BDNF-TrkB信号通路在新型毒品K粉依赖中的作用及机制研究

氯胺酮滥用流行加剧，但其依赖形成的分子机制不明。既往的研究显示，多巴胺奖赏系统的激活可能在其中发挥了重要作用。我们前期在氯胺酮滥用小鼠模型中发现，氯胺酮诱导的中脑高多巴胺能状态与BDNF表达上调有关。结合文献，我们推测：氯胺酮可能通过BDNF-TrkB信号通路来激活多巴胺奖赏系统，导致对其产生精神依赖。为了进一步证明该假说，本研究首先将构建慢性氯胺酮滥用小鼠模型，应用动物行为学方法研究氯胺酮的成瘾规律，采用免疫组化和分子生物学方法观察氯胺酮对BDNF-TrkB信号通路的上调作用，初步阐明该信号通路在氯胺酮依赖中的作用；然后，通过立体定位注射技术证实BDNF-TrkB信号通路在氯胺酮依赖中的作用并探讨其分子机制，明确该信号通路在氯胺酮依赖中发挥作用的脑区。本研究不仅有助于阐明氯胺酮依赖形成的分子机制，而且有望为该类新型毒品成瘾治疗提供新靶点。

Ketamine abuse has been increasing rapidly, but the mechanism of ketamine dependence remains elusive. Numerous studies have shown that dopamine rewarding system had played a vital role in the formation of drug dependence. In our previous study, we have found that high dopaminergic status induced by chronic ketamine treatment was related to up-regulated BDNF expression in a ketamine abuse animal model. Together with literature, we hypothesize that ketamine activates dopamine rewarding system via BDNF-TrkB signaling pathway during the formation of dependence. To test the hypothesis, a ketamine abuse model will be established in ICR mice to examine the role of BDNF-TrkB signaling pathway in the process of ketamine dependence and withdrawal. Firstly, effects of ketamine on BDNF-TrkB signaling pathway will be examined by immunohistochemistry and Western Blot. Secondly, blocking agent or BDNF will be delivered to specific brain regions through stereotactic surgery to inhibit or activate the pathway, and then the animal behavioral studies will be performed to examine their effects on psychological dependence and withdrawal symptoms and to clarify the brain regions which invovled in ketamine dependence. The present study will not only elucidate the mechaninsm of ketamine dependence, but also prvovide new target to beat the newly abuse drug.