基于LC-MCH/MCHR1系统的抑郁形成新机制及药物靶点确认

The treatment of depression also has the disadvantages such as slow effect, incomplete symptom relief, high relapse rate and long-term medication. The main reason is that the etiology mechanism of depression is not quite clear. Therefore, it is very urgent to investigate the new etiology mechanisms and identify new targets for the development of antidepressants drugs. In the previous research, we found that the microinjection of melanin concentrating hormone (MCH) into the rat locus coeruleus (LC) could induce depressive-like behaviors, while the direct injection of MCH1 receptor(MCHR1) antagonist SNAP-94847 into LC could inhibit the depressive behaviors in depression models induced by the microinjection of MCH into LC and the intracerebroventricular injection or by the chronic administration of corticosteroid (s.c.). We also found that the effects of a novel antidepressant YH-200 might be related to the LC-MCH/MCHR1 system. From these results, it should be hypothesized that the LC-MCH/MCHR1 system may be involved in the regulation of depressive behaviors. To date, there were no reports concerned the role of LC-MCHergic system in the regulation of depression. In this research, we will investigate the new mechanism of depression formation by evaluating the LC-MCH/MCHR1 and identify the new drug target, and provide scientific experimental evidences from a new perspective and to find a new way for the treatment of depression.

抑郁症的治疗还存在起效慢、症状缓解不彻底、复发率高和长期用药等缺点。究其原因，主要是因为对抑郁症的病因学机制尚不十分清楚。因此寻求和探索新病因学机制、确认新的作用靶点对抗抑郁药的研发很有必要。课题组前期研究发现，分别在蓝斑核(LC)、侧脑室定位注射黑色素聚积激素(MCH)均可引起抑郁样行为，而LC中定位注射MCH1受体(MCHR1)拮抗剂SNAP-94847可以逆转这两种模型以及长期皮质酮引起的抑郁样行为。推测LC中MCH/MCHR1系统有可能参与抑郁的形成过程。但至今尚未见LC中MCH能系统与抑郁调控相关文献报道。此外，本课题组自主研发的新型抗抑郁药YH-200的作用机制可能与LC中MCH/MCHR1系统有关。本课题将以LC-MCH/MCHR1系统为切入点，探索抑郁形成的新机制，确认YH-200的抗抑郁作用机制及新的作用靶点，为发现新的治疗途径和方法提供科学实验证据。

抑郁症的形成机制尚未完全阐明。黑色素聚集激素（MCH）是一种由19个氨基酸组成的神经肽，在外侧下丘脑和未定带区域MCH神经元胞体合成，并广泛投射到不同的中枢神经系统，发挥多种生理作用。本实验室前期研究发现，蓝斑核中的MCH/MCH-R1系统可能参与了抑郁样行为的调控，但其具体的神经通路和分子机制尚不清楚，基于此，开展了本项目的研究。主要采用慢性不可预测性应激（CUS）模型进行了研究。发现在第7、21及28天时出现抑郁样行为，第14天时抑郁样行为消失，而出现抑郁行为时，大鼠外侧下丘脑MCH水平显著升高，未出现抑郁样行为时，MCH水平未出现明显变化；此外，对去甲肾上腺素（NE）能神经核团蓝斑核的研究表明，MCH及其受体MCH-R1与NE能神经元共表达。随CUS时间进程呈差异性变化，即在CUS 7和28天时MCH水平显著上升，MCH-R1水平显著下调；在CUS 21天时MCH水平呈上升趋势，MCH-R1水平呈下调趋势；在CUS 14D时MCH与MCH-R1均未观察到变化。表明CUS大鼠形成抑郁样行为的过程可能与外侧下丘脑及蓝斑核中MCH/MCH-R1系统的改变密切相关。大鼠蓝斑核合成NE的两个关键酶：酪氨酸羟化酶（TH）和多巴胺β羟化酶（DBH）以及NE转运蛋白（NET）的水平随慢性应激时间也呈现差异性变化，即在第7和28天出现抑郁样行为时，TH和DBH表达水平显著下调，NET的表达水平则上调；在CUS-21天时大鼠出现抑郁样行为，TH和DBH水平呈下调趋势，NET水平呈上升趋势；然而，第14天未出现抑郁样行为时，均未产生明显改变。另外，在CUS抑郁模型大鼠蓝斑核中定位注射MCH-R1拮抗剂SNAP-94847可以明显改善抑郁样行为，并使抑郁大鼠蓝斑核中MCH/MCH-R1系统和NE能系统功能恢复正常。在正常大鼠蓝斑核中直接定位注射MCH诱发抑郁样行为，而SNAP-94847通过恢复蓝斑核中的NE能系统功能，抑制抑郁样行为的形成。以上结果提示，蓝斑核-MCH/MCH-R1系统可能是通过抑制蓝斑核NE能神经元功能参与抑郁样行为的调控.