Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism.
Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism.
复制标题
氯氮平通过烟碱胆碱能机制改善 DBA/2 小鼠的抑制性听觉处理缺陷。
DOI：
10.1007/s00213-002-1285-x
复制
发表时间：
2003
影响因子：
3.4
通讯作者：
Freedman,Robert
中科院分区：
文献类型：
--
作者：
Simosky,JohannaK;Stevens,KarenE;Adler,LawrenceE;Freedman,Robert
在大多数精神分裂症患者中观察到P50听觉诱发电位（AEP）的抑制性处理不足，并且不能被典型的抗精神病药物（如氟哌啶醇）改善。这种抑制性加工缺陷与海马α7烟碱受体（nAChR）的低于正常水平有关，激活这些受体的药物使缺陷正常化。非典型抗精神病药氯氮平也正常化这种赤字在精神分裂症patients.Objective. Similarly精神分裂症患者，DBA/2小鼠自发表现出缺陷的抑制处理的P20-N40 AEP，这是一个啮齿类动物的类似物的人P50 AEP。本研究确定了氯氮平是否改善了DBA/2小鼠的这种缺陷，以及通过何种机制。方法：使用配对听觉刺激的条件测试范式来评估DBA/2小鼠抑制性P20-N40 AEP加工，氯氮平（0.1，1，3.33，或10 mg/kg，i. p.）和氟哌啶醇（lmg/kg，i. p.）进行了评估。氯氮平（1 mg/kg）单独给药和预先给药α7 nAChR拮抗剂α-银环蛇毒素或α4β2 nAChR拮抗剂二氢-β-赤藓定后，均能改善DBA/2小鼠P20-N40 AEP抑制加工的不足，且呈剂量依赖性。与α7激动剂一样，1 mg/kg氯氮平选择性地增加了对第二个成对听觉刺激的P20-N40反应的抑制。1 mg/kg氯氮平的正常化作用可被α-银环蛇毒素阻断，但不被二氢-β-赤藓定碱阻断。氟哌啶醇不能改善DBA/2小鼠P20-N40 AEP加工缺陷。结论：氯氮平改善DBA/2小鼠P20-N40 AEP抑制加工缺陷，这可能是通过刺激α7烟碱受体实现的。典型的抗精神病药物氟哌啶醇不具有这种作用。
AbstractRationale.Insufficient inhibitory processing of the P50 auditory evoked potential (AEP) is observed in most schizophrenia patients and is not improved by typical antipsychotic drugs, such as haloperidol. This inhibitory processing deficit is associated with a subnormal level of hippocampal α7 nicotinic receptors (nAChRs), and drugs that activate these receptors normalize the deficit. The atypical antipsychotic clozapine also normalizes this deficit in schizophrenia patients, but by an unknown mechanism.Objective.Similar to schizophrenia patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 AEP, which is a rodent analogue of the human P50 AEP. The present study determined whether clozapine improved this deficit in DBA/2 mice, and by what mechanism.Method.Using a conditioning-testing paradigm with paired auditory stimuli to assess inhibitory P20-N40 AEP processing in DBA/2 mice, the effects of clozapine (0.1, 1, 3.33, or 10 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) were assessed. The effect of clozapine (1 mg/kg) was assessed alone and after pre-administration of either α-bungarotoxin, an α7 nAChR antagonist, or dihydro-β-erythroidine, an α4β2 nAChR antagonist.Results.In a dose-dependent manner, clozapine improved the deficient inhibitory processing of the P20-N40 AEP normally exhibited by DBA/2 mice. Like α7 agonists, 1 mg/kg clozapine selectively increased the inhibition of the P20-N40 response to the second of paired auditory stimuli. The normalizing effect of 1 mg/kg clozapine was blocked by α-bungarotoxin, but not by dihydro-β-erythroidine. Haloperidol did not improve DBA/2's deficient P20-N40 AEP processing.Conclusions.Clozapine improved the deficient inhibitory processing of the P20-N40 AEP in DBA/2 mice, apparently through stimulation of α7 nicotinic receptors. This effect was not shared by the typical antipsychotic haloperidol.