新型抗抑郁剂JZ-1201通过5-HT1A受体调节GABA/Glu系统平衡的作用机制研究

抑郁症已成为严重的公共卫生问题，开发具有快速起效和不良反应少的抗抑郁药物是全球性的重大需求。研究发现，Glu和GABA系统失衡与抑郁症的发生关系密切。我们前期研究证实，具有5-HT1A受体部分激动和5-HT/NE重摄取抑制作用的全新三靶标化合物JZ-1201具有强效、快速的抗抑郁效应，并且可以逆转抑郁症模型小鼠海马中的Glu和GABA系统失衡。目前国内外无此类靶点组合的药物上市。本研究拟通过行为药理学、分子生物学、电生理学和光遗传学等手段，在受体、神经元电活动和神经可塑性等层面来探讨：①5-HT1A受体是否是JZ-1201快速起效抗抑郁作用的关键靶点；②通过5-HT1A受体调节前额皮层-海马-中缝背核中GABA/Glu系统平衡是否是JZ-1201抗抑郁作用的关键步骤？本研究将为JZ-1201发展成具有自主知识产权的Ⅰ类新药奠定基础，同时为快速起效的多靶标抗抑郁新药研究提供思路和方法。

Major depressive disorder has become a global public health problem of serious concern. Therefore, it is the direction to break through the classic monoamine strategy framework for developing antidepressants that have fast-acting, lower side effects, and cognitive enhancement, to satisfy the major clinical needs. Recent evidences suggested, the imbalance between Glu and GABA was the important causal factors in the precipitation of depression. We have previously found that, JZ-1201, a new chemical compound, exerted a notable antidepressant-like effect in several experimental animal models. And also, JZ-1201 could reverse the imbalance between Glu and GABA in hippocampus induced by learned helpless. With the method of behavioral pharmacology, molecular biology and cell biology, the aim of this study is to explore whether the balance between Glu and GABA is necessary for JZ-1201’s antidepressant-like effect. There are two critical questions included in this study. At first, whether 5-HT1A receptor plays an important role in JZ-1201’s antidepressant-like effect. Then, whether the antidepressant-like effects of JZ-1201 depends on the normalization of imbalance between Glu and GABA. All in all, our results would demonstrate the mechanisms for JZ-1201’s antidepressant-like effect and provide a rational and conceptual foundation for strategies for antidepressant drugs discovery and development. It is hoped that these researches will provide possible strategies for the further development of a new generation of antidepressants and provide a useful reference for the further discovery of fast-onset antidepressant candidate targets.