NEUROCHEMICAL ALTERATIONS BY DESIGNER DRUGS

苯丙胺类似物3，4-亚甲基二氧基甲基苯丙胺的滥用 (MDMA)仍然是一个重大的公共卫生问题。治疗 服用MDMA的大鼠破坏大脑5-羟色胺能神经末梢 伴随着色氨酸羟化酶(TPH)的长期下降 活动。这种神经元损伤发生的机制仍然存在。 未知。 有趣的是，MDMA在中枢5-羟色胺能引起双相反应。 系统。第一阶段包括大脑TPH的迅速下降 在给药后15分钟内检测到的活性。这 通过体外孵育酶来逆转早期阶段(L阶段)。 减少条件。在第二阶段，TPH活性下降 (阶段2)在服用MDMA几天后观察，并延长持续时间 一段时间；与L阶段相反，第二阶段不能被 减少条件。TPH活性的长期变化是 与MDMA诱导的神经毒性有关。在这份文件中提供的证据 建议认为，TPH蛋白经历了最初的可逆过程 在阶段1期间进行转换，在阶段1期间进行其他可能的转换 发生在TPH蛋白之前的中间过渡阶段 由于神经元损伤而造成的破坏(阶段2)。前列腺增生症的L时相减少 活性是由氧化条件引起的，这种条件被认为是 使5-羟色胺能神经元容易受到永久性神经元损伤。 由于TPH对MDMA诱导的氧化改变非常敏感， 5-羟色胺能系统，我们建议使用这种酶作为探针 监测并描述这一现象。对这些的描述 氧化条件将通过识别不同的阶段来实现 通过关联MDMA诱导的TPH蛋白转化 TPH活性与其蛋白浓度及酶活力恢复的关系 由还原条件引起的活性。MDMA生成的氧化剂 条件将通过研究影响进一步表征 不同自由基清除剂对TPH三个阶段的影响 转型。谷胱甘肽作为一种保护系统在体内的作用 5-羟色胺能系统也将被研究。最后，被动的 MDMA产生的物质将通过研究 不同发育阶段分离的TPH蛋白的变化 免疫沉淀和电泳法。这项研究应该有助于 鉴定MDMA及其类似物引起的生化改变 苯丙胺类似物及其对大脑蛋白质的影响。

The abuse of the amphetamine analog, 3,4-methylenedioxymethamphetamine (MDMA), continues as a significant public health problem. Treatment of rats with MDMA destroys brain serotonergic nerve terminals which is accompanied by a long-lasting decrease in tryptophan hydroxylase (TPH) activity. The mechanism by which this neuronal damage occurs remains unknown. Interestingly, MDMA causes a biphasic response in the central serotonergic system. The first phase consists of a rapid decrease in the cerebral TPH activity which is detected within 15 min of drug administration. This early phase (phase l) is reversed by incubating the enzyme in vitro under reducing conditions. In the second phase, a decrease in TPH activity (phase 2) is observed days after MDMA administration and last for extended periods of time; in contrast to phase l, phase 2 cannot be reversed by reducing conditions. The long-lasting change in TPH activity is associated with MDMA-induced neurotoxicity. Evidence presented in this proposal suggests that TPH protein undergoes an initial reversible transformation during phase 1, with other possible transformations during an intermediate transitional stage occurring prior to TPH protein destruction due to neuronal damage (phase 2). The phase l decrease in TPH activity is caused by oxidative conditions which are proposed to predispose the serotonergic neuron to permanent neuronal (damage. Since TPH is sensitive to MDMA-induced oxidative alterations present in the serotonergic system, we propose to use this enzyme as a probe to monitor and characterize this phenomenon. The characterization of these oxidative conditions will be achieved by identifying the different stages of TPH protein transformation by correlating the MDMA-induced decrease in TPH activity with its protein concentration and with recovery of enzyme activity induced by reducing conditions. The MDMA-generated oxidative conditions will be further characterized by studying the effects of different free radical scavengers on the three stages of TPH transformation. The role of glutathione as a protective system in the serotonergic system will also be investigated. Finally, the reactive substances generated by MDMA will be investigated by studying the alterations of the TPH protein isolated during the different stages by immunoprecipitation and electrophoresis. This study should assist in identifying the biochemical alterations induced by MDMA and similar amphetamine analogs and their impact on brain proteins.