Effects of olanzapine on the hypoglutamatergic schizophrenia model in mice

目的 观察奥氮平对谷氨酸功能低下小鼠模型表现出的高活动性及前脉冲抑制(PPI)缺失的作用.方法 昆明种小鼠165只.(1)取36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种奥氮平剂量(0.1 mg/kg体质量,0.2 mg/kg体质量,0.3 mg/kg体质量,腹腔注射)组,每组8～10只;观察奥氮平对小鼠探究行为和自主活动的影响.(2)取49只小鼠分为5组:对照组,地卓西平马来酸盐(MK-801)模型组(溶媒+MK-801,0.25 mg/kg体质量,腹腔注射),3种剂量(同上)奥氮平干预组(奥氮平+MK-801 0.25 mg/kg体质量,腹腔注射),每组9～10只;观察奥氮平对MK-801致小鼠自主活动增加的影响.(3)取80只小鼠分为8组:对照组,MK-801模型组(溶媒+MK-801,0.5 mg/kg体质量,腹腔注射),3种奥氮平剂量给药组(奥氮平+生理盐水,奥氮平剂量分别为0.3 mg/kg体质量,1 mg/kg体质量,3 mg/kg体质量),3种奥氮平剂量(同上)干预组(奥氮平+MK-801 0.5 mg/kg体质量,腹腔注射),每组10只;观察奥氮平对基线前脉冲抑制(PPI)及MK-801引起的PPI缺失的影响.结果 (1)与对照组比较,奥氮平剂量为0.2 mg/kg体质量和0.3mg/kg体质量时,小鼠的探究行为及自主活动总路程减少(P均＜0.05);但剂量为0.1 mg/kg时,对小鼠的探究行为(P=0.363)及自主活动(P=0.196)无影响.(2)奥氮平剂量为0.1～0.3 mg/kg体质量时,呈剂量依赖性抑制MK-801引起的自主活动增加(P均＜0.05).(3)奥氮平剂量为0.3～3mg/kg体质量时,对基线的PPI无影响(P均＞0.05),剂量为1～3 mg/kg时呈剂量依赖性修复了MK-801引起的PPI缺失(P均＜0.05).结论 奥氮平能够特异性地抑制谷氨酸功能低下小鼠模型表现出的高活动性和PPI缺失,与奥氮平的临床药理作用一致.Objective To investigate the effects of olanzapine on hyperlocomotion and deficient prepusle inhibition (PPI) of hypoglutamatergic schizophrenia model in mice produced by dizocilpine maleate (MK-801), an N-methyl-D-aspartate (NMDA)antagonist.Methods (1) To investigate the effects of olanzapine on explorative behavior and spontaneous activity, three doses of olanzapine ( 0.1, 0.2, 0.3 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 olanzapine on MK-801-induced hyperlocomotion, mice were administered with olanzapine (0.1, 0.2 and 0.3 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.( 3 ) To explore the effects of olanzapine on intact and MK-801-disrupted sensorimotor gating, olanzapine (0.3, 1,3 mg/kg, i.p.) or the vehicle were injected 35 min before the start of the experiment, MK-801 (0.5 mg/kg, i.p.) or the same volume of saline was administered 5 min before the PPI experiment.Results ( 1 ) Olanzapine (0.2 and 0.3 mg/kg) significantly inhibited the explorative behavior and spontaneous activity (P ＜ 0.05 ) .Olanzapine at 0.1 mg/kg did not affect exploration ( P = 0.363 ) and spontaneous activity ( P = 0.196 ).Olanzapine (0.1 - 0.3 mg/kg) dose-dependently antagonized MK-801 -induced hyperlocomotion.(2) None of the olanzapine doses tested had a significant effect on baseline PPI.Olanzapine ( 1 - 3 mg/kg) dosedependently restored the MK-801-induced deficits in PPI.Conclusion Olanzapine specifically inhibited the MK-801-induced hyperlocomotion and deficits in PPI in mice and the results are also consistent with clinical findings.国家自然科学基金中文核心期刊要目总览(PKU)中国科技核心期刊(ISTIC)中国科学引文数据库(CSCD)02111-1154