to both prophylactic and therapeutic approaches designed to prevent and/or reverse toxicity. These studies may also suggest the mechanism of toxicity for new and/or untested agents and also serve as a means of modeling naturally occurring degenerative disease processes or normal cell death during aging due to similar mechanisms.