（一）左旋千金藤啶碱抗抑郁的药理机制研究（二）新型离子通道的功能机制探究

发布时间：2018-05-26 23:03

本文选题：抑郁症 + 认知功能　；参考：《中国科学院大学(中国科学院上海药物研究所)》2017年博士论文

【摘要】：抑郁症是一种常见神经精神类疾病,患者常表现为情绪低落、绝望、动机缺乏、快感缺失和不同程度的认知功能损伤。内侧前额叶皮质(mPFC)是主导认知、决策和情绪调控等多种功能的高级中枢,已有研究证实,mPFC多巴胺能突触传递功能减弱与抑郁症的发病密切相关。左旋千金藤啶碱(l-stepholidine,l-SPD)是一种兼有多巴胺D1型受体(D1R)部分激动和多巴胺D2型受体(D2R)拮抗双重作用的天然产物,已有证据显示,l-SPD可通过在mPFC的D1R激动作用,增强mPFC功能,从而改善精神分裂症病人的阴性症状和认知功能缺陷。但是,目前尚没有l-SPD抗抑郁作用的研究报道,因此本论文将重点研究l-SPD的抗抑郁作用及其在mPFC的药理学机制。研究结果显示,l-SPD在正常C57BL/6小鼠和慢性不可预知性温和性应激(CUMS)Sprague-Dawley大鼠抑郁症模型中均表现出较好的抗抑郁及抗焦虑作用。机制研究表明,l-SPD可在mPFC激活mTOR信号通路和增强突触相关蛋白(PSD95、Synapsin I)的表达,并且修复CUMS抑郁模型中蛋白激酶A(PKA)功能低下导致的兴奋性突触传递功能降低。在原代培养皮层神经元上的实验证实,l-SPD是通过D1R激动作用(而不是D2R拮抗作用),继而激活PKA/mTOR信号通路和增加突触相关蛋白的表达。此外电生理结果显示,l-SPD可诱发mPFC产生长时程增强(LTP),而这种增强作用可被D1R拮抗剂、PKA抑制剂和mTOR抑制剂阻断,表明l-SPD的抗抑郁作用与其在mPFC选择性激活D1R继而增强兴奋性突触传递功能有关。总之,本论文的研究结果表明,l-SPD在mPFC的D1R激动作用,会进一步激活D1R/PKA/mTOR信号通路,继而促进mPFC的突触可塑性,这可能是l-SPD的抗抑郁样药效的药理学机制。本论文的研究结果为理解中脑皮质多巴胺能系统及mTOR信号通路功能紊乱与抑郁症发病之间的关系提供新的见解,也可为针对多巴胺系统的抗抑郁的药物研发提供更多的理论依据。
[Abstract]:Depression is a common neuropsychiatric disease, patients often show depression, despair, lack of motivation, lack of pleasure and varying degrees of cognitive impairment. Medial prefrontal cortex mPFC is an advanced center that dominates cognitive decision-making and emotional regulation. It has been proved that the decrease of dopaminergic synaptic transmission function of mPFC is closely related to the pathogenesis of depression. Levofolidine is a natural product of both dopamine D1 receptor D1R partial activation and dopamine D2 receptor D2R antagonism. It has been shown that l-SPD can enhance mPFC function through D1R stimulation in mPFC. In order to improve the schizophrenia patients negative symptoms and cognitive impairment. However, there are no studies on the antidepressant effect of l-SPD, so this thesis will focus on the antidepressant effect of l-SPD and its pharmacological mechanism in mPFC. The results showed that Sprague-Dawley rats had good antidepressant and anti-anxiety effects in normal C57BL/6 mice and chronic unpredictable mild stress model CUMS Sprague-Dawley rats. It is suggested that mPFC can activate the mTOR signaling pathway and enhance the expression of synaptic associated protein PSD95 (Synapsin I), and repair the decrease of excitatory synaptic transmission induced by the low function of protein kinase (PKA) in the depression model of CUMS. In primary cultured cortical neurons, it was confirmed that PKA/mTOR signaling pathway was activated and synaptophysin expression was increased by D1R activation (not antagonistic effect of D2R). In addition, electrophysiological results showed that mPFC could be induced to produce long term potentiation, which could be blocked by D1R antagonists, such as PKA inhibitors and mTOR inhibitors. The results suggest that the antidepressant effect of l-SPD is related to the selective activation of D1R in mPFC and the enhancement of excitatory synaptic transmission. In conclusion, the results of this study suggest that the D1R activation of mPFC may further activate the D1R/PKA/mTOR signaling pathway and promote the synaptic plasticity of mPFC, which may be the pharmacological mechanism of the antidepressant effect of l-SPD. The results of this study provide new insights into the relationship between the dysfunction of the midbrain cortex dopaminergic system and mTOR signaling pathway and the pathogenesis of depression. It can also provide more theoretical basis for the development of antidepressant drugs for dopamine system.
【学位授予单位】：中国科学院大学(中国科学院上海药物研究所)
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R285.5

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（一）左旋千金藤啶碱抗抑郁的药理机制研究 （二）新型离子通道的功能机制探究

（一）左旋千金藤啶碱抗抑郁的药理机制研究（二）新型离子通道的功能机制探究