氯氮平对地卓西平马来酸盐诱导的精神分裂症大鼠前额叶皮质神经调节蛋白1基因表达的影响

Effect of clozapine on neuregulin-1 gene expression in prefrontal cortex of schizophrenic model rats induced by dizocilpine maleate

目的观察地卓西平马来酸盐(MK-801)诱导的精神分裂症模型大鼠前额叶皮质神经调节蛋白1(NRG-1)的表达及氯氮平干预后的变化,分析NRG-1基因mRNA的表达水平和动物行为之间的关系。方法 79只大鼠分为对照组(n=31)、模型组(n=36)和干预组(n=12)。对照组腹腔注射生理盐水,模型组和干预组大鼠腹腔注射MK-801,干预组大鼠在注射MK-801 5 min后给予氯氮平进行干预。采用自发活动、共济失调、刻板行为、前脉冲抑制(PPI)测试评定大鼠的精神分裂样行为。应用实时定量反转录-聚合酶链反应(RT-PCR)检测大鼠前额叶皮质NRG-1mRNA基因各亚型(Hrg、Ggf、Smdf)的表达水平。结果 3组大鼠自发活动90 min总路程、总共济失调评分、总刻板行为评分两两比较差异均有统计学意义(P<0.05);3组72、74、78 dB下PPI结果两两比较差异均有统计学意义(P<0.05)。在药物作用90 min时,模型组大鼠前额叶皮质Hrg mRNA的表达高于对照组和干预组(P<0.05),模型组Smdf mRNA的表达高于干预组(P<0.05)。模型组大鼠前额叶皮质Hrg mRNA在末次药物注射120 min时的表达低于其在0、30、60、90 min的表达(P<0.05)。大鼠前额叶皮质总NRG-1、Hrg和Smdf mRNA表达水平与自发活动的移动路程存在显著相关(P<0.05);Hrg mRNA的表达与刻板行为评分存在相关性(P<0.05)。结论 MK-801和氯氮平可影响大鼠前额叶皮质总NRG-1、Hrg、Smdf mRNA的表达,大鼠前额皮质NRG-1、Hrg、Smdf mRNA的表达水平与精神分裂样行为之间存在相关性;总NRG-1、Hrg、Smdf mRNA可能参与精神分裂症的发病。

Objective To observe the expression of neuregulin-1（NRG-1） gene in the prefrontal cortex of schizophrenic model rats induced by dizocilpine maleate（MK-801） and its changes after injection the clozapine.The relationship between NRG-1 expression and rats behaviors was analysed.Methods Seventy-nine rats were divided into control group（n=31） which were injected physiological saline,model group（n=36） which were injected MK-801 and intervention group（n=12）which were injected clozapine at 5 minutes after injection of MK-801.The schizotypic behaviors were evaluated by using spontaneous activity,ataxia,stereotyped behavior and prepulse inhibition（PPI）.Expression levels of three NRG-1 mRNA isoforms（Hrg,Ggf and Smdf） were measured by reverse transcription-polymerase chain reaction.Results There were significant differences in total distance travelled in the open-field,total scores of ataxia and stereotyped behavior scores among the control group,model group,and intervention group（P0.05）;the statistical differences of PPI under the stimulation of 72,74,78 dB white noise were also found among the three groups（P0.05） at 90 minutes after spontaneous activity.At 90 minutes after drug action,the expression of Hrg mRNA in the prefrontal cortex of rats in model group was significantly higher than those in the control group and intervention group（P0.05）;the expression of Smdf mRNA in the model group was significantly higher than that in the intervention group（P0.05）.In the model group,the expression of Hrg mRNA in the model group at 120 minutes after MK-801 injection was significantly lower than those at 0,30,60,and 90 minutes（P0.05）.Total NRG-1,Hrg,and Smdf mRNA expression levels in the prefrontal cortex were correlated with total distance travelled in the open-field（P0.05）;the Hrg mRNA expression level was correlated with stereotyped behavior scores（P0.05）.Conclusion The MK-801 and clozapine can influence the expression of NRG-1,Hrg,and Smdf mRNA.The expression levels of NRG-1,Hrg,Smdf mRNA are related with schizotypic behaviors.The total NRG-1,Hrg,Smdf mRNA may be involved in the pathogenesis of schizophrenia.