精神分裂症社会行为动物模型的建立及抗精神病药的影响

Social behavior in animal model of schizophrenia and the effects of antipsychotics

目的:观察非竞争性N-甲基-D-天冬氨酸受体拮抗剂苯西克定长期应用对小鼠社会行为的影响,建立精神药理学研究用精神分裂症社会行为动物模型,并观察不同抗精神病药物对小鼠模型的干预作用。方法:实验于2003-06/09在日本名古屋大学医学部动物实验室完成。①实验1,苯西克定剂量及用药时间对小鼠社会行为的影响:选用6周龄的DDY种雄性小鼠,在饲养2周后,被抽签随机分成5组,每组12只,两笼饲养。高剂量苯西克定长期用药组:10mg/kg,14d;低剂量苯西克定长期用药组:3mg/kg,14d;长期用药对照组:生理盐水,14d;高剂量苯西克定短期用药组:10mg/kg,7d;短期用药对照组:生理盐水,7d。所有药物均采用皮下注射方式。在停药第3,7,14,21,28天分别进行社会行为测验。②实验2,抗精神病药对苯西克定小鼠社会行为的影响:另选小鼠60只分为5组,每组12只,分两笼饲养。大剂量氯氮平组:连续注射大剂量苯西克定14d,停药14d后注射氯氮平10mg/(kg·d)7d;小剂量氯氮平组:连续注射大剂量苯西克定14d,停药14d后注射氯氮平3mg/(kg·d)7d;大剂量氟哌啶醇组:连续注射大剂量苯西克定14d,停药14d后注射氟哌啶醇3mg/(kg·d)7d;小剂量氟哌啶醇组:连续注射大剂量苯西克定14d,停药14d后注射氟哌啶醇1mg/(kg·d)7d;生理盐水组:连续注射生理盐水14d,停14d后注射生理盐水7d。各组在停止氯氮平、氟哌啶醇或生理盐水后当日和7d后进行社会行为测验。结果:120只小鼠均进入结果分析,中途无脱落。①实验1显示,高剂量苯西克定长期用药组小鼠停药后3,7,14,21,28d进行社会行为的时间减少眼(16.8±4.3),(13.4±3.5),(15.5±3.9),(28.2±5.0),(32.5±4.9)s,P<0.01演,这一效果在停药后第28天仍然存在。②实验2显示,高剂量苯西克定连续用药所导致小鼠社会行为的减少在给予氯氮平连续7d的治疗后这一现象明显改善穴用药前押(13.8±1.6)s熏停药当天押(143.1±36.1)s熏停药7d后押(64.8±10.3)s熏P<0.01,P<0.05雪,小剂量氯氮平用药7d后苯西克定所致小鼠社会行为的减少没有改变。氯氮平对苯西克定所致小鼠社会行为的改善在停药1周后其作用消失。氟哌啶醇对苯西克定所致小鼠社会行为的影响没有改善作用。结论:10mg/kg苯西克定长期用药可所导致小鼠社会行为减少,10mg/(kg·d)氯氮平可逆转以上苯西克定的作用,提示10mg/kg苯西克定长期用药所致小鼠行为改变可作为抗精神病药物治疗精神分裂症社会行为的动物模型。

AIM： To observe the effect of long-time intake of phecyclidine （PCP）, the receptor antagonist of noncompetitive N-methyl-D-aspartic acid （NMDA）, on the social behavior of mice, and establish animal models of schizophrenia as well as observe the interventional effects of different antipsychotics on mouse models. METHODS： The experiment was conducted in the Animal Laboratory of Medical Department, Nagoya University of Japan between June and September 2003. ① First experiment, the effects of PCP on social behavior of mice at different dose and administration time： 60 DDY male mice of 6 months old were randomly divided into 5 groups after 2-week feeding with 12 mice in each group and fed in two separate coops. Mice in high-dose long-term PCP group were treated with 10 mg/kg for 14 days. Mice in low-dose long-term PCP group were treated with 3 mg/kg for 14 days, and mice in long-term administration control group were treated with normal saline for 14 days. Mice in high-dose short-term PCP group were treated with 3 mg/kg for 14 days. Mice in long-term administration control group were treated with normal saline for 14 days. Mice in high-dose short-term PCP group were treated with 10 mg/kg for 7 days. Mice in short-term administration control group were treated with normal saline for 7 days. All mice were administrated by subcutaneous injection. The social behaviors of mice were tested respectively on the 3^rd, 7^th, 14^th, 21^st and 28^th day after drug withdrawal. ② Second experiment. The effects of antipsychotics PCP on the social behaviors of mice： another 60 mice were randomly divided into 5 groups with 12 rats in each group, which were fed in two separate coops. Mice in high-dose clozapine group were continuously injected with high-dose PCP for 14 days, and then were injected with clozapine 3 mg/kg per day for 7 days at 14 days after withdrawal. Mice in high-dose aloperidin group were continuously injected with high dose of PCP for 14 days and then were injected with aloperidin 3 mg/kg per day for 7 days at 14 days after withdrawal. Mice in low-dose aloperidin group were continuously injected with high-dose alperidin for 14 days, and then were injected with alperidin 1 mg/kg per day for 7 days. Mice in the normal saline group were continuously injected with normal saline for 14 days and then were injected with normal saline for 7 days at 14 days after withdrawal. Social behaviors were tested on withdrawal day and 7 days after withdrawal. RESULTS： All of 120 mice were involved in the analysis of results, and no one withdrew from the study. ① The first experiment showed that the social behavior of rats in the high-dose long-term PCP group were reduced respective on the 3^rd, 7^th, 14^th, 21^st and 28^th day after withdrawal [（16.8±4.3）, （13.4±3.5）, （15.5±3.9）, （28.2±5.0）, （32.5±4.9） s, P 〈 0.01], which continued on the 28th day after withdrawal. ② The second experiment showed that the social behavior deficit of mice induced by continuous administration of high-dose PCP was obviously ameliorated at 7 days after continuous treatment with clozapine [before administration： （13.8②1.6） s, the day of drug withdrawal： （143.1②36.1） s, 7 days after withdrawal： （64.8②10.3） s, P 〈 0.01, P 〈 0.05]. There was no changes in the social behavior deficit of mice induced by low-dose of clozapine and PCP at 7 days after that. The effect of clozapine on social behavior of mice induced by PCP was attenuated at one week after withdrawal. There was no ameliorating effect of aloperidin on the social behavior of mice induced by PCP. CONCLUSION： The social behavior of mice can be reduced by long-term administration of PCP （10 mg/kg）, while the clozapine （10 mg/kg·day） has anti-effect on that mentioned above, which indicate that long-term administration of PCP, which can change the social behavior of mice, can be taken as the antipsychotics in the treatment of social behavior animal model of schizophrenia.