甲基苯丙胺依赖谷氨酸兴奋性神经毒性的分子机制及诊断标志物研究

The synthetic drugs represented by Methamphetamine (MA) have spread rapidly in China in recent years, and have replaced the traditional drugs to become the first popular drugs. MA has neurotoxicity and can impair cognition function, which is one of the most important clinical features of MA dependence. Cognitive impairments are closely related with craving and relapse. Numerous studies have demonstrated that glutamate excitotoxicity is the major cause of MA induced cognition impairment. Our previous study have found that the expression of glutamate receptor 2 (GRIA2) increased in MA dependent patients’ peripheral blood, which is negatively regulated by miR-181. And methamphetamine can decrease the expression of vesicular glutamate transporter 1 (VGLUT1) in the mice vmPFC, but the underlying mechanism is not very clear. This study will use MA cognition impairment mouse model to confirm the role of VGLUT1 in the MA cognition impairment and the regulation mechanism of VGLUT1 will be further explored. Meanwhile clinical cohort study will be conducted to investigate the biomarkers for MA dependence diagnoses, we will screen biomarkers from brain structure and function, brain glutamate level, peripheral blood molecules related to glutamate system function and miRNAs. This study will elucidate the underling mechanisms of MA glutamate excitotoxicity and identify potential intervention targets. It will provide scientific basis for MA dependence diagnosis and intervention which has important social significance to reduce the hazards and the spread of synthetic drugs.

以甲基苯丙胺(MA)为代表的合成毒品近年来在我国迅速蔓延，已替代传统毒品成为我国第一流行毒品，MA神经毒性大，认知损害是MA依赖的一个重要临床特征，与心理渴求及复发密切相关。大量研究表明谷氨酸兴奋性毒性是MA所致认知损伤的重要原因，我们前期研究发现MA依赖者外周血谷氨酸受体GRIA2蛋白表达升高，并与miR181负向调控有关；动物实验发现MA导致小鼠前额叶囊泡型谷氨酸转运体1型（VGLUT1）表达降低，但其具体分子机制尚不清楚。本研究首先采用动物模型确定VGLUT1异常在MA依赖认知损害中的作用，并进一步探索VGLUT1表达异常的分子调控机制，同时采用临床队列研究，聚焦谷氨酸系统，从脑功能影像学及外周分子探索MA依赖认知损害的相关标志物。本研究对阐明MA谷氨酸兴奋性毒性的分子机制与潜在干预靶标，建立MA依赖诊断评估客观标记物提供科学依据，对降低合成毒品危害、遏制毒品蔓延具有重要社会意义。

甲基苯丙胺具有很强的神经毒性，认知损害是甲基苯丙胺成瘾的重要特征，与心理渴求及复吸密切相关。研究表明谷氨酸兴奋性毒性是甲基苯丙胺所致认知损伤的重要原因，我们前期研究发现甲基苯丙胺依赖者外周血谷氨酸受体GRIA2蛋白表达升高，并与miR181负向调控有关；动物实验发现甲基苯丙胺导致小鼠前额叶囊泡型谷氨酸转运体1型（VGLUT1）表达降低，但其具体分子机制尚不清楚。本研究首先采用动物模型确定VGLUT1异常在甲基苯丙胺所致认知损害中的作用，并进一步探索VGLUT1表达异常的分子调控机制，同时采用临床队列研究，聚焦谷氨酸系统，从脑功能影像学及外周分子探索甲基苯丙胺所致认知损害的相关标志物。本项目发现甲基苯丙胺引起VGLUT1增加介导mPFC脑区谷氨酸系统异常，诱导认知损伤行为的发生，mPFC内kappa受体调控甲基苯丙胺认知损伤行为的发生，验证了谷氨酸系统异常是甲基苯丙胺成瘾的机制之一。同时在外周血生物标志物分析中发现包括抗氧化酶、超氧化产物、抗炎因子和促炎因子改变，说明在成瘾患者中出现了氧化应激和炎症反应的激活。此外，还发现心肌损害标志物、微生物及神经递质分子均发生显著异常。褪黑素与白介9水平与小脑、伏隔核及尾状核的体积显著相关。本研究对阐明甲基苯丙胺所致谷氨酸兴奋性毒性的分子机制与潜在干预靶标，建立甲基苯丙胺成瘾诊断评估客观标记物提供科学依据，并为临床实践提供了询证证据。

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