PSD-95信号通路介导5-HT1A受体激动剂改善大鼠病理性攻击行为的调控机制

Mediated mechanism of PSD-95 signaling pathway in 5-HT1A receptor agonist reducing pathological aggression in rats

目的探索突触后致密物-95(postsynaptic density-95,PSD-95)信号通路是否参与并介导5-HT1A受体激动剂对大鼠病理性攻击行为的改善作用及调控机制。方法将成功构建的24只病理性攻击大鼠按照抽签法分为4组,分别为8-OH-DPAT组、8-OH-DPAT+ZL006组、ZL006组、Na Cl组,5-HT1A受体激动剂(8-OH-DPAT)以1 mg/kg每日腹腔注射并持续2周、PSD-95阻断剂(ZL006)以1 mg/kg每隔3天腹腔注射并持续2周。分别在给药前、给药1周后及给药2周后用居住-入侵实验测试大鼠病理性攻击行为变化,且每次居住-入侵实验前取大鼠眼眶后静脉血。取前额叶皮层、大鼠海马及下丘脑组织,用Western blot检测各脑区五羟色胺1A受体(serotonin 1A receptor,5-HT1AR)、PSD-95及糖皮质激素受体(glucocorticoid receptor,GR)的表达,并采用ELISA试剂盒检测血清糖皮质激素含量。结果 8-OH-DPAT组大鼠攻击总数、攻击持续时间及攻击要害部位比在给药1周及2周后均有明显下降(P<0.05);8-OH-DPAT+ZL006组大鼠仅在给药1周后有降低(P<0.05)。Western blot检测结果显示8-OH-DPAT组、8-OH-DPAT+ZL006组前额叶皮层及海马5-HT1A受体表达均高于其余两组(P<0.05);8-OH-DPAT组大鼠前额叶皮层及海马PSD-95表达高于其余3组(P<0.05);且该组海马GR表达低于其余3组(P<0.05);各组大鼠下丘脑5-HT1AR、PSD-95表达差异无统计学意义(P>0.05)。ELISA结果显示:给药2周后8-OH-DPAT组血清糖皮质激素浓度有明显上升(P<0.05),而其余3组在干预前后血清糖皮质激素无明显变化(P>0.05)。结论 PSD-95信号通路参与并介导了5-HT1A受体激动剂(8-OH-DPAT)对大鼠病理性攻击行为的改善作用,可能是通过对血清糖皮质激素的调控而发挥作用。

Objective To explore the mediated effect of postsynaptic density-95 （PSD-95） signaling pathway on pathological aggression reduced by 5-HT1A receptor agonist in rats. Methods Twentyfour pathological aggression rats were randomly assigned to 4 groups, that is, 8-OH-DPAT, 8-OH-DPAT＋ZL006, ZL006, and NaCl groups. The rats were given corresponding treatment, 1 mg/kg 5-HT1A receptor agonist （8-OH-DPAT） i.p. for 2 consecutive weeks, and/or 1 mg/kg PSD-95 blockade （ZL006） i.p. every 3 days for 2 weeks. Resident-intruder test was taken respectively before intervention, in 1 and 2 weeks after intervention. After the test, blood sample was harvested from posterior orbital vein. Expression of serotonin 1A receptor （5HT1AR）, PSD-95 and glucocorticoid receptor （GR） in prefrontal cortex, hippocampus and hypothalamus were measured by Western blotting. The serum level of glucocorticoid was tested by ELISA. Results For the aggressive behaviors, attack times, duration of attack and ratio of attack to key parts of body were all decreased in the 8-OH-DPAT group in 1 and 2 weeks after treatment （P〈0.05）. While, the declines were only found in the 8-OH-DPAT＋ZL006 group in 1 week after treatment （P〈0.05）. Western blotting showed that the expression of 5HT1AR in prefrontal cortex and hippocampus were significantly higher in the 8-OH-DPAT and 8-OH-DPAT＋ZL006 groups than the other 2 groups （P〈0.05）, and in the 8-OH-DPAT group, the expression of PSD-95 in the prefrontal cortex and hippocampus was obviously higher, and that of GR in hippocampus was notably lower than the other 3 groups （P〈0.05）. There were no significant differences in the 5-HT1AR and PSD-95 levels in the hypothalamus among the 4 groups （P〉0.05）. The results of ELISA showed the serum glucocorticoid level was obviously increased in the 8-OH-DPAT group in 2 weeks after treatment （P〈0.05）, but no such increase was seen in the other 3 groups （P〉0.05）. Conclusion PSD-95 signaling pathway takes part in and mediates the attenuation of pathological aggressive behaviors induced by 5-HT1A receptor agonist （8-OH-DPAT）, which probably through its increasing effect on serum glucocorticoid.