目的：通过构建普通攻击大鼠和病理性攻击大鼠模型，探讨PSD-95阻断剂（ZL006）对不同性质大鼠攻击行为的作用及机制。
方法：构建普通攻击和病理性攻击大鼠模型各18只，并同时正常饲养对照组大鼠（18），后将每组大鼠随机分为模型+ZL006组、模型+Nacl组、对照+ZL006组、对照+Nacl组，分别给予ZL006（1.0 mg/kg i.p.）和生理盐水(2ml/只)腹腔注射，利用居住-入侵实验检测各组大鼠攻击行为， Western blot检测海马区突触后致密物（PSD-95）、神经元型一氧化氮合酶（nNOS）及海马糖皮质激素受体（GR）的表达，并进一步采用ELISA试剂盒检测血清糖皮质激素含量。
结果：模型+ZL006组攻击总次数低于模型+Nacl组（p<0.05）。模型+ZL006与模型+Nacl组大鼠海马区PSD-95和nNOS水平均差异无统计学意义（p>0.05）。病攻+ZL006组与病攻+Nacl组、正常+ZL006组与正常+Nacl组相比海马区GR表达差异无显著性（p>0.05），而普攻+ZL006组GR表达则低于普攻+Nacl组（p<0.05），且打药后普攻+ZL006组血清糖皮质激素水平低于普攻+Nacl组（p<0.05）。
结论：ZL006可改善普通攻击大鼠攻击行为，而同等剂量下的ZL006对病理性攻击大鼠攻击行为无明显改善作用。
关键词：普通攻击行为；病理性攻击行为；PSD-95阻断剂（ZL006）；糖皮质激素；海马
The Effects of PSD-95 Blocker (ZL006) on Different Styles of Aggression in Rats
ZHAO Yuan1, CAI Ya-lan1 ,CHEN Zhu1, QU Yuan1, QIN Guang-cheng2, CHEN Li-xue2, HU Hua1*
1.Department of Psychiatry, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
2.Experimental Research Center, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
Abstract
Objective: To explore the effects of PSD-95 blocker (ZL006) on aggression of rats and it′s underlying neuroregulation mechanism by establishment of aggression rat models.
Methods: Choose 6 rats from every group randomly after establishments of 18 normal aggression model rats(NA),18 pathological aggression model rats（PA）and 18 control rats (fed as normal). Aggressive behaviors were tested by resident-intruder test. expression of PSD-95, neuronal nitric oxide synthase (nNOS) and glucocorticoid receptor (GR) were tested by Western Blot. The level of glucocorticoid in serum was examed by ELISA kit. Randomized the left rats into PA+ZL006, PA+Nacl, NA +ZL006, NA+Nacl, Control (Ctrl)+ZL006, Ctrl+Nacl groups.ZL006 (1.0 mg/kg i.p.) and Nacl (2ml/per) were given respectively once every three days for 2 weeks. Aggressive behaviors and biomarkers were tested as previously mentioned.
Results:(1)The amount of aggressive behavior and pathological aggression of PA was higher than NA group and Ctrl group（p<0.01）. The expression of GR in hippocampus of PA was higher than other two groups（p<0.01）. PSD-95 and nNOS of PA was lower than NA and Ctrl group（p<0.01）, as well as level of glucocorticoid in serum（p<0.01）. (2)After intervention, aggressive behavior of NA and glucocorticoid in serum were decreased (p<0.05). The expression of GR in hippocampus of NA+ZL006 was lower than NA+Nacl（p<0.05）. However, it did not affect expression of PSD-95 and nNOS （p＞0.05）. There was no significant difference between ZL006 and Nacl in PA groups, as well as control groups（p＞0.05）.
Conclusions: ZL006 can reduce aggressive behavior of normal aggression rats models, but no obvious effects on aggressive behavior of pathological aggression rats models were found on same dosage of ZL006.
Key words : normal aggression; pathological aggression;PSD-95 blocker(ZL006)；glucocorticoid; hippocampus
暴力攻击行为危害社会和谐及民众财产，是众多精神疾病患者易出现的危险症状之一[]，其发生发展及治疗成为近年来的研究热点。根据攻击行为严重程度，将攻击行为分为一般（普通）攻击和病理性攻击行为[]。一般攻击行为，常见于脑损伤、癫痫、阿尔茨海默病、酒精滥用、精神分裂症、注意力缺陷多动障碍等精神疾病，常与外伤或突发性应激事件有关，其中还包括抑郁症患者发生自残、自伤行为也被认为是个体对自己产生的攻击行为。有别于普通攻击行为，病理性攻击行为是超出种属特异性的，表现为手段凶残且冷血无情，可见于品行障碍、反社会性人格障碍患者。
大量研究证实，攻击行为的发生与下丘脑、前额叶皮层及海马等攻击中枢神经损伤有关。突触后致密物-95（postsynaptic density,PSD-95）是兴奋性神经元突触后膜上的特殊结构，由受体、支架蛋白及细胞内信号转导分子组成，是神经突触可塑性的特异性指标之一，与神经兴奋性密切相关，在神经发育、突触可塑性及神经元损伤与修复中发挥重要的作用[]。早年应激可造成神经突触可塑性损伤，进而影响神经功能。
PSD-95整合nNOS-NMDA信号通路是一条特异性通路，即PSD-95仅能通过nNOS信号通路传导信息[]。PSD-95阻断剂（ZL006）是NMDAR/PSD-95/nNOS复合物解耦联剂，其对于脑缺血、缺氧的有效改善，已得到众多研究证实，该药物在体内有非常好的神经保护作用并能改善缺血损伤[]。ZL006特异性阻断PSD-95信号通路，不会抑制NMDAR的功能，对动物的空间记忆能力无影响[]。小剂量(1mg/Kg)的PSD-95阻断剂(NA-1)还具有抗抑郁的作用[]，而ZL006对攻击行为的作用尚未有研究报道。因此，本研究旨在探索PSD-95阻断剂（ZL006）对不同性质大鼠攻击行为的作用及相关神经可塑性和神经内分泌的调节作用，从而为攻击行为的发生机制及治疗提供新的研究靶点。
