阿戈美拉汀拮抗5-HT2C受体治疗抑郁症的机制初探

Agomelatine is a novel antidepressant with melatonin MT1/MT2 receptor agonist and serotonin 5-HT2C receptor antagonist properties. Because of its peculiar pharmacological profile, this drug caters the potential to improve both sleep disturbances and depressive symptomatology. At present, about the antidepressant mechanism of agomelatine, researchers mainly focused on it as MT receptor agonist, but ignored that it can also antagonize 5-HT2C receptors. In our prelimiary study, we found that the expression of 5-HT2C receptor mRNA in suprachiasmatic nucleus (SCN) of depressed rats was significantly higher than that of normal rats. Therefore, based on our previous work, we plan to establish a model of depression associated with sleep disorders to detect whether the actions of agomelatine as a 5-HT2C receptor antagonist are located within the SCN, and to investigate the effect and molecular mechanisms. The expected outcome of this study will provide new evidence to help to open new avenues for the discovery of antidepressive agents.

阿戈美拉汀是近年来新上市的一种抗抑郁药物，具有激动褪黑素MT1/MT2受体和拮抗五羟色胺5-HT2C受体的双重作用，其优点在于抗抑郁治疗的同时能有效的调节睡眠障碍。目前关于阿戈美拉汀抗抑郁作用机制的研究，主要集中在MT受体激动剂方面，作为5-HT2C受体拮抗剂的研究较少。本项目拟在我们前期研究发现，慢性温和性刺激获得的抑郁症模型大鼠SCN内5-HT2C受体mRNA表达上调的基础上，利用抑郁症伴睡眠障碍大鼠模型，从5-HT2C受体的角度探讨阿戈美拉汀发挥抗抑郁作用的靶点在SCN，并初步探讨其抗抑郁作用的机制，为抗抑郁药物的研究提供新的思路。

阿戈美拉汀是近年来新上市的一种抗抑郁药物，具有激动褪黑素受体和拮抗五羟色胺5-HT2C受体的双重作用，其优点在于抗抑郁治疗的同时能有效的调节睡眠障碍。目前关于阿戈美拉汀抗抑郁作用机制的研究，主要集中在褪黑素受体激动剂方面，作为5-HT2C 受体拮抗剂的研究较少。本项目拟在我们前期研究发现，慢性温和性刺激获得的抑郁症模型大鼠SCN内5-HT2C受体mRNA表达上调的基础上，采用离体电生理的方法，使用体外大鼠脑切片模型，发现了阿戈美拉汀、褪黑素和选择性5-HT2C受体拮抗剂S32006均能浓度依赖性的抑制SCN神经元放电频率，给予褪黑素受体拮抗剂或5-HT2C受体激动剂能部分逆转阿戈美拉汀的抑制作用，证明了阿戈美拉汀通过作用于褪黑素受体和5-HT2C受体调节SCN神经元活动，为抗抑郁药物的研究提供新的思路。