背侧纹状体miRNA-30a/miRNA-134/miRNA-485网络对甲基苯丙胺成瘾的调节作用

Amphetamine-type stimulants (ATS) abuse has been spread widely in China. Compared with those of traditional drugs, such as heroin and cocaine, the pharmacological actions and addiction mechanisms of ATS are more complex, and the damages to central nervous system of ATS are more severe. Drug addiction is a continuous development from accidental and regular drug use to compulsive drug use, and compulsive drug use behavior is the core characteristics. Therefore, finding the specific neurobilogical mechanism of compulsive drug use, as compared with regular drug use, is important to accuratly understand the essence of drug addiction. Nowadays, it has been increasing attention to the role of miRNAs in drug addiction. It has been realized that drosal striatum is one of key brain regions in compulsive drug use. In rat methamphetamine self-administration model with the characteristic of compulsive drug use, we found that miR-30a, miR-134 and miR-485 in expressed differentially drosal striatum. Therfore, the project is aimed to illuminate the relationship between the miR-30a/miR-134/miR-485 network and methamphetamine-induced compulsive drug use, and investigating the molecular mechnism of this miRNA network participating in compulsive drug use behavior. Through this research, it will lay a foundation to illuminating the mechanisms of drug addiction.

苯丙胺类兴奋剂（ATS）滥用已在我国广泛流行。与传统毒品相比，ATS的药理作用和成瘾机制更复杂，对中枢神经系统损伤更严重。药物成瘾是从偶然用药、规律用药发展为强迫性用药的过程，强迫性用药是成瘾的核心特征。因此，与规律性用药相对比, 发现强迫性用药行为特有的神经生物学机制，是准确理解药物成瘾机制的关键。miRNA在药物成瘾中的作用越来越受到关注。背侧纹状体（dStr）是强迫性用药行为的关键核团之一，我们前期在强迫性用药特征的大鼠甲基苯丙胺自身给药模型中发现了dStr中miR-30a、miR-134和miR-485差异表达。本课题拟继续研究miR-30a/miR-134/miR-485网络与甲基苯丙胺强迫性用药行为的相关性；并从miR-30a靶向TNRC6A调节miR-134、miR-485对其靶基因转录后抑制的角度研究此miRNA网络参与强迫性用药行为的分子机制，为阐明药物成瘾机制奠定基础。

甲基苯丙胺（MA）滥用在我国乃至世界范围内增长迅猛。相比于海洛因、可卡因等传统毒品，MA的成瘾性更强、中枢神经系统损害更严重，但对MA成瘾的研究较为滞后，国内外尚无批准的治疗药物。药物成瘾是从偶然用药、规律性用药转变为强迫性用药的连续过程，其中强迫性用药是成瘾的核心特征，是构成毒品危害和复吸的主要原因。但是几十年来的研究主要集中在偶然用药和规律性用药阶段，而对强迫性用药的研究很少，尤其是其分子机制尚不清楚。本项目研究了miRNAs在MA强迫性用药中的作用，首先发现在MA自身给药大鼠中，强迫性用药导致大鼠背侧纹状体中的miR-30a表达下调、而miR-134和miR-485表达上调。进一步研究发现，MA规律性用药转变为强迫性用药时，诱导miR-30a的表达下调由控制目标导向行为的伏隔核过渡到控制刺激-反应习惯行为的背外侧纹状体（dlStr）；且dlStr的miR-30a负性调控MA强迫性用药行为，机制与靶分子Tnrc6a无关，可能是通过靶分子BDNF作用于TrkB受体及其下游PI3K通路实现的。对参与突触传递及可塑性的另一关键分子miR-134的研究发现，MA强迫性用药特异性诱导dlStr内miR-134表达上调，此作用依赖于习惯学习；而dlStr的miR-134可能通过靶分子LIMK1正性调控MA强迫性用药行为。综上所述，本项目发现dlStr中miR-30a及miR-134对MA强迫性用药的调节作用及可能机制，从分子水平支持了dlStr介导的S-R习惯形成是由规律性药物使用向强迫性药物使用及成瘾过渡的重要机制的假说，为精确阐明药物成瘾的机制提供了实验证据。