新精神活性物质或将成为全球流行的第三代毒品强力冲击、替代传统和合成毒品，其毒性、危害性较之传统毒品有过之而无不及。典型代表甲卡西酮摄入后易致精神依赖和药物滥用。我们前期研究显示，甲卡西酮染毒大鼠体内抗氧化酶活性降低，nNOS蛋白表达水平明显升高，线粒体膜电位下降、caspase3活化增强，凋亡增加，自噬表达下调。结合氧化应激通路DDAH1/ADMA/NOS系统诱使NO含量升高、ROS改变；NO促进GSTP1-P35/P25-CDK5复合物形成、破坏细胞骨架。我们推测甲卡西酮可能通过上述通路产生神经毒性作用，具体机制有待探索。本项目拟应用行为学、病理学、分子生物学、神经生物学等技术，建立不同剂量甲卡西酮染毒体内、外模型，经多种抑制剂分步骤干预、观察染毒后信号通路中主要要素表达变化、调控及细胞凋亡、自噬，明确氧化应激作用效应，为阐明甲卡西酮神经毒性损伤机制及寻找药物治疗靶点提供基础。

New psychoactive substance would be about to the global epidemic third generation drug shocked and replaced the first classic and the second synthetic drug, the toxicity and perniciousness of which was even more serious. Methcathinone, a typical new psychoactive substance, induced psychological dependence and drug abuse. The activity of antioxidant enzymes was decreased dose-dependently; nNOS protein expression level was elevated obviously; mitochondrial membrane potential declined; caspase3 activation enhanced; which indicated increase of apoptosis while autophagy expression decreased in previous work. DDAH1/ADMA/NOS system played a critical role in the oxidative stress by increasing NO and ROS, which enhanced the nitrification level of glutathione-S-transferase pi (GSTP1), as a result of combination of GSTP1-P35/P25-CDK5 with CDK5 and cytoskeleton damage. It would be proposed the pathway was involved with toxic mechanism of methcathinone. In this research, culture in vitro and in vivo with different dose methcathinone, interference with inhibitors will be used by step to investigate the changes and the regulation of key factors, and to reveal the pathway on the apoptosis and autophagy by behavioristics, pathology, molecular biology, neurobiology and so on. This study is designed to definitude the mechanism of oxidative stress and provides basis for a comprehensive explanation of the neurotoxicity and new targets for drug therapy.