氯氮平对谷氨酸功能低下精神分裂症小鼠模型的作用

目的 观察氯氮平对地卓西平马来酸盐（MK-801）所致谷氨酸功能低下精神分裂症小鼠模型的高活动性及刻板行为的作用。方法 昆明种小鼠130只。（1）取34只小鼠分为4组：溶媒空白对照组（腹腔注射溶媒，以下简称对照组）；3种氯氮平剂量（1．0，1．5，2．0mg／kg体质量，腹腔注射）组；每组8～10只，观察氯氮平对小鼠探究行为和自主活动的影响。（2）取46只小鼠分为5组，分别为对照组、MK-801模型组（溶媒＋MK-801，0．25mg／kg体质量，腹腔注射）及3种剂量（同上）氯氮平组分别加MK-801（0．25mg／kg体质量，腹腔注射），每组8～10只，观察氯氮平对MK-致801小鼠自主活动增加的影响。（3）取50只小鼠，每组10只，给药方案同“（2）”，观察氯氮平对MK-801引起的刻板行为的影响。结果 （1）与对照组比较，氯氮平剂量为1．5mg／kg体质量和2．0mg／kg体质量时，小鼠的探究行为及自主活动总路程减少（P均〈0．001）；但剂量为1．0mg／kg时，对小鼠的探究行为及自主活动均无影响（P均〉0．05）。（2）氯氮平剂量为1．0～2．0mg／kg体质量时，呈剂量依赖性抑制由MK-801引起的自主活动增加（均P〈0．05）。（3）氯氮平剂量为1．5～2．0mg／kg体质量时，呈剂量依赖性抑制MK-801引起的刻板行为（均P〈0．05）。但低剂量（1．0mg／kg体质量）氯氮平对MK-801引起的刻板行为无明显影响（P〉0．05）。结论 氯氮平对MK-801所致谷氨酸功能低下精神分裂症小鼠模型不同脑区的作用有选择性，低剂量时抑制由中脑边缘、中脑皮质系统介导的高活动性，较高剂量时抑制由中脑边缘、中脑皮质系统及黑质纹状体系统控制的高活动性及刻板行为。

Effects of clozapine on the hypoglutamatergic schizophrenia model in mice

Objective To investigate the effects of clozapine on Dizocilpine maleate (MK-801)induced hypoglutamatergic schizophrenia model in mice.Methods (1) To investigate the effects of clozapine on explorative behavior and spontaneous activity, three doses of clozapine (1.0, 1.5, 2.0 mg/kg, i.p.) or vehicle was injected 30 min before the test. Locomotor activity was recorded for 30 min with an automated video tracking system, in which the components of the locomotor activity were divided into exploration (the first 10 min) and spontaneous activity (the second 20 min). (2) To examine the effects of clozapine on MK-801-induced hyperlocomotion and stereotyped behavior, mice were administered with clozapine (1.0, 1.5 and 2.0 mg/kg) or vehicle 5 min before administration of MK-801 (0.25 mg/kg). After the second injection, locomotor activity was recorded for 90 min by the video tracking system; stereotyped behavior was evaluated for 90 min with a ranked intensity scale by two raters who were blind to the drug treatment.Results Clozapine (1.5 and 2.0 mg/kg) significantly inhibited the explorative behavior and spontaneous activity (P<0.001). Clozapine at 1.0 mg/kg did not affect exploration and spontaneous activity (P>0.05). Clozapine (1.0-2.0 mg/kg) dose-dependently antagonized MK-801-induced hyperlocomotion. (2) Clozapine(1.5-2.0 mg/kg)dose-dependently reduced MK-801-induced stereotypy. The lowest dose (1.0 mg/kg) had no effect on stereotypy induced by MK-801. Conclusion Clozapine has the selective action on the brain region. At lower dose, clozapine selectively inhibited hyperlocomotion mediated by the mesolimbic/mesocortical system while at higher doses it inhibited hyperlocomotion and stereotypy mediated by both mesolimbic/mesocortical and nigrostriatal systems.