Olanzapine improves deficient sensory inhibition in DBA/2 mice.
Olanzapine improves deficient sensory inhibition in DBA/2 mice.
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DOI：
10.1016/j.brainres.2008.07.057
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发表时间：
2008-10-03
期刊：
影响因子：
2.9
通讯作者：
Stevens KE
中科院分区：
文献类型：
--
作者：
Simosky JK;Freedman R;Stevens KE
大多数精神分裂症患者对第二次重复的听觉刺激并不能抑制其P50听觉诱发电位，这反映了对不相关的感觉输入抑制反应的失败。典型的抗精神病药物不能改善这种缺陷，而一些非典型的抗精神病药物可以。先前的一项研究使用动物模型，在DBA/2小鼠中缺乏P20-N40（对应于人类P50）抑制加工，发现氯氮平（典型的非典型抗精神病药）改善了感觉抑制，但氟哌啶醇（典型的抗精神病药）没有改善。氯氮平后的改善是由α7烟碱受体介导的。本研究探讨了另一种非典型抗精神病药奥氮平是否也会改善小鼠模型中的感觉抑制缺陷。研究了奥氮平单独（0.01、0.033、0.1、0.33 mg/kg， IP）和奥氮平有效剂量（0.033 mg/kg， IP）联合α7烟碱受体拮抗剂α-班加罗毒素或α4β2烟碱受体拮抗剂二氢-β-红啶后，自发性出现精神分裂症样抑制性加工缺陷的DBA/2小鼠P20-N40听觉诱发电位的电生理记录。所有剂量的奥氮平均能改善DBA/2小鼠的P20-N40抑制加工。0.033 mg/kg剂量奥氮平后观察到的正常化是由于对第二听觉刺激的反应选择性降低，表明抑制性加工增加。α-班加罗毒素可阻断这种改善，而二氢-β-红胞嘧啶则不能。与氯氮平一样，奥氮平通过α7烟碱受体起作用，引起听觉刺激的抑制性加工的改善。
Most schizophrenia patients do not inhibit their P50 auditory evoked potential to the second of duplicate auditory stimuli, reflecting a failure to inhibit responses to irrelevant sensory input. Typical antipsychotic drugs do not improve this deficit while some atypical antipsychotics do. A previous study using an animal model, deficient P20-N40 (which corresponds to the human P50) inhibitory processing in DBA/2 mice found that sensory inhibition was improved by clozapine, the prototypical atypical antipsychotic, but not by haloperidol, a typical antipsychotic. The improvement after clozapine was mediated by α7 nicotinic receptors. The present study addresses whether another atypical antipsychotic, olanzapine, will also improve sensory inhibition deficits in the mouse model. In vivo electrophysiological recordings of the P20-N40 auditory evoked potential in anesthetized DBA/2 mice, which spontaneously exhibit a schizophrenia-like inhibitory processing deficit, were obtained after olanzapine alone (0.01, 0.033, 0.1, 0.33 mg/kg, IP) and the efficacious dose of olanzapine (0.033 mg/kg, IP) in combination with either the α7 nicotinic receptor antagonist α-bungarotoxin or the α4β2 nicotinic receptor antagonist di-hydro-β-erythroidine. All doses of olanzapine produced improved P20-N40 inhibitory processing in DBA/2 mice. The normalization observed after the 0.033 mg/kg dose of olanzapine was due to a selective decrease in response to the second auditory stimulus indicating an increase in inhibitory processing. This improvement was blocked by pre-administration of α-bungarotoxin but not di-hydro-β-erythroidine. Like clozapine, olanzapine acts via α7 nicotinic receptors to elicit improved inhibitory processing of auditory stimuli.
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