抗抑郁候选新药YL-0919对慢性应激大鼠行为及海马树突复杂性的影响

Effect of YL-0919,a new antidepressant candidate,on behavior and hippocampal dendritic complexity of chronically stressed rats

目的：研究5-羟色胺1A受体（5-HT1A）部分激动和5-羟色胺（5-HT）重摄取抑制双靶标抗抑郁候选新药YL-0919的抗抑郁作用及对树突复杂性的影响。方法每天从10种刺激中随机选1～2种连续4周建立大鼠慢性应激抑郁模型,每天应激前1 h 分别ig 给予氟西汀10 mg·kg^－1, YL-09190.625,1.25和2.5 mg·kg^－1。应激结束后第2天行开场实验观察水平运动和垂直运动,第4天行蔗糖饮水实验检测蔗糖偏嗜度,第5天行新奇抑制摄食实验检测摄食潜伏期；第6天取脑,高尔基染色法观察海马齿状回锥体神经元树突长度、分支数以及树突棘密度。结果慢性应激模型组大鼠水平运动和垂直运动显著降低,蔗糖偏嗜度显著降低,新奇抑制摄食潜伏期时间显著延长（ P＜0.01）。给予YL-09192.5 mg·kg^－1或氟西汀10 mg·kg^－1可显著逆转上述抑郁样行为改变；高尔基染色结果显示,与应激模型组比较,YL-09191.25和2.5 mg·kg^－1或氟西汀10 mg·kg^－1组海马齿状回锥体细胞树突长度分别显著增加24.3％,64.7％和76.0％（ P＜0.01）,分支数分别显著增加38.0％,118.2％和109.1％（ P＜0.01）,YL-09192.5 mg·kg^－1或氟西汀10 mg·kg^－1组树突棘密度分别显著增加20.5％和21.4％（ P＜0.05）。给予 YL-0919可显著增强树突复杂性。结论YL-0919的抗抑郁作用与保护海马齿状回锥体神经元树突结构可塑性,增强树突复杂性有关。

OBJECTlVE To investigate the effect on anti-depression and dendritic complexity of YL-0919, a novel dual-acting antidepressant with 5-HT1A receptor agonist and serotonin reuptake inhibitor properties. METHODS To apply the chronic unpredicted stress （CUS） model in rats, the animals were subjected to 1-2 stressors randomly chosen from 10 different stressors except for control non-stressed group. The vehicle or YL-0919（0.625, 1.25 or 2.5 mg·kg^-1） or fluoxetine（10 mg·kg^-1） was adminis-tered orally 1 h before the stress procedure. After 4-week stress, the open field test （ OFT ） , sucrose preference test, and novelty-suppressed feeding （ NSF） test were performed to evaluate the changes in behavior. Golgi staining was applied to evaluate the changes in dendritic length, branching points and spine density of the hippocampus pyramidal neurons. RESULTS The locomotor activity and sucrose preference of chronically stressed rats were significantly decreased, but the latency to NSF was increased, while administration of fluoxetine（10 mg·kg^-1, ig） and YL-0919（2.5 or 1.25 mg·kg^-1, ig） reversed those effects. Golgi staining showed that YL-0919 increased dendritic complexity. After adminis-tration of YL-0919 （2.5 or 1.25 mg·kg^-1, ig） and fluoxetine（10 mg·kg^-1, ig）, the total dendritic length was increased by 24. 3%, 64. 7% and 76. 0%（ P〈0. 01 ） , respectively, while the number of dendritic branching points was increased by 38.0%, 118.2%and 109.1%（ P〈0.01） , respectively. After administra-tion of YL-0919（ 2.5 mg·kg^-1 , ig） and fluoxetine（ 10 mg·kg^-1 , ig） , dendritic spine density was increased by 20.5% and 21.4%（P〈0.05）. Chronic treatment with YL-0919 increased dendritic complexity signifi-cantly. CONCLUSlON These results indicate that YL-0919 produces reliable antidepressive effect on the chronically stressed rat models. The dendritic complexity of hippocampus pyramidal neurons contrib-utes to the pathophysiology of depression, and the antidepression-like effect of YL-0919 may be related to the protection of neurons.