不均衡抑制5-HT/NE/DA再摄取的强度比例对抑郁治疗和改善传统抑郁药治疗缺陷的差异形成及机制

Depression remains a major public health issue. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) are the most commonly prescribed antidepressants, but they have modest remission rates, slow onset of action, do not treat some symptoms well such as fatigue, anhedonia, and cognitive impairment, and have troublesome sexual dysfunction. Putative antidepressants that can inhibit dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively) are referred to as SNDRIs and are thought to offer advantages over currently available antidepressants. It has been postulated that the enhancement of dopamine (DA) neurotransmission, in addition to 5-HT and/or NE neurotransmission, might provide superior efficacy in major depressive disorder (MDD) and diminish certain adverse events associated with SSRIs and SNRIs. Most SNDRIs failed in clinical phases because they did not illustrate the complex relationships between different 5-HT/NE/DA reuptake inhibition intensity and antidepressant therapy. So it's difficult to predict clinical efficacy and side effects through preclinical research results. Based on the orthogonal design this study will investigate eight compounds which have different 5-HT/NE/DA reuptake inhibition ratio on CUMS model to elucidate the impact that different inhibition ratio on antidepressant behavior and several signaling pathways and mechanism of different ratio resulted different therapy effects and discrepancy of traditional antidepressant therapy deficiencies. This study will also find the appropriate ratio range of 5-HT/NE/DA reuptake inhibition for antidepressant therapy and provide guiding role for new drug developments and basic experimental support for clinical researches and applications.

单胺类神经递质再摄取抑制(SSRI和SNRI)是抑郁症最主要的治疗方式，但起效缓慢，不能有效改善快感缺乏、奖励激励驱动、目标导向行为和认知能力，且易导致性功能障碍。选择性5-HT/NE/DA三重再摄取抑制剂（SNDRIs）能够克服上述缺陷，但均在临床阶段失败，主要原因是对不同强度比例抑制5-HT、NE和DA再摄取的机制和影响抑郁行为改善之间的关系不清楚，难以预测临床疗效。本课题基于正交设计，选择8个具有不同再摄取抑制强度比例特征的化合物，研究不同强度比例抑制5-HT/NE/DA再摄取对抑郁治疗和相关信号通路的调节作用，明确不同强度比例抑制5-HT/NE/DA再摄取对于发挥抑郁治疗作用和改善传统抗抑郁药治疗缺陷的差异形成及机制，并构建用于抑郁治疗的SNDRIs对于5-HT/NE/DA再摄取抑制的合理比例范围，为国内外研究SNDRIs起理论指导作用，也为其临床研究和应用提供基础实验支持。

单胺类神经递质再摄取抑制是抑郁症最主要的治疗方式，但起效缓慢，不能有效改善快感缺乏、奖励激励驱动、目标导向行为和认知能力，且易导致性功能障碍。理论上选择性SNDRIs能够克服上述缺陷，但均在临床阶段失败，主要原因是对不同特征的SNDRIs作用机制和影响抑郁行为改善之间的关系不清楚，难以预测临床疗效。本课题建立了稳定的大鼠慢性不可预知温和应激（CUMS）模型，通过对CUMS大鼠抑郁行为、快感、奖励激励驱动和目标导向行为、认知能力、性功能障碍等4个独立的具体实验研究，明确了选择性5-HT/NE/DA三重再摄取抑制剂（SNDRIs）对于抑郁治疗的优势，例如，可以在7天之内更快的起效，能够激活奖赏通路，改善快感缺失现象，增强探索和记忆能力，改善雄性动物的性功能障碍，等；实验也以PKA、ERK1/2、PKC、Akt、BDNF、CREB、mTOR、PSD95、GluA1、SEAP、ANP、LTP、GnRHR、17β-HSD3、3β-HSD1等作为信号通路的分子标志，考察相关信号通路的激活时间、活化强度，并将机制研究与行为改善和起效时间进行相关性分析，将信号通路的变化与抑郁治疗和改善传统治疗药物缺陷作用相结合，通过极差分析和方差分析，明确了不同强度抑制SERT、NET、DAT对于发挥抑郁治疗作用和改善传统再摄取抑制类抗抑郁药治疗缺陷的差异形成及分子生物学基础，构建了用于抑郁症治疗的SNDRIs的分子生物学特征，为国内外研究SNDRIs起理论指导作用，也为其临床研究和应用提供基础实验支持。