Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice
Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice
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DOI：
10.1007/s00213-003-1635-3
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发表时间：
2004-03-01
影响因子：
3.4
通讯作者：
Geyer, MA
中科院分区：
文献类型：
--
作者：
Brody, SA;Conquet, F;Geyer, MA
基本原理。休克反应的脉冲前抑制（PPI）是一种感觉运动门控模型，在精神分裂症患者中是缺乏的。在啮齿类动物中，PPI诱导缺陷的逆转证明了确定抗精神病药物的预测有效性。代谢性谷氨酸受体5 （mGluR5）与精神分裂症有关，部分原因是mGluR5敲除（KO）小鼠表现出PPI缺陷。我们研究了mGluR5 KO小鼠是否可以作为检测抗精神病药物的新模型。方法。使用C57BL/6J或129SvPasIco小鼠，我们首先确定了典型抗精神病药氯氯pride或非典型抗精神病药氯氮平的剂量，它们分别有效阻断安非他明或氯胺酮的ppi破坏作用。然后，我们检查了这些剂量对mGluR5 KO小鼠PPI缺陷的影响。结果。服用氯氯pride或氯氮平可以逆转安非他明或氯胺酮引起的PPI缺陷，就像在之前的研究中新型情绪稳定剂拉莫三嗪一样。相比之下，mGluR5 KO小鼠的PPI缺陷没有被给予氯氯pride、氯氮平或拉莫三嗪改变。血清素（2A）拮抗剂M100,907在逆转PPI患者的mGluR5 KO缺陷方面也无效。结论。大多数检测的化合物至少改善了药理学诱导的PPI缺陷的一部分。没有一种抗精神病药物能减轻mGluR5 KO小鼠的PPI缺陷，这表明该模型不能预测已知的精神分裂症治疗方法，但并不排除mGluR5受体在精神分裂症或其他精神疾病中的作用。
Rationale. Prepulse inhibition of the startle response (PPI), a model of sensorimotor gating, is deficient in persons with schizophrenia. In rodents, the reversal of induced deficits in PPI demonstrates predictive validity for identifying antipsychotic treatments. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in schizophrenia, in part because mGluR5 knockout (KO) mice exhibit PPI deficits.Objective. We examined whether mGluR5 KO mice might serve as a novel model for detecting antipsychotic treatments. Methods. Using C57BL/6J or 129SvPasIco mice, we first determined doses of the typical antipsychotic raclopride or the atypical antipsychotic clozapine that were effective in blocking the PPI-disruptive effects of amphetamine or ketamine, respectively. We then examined the effects of these doses on the deficit in PPI in mGluR5 KO mice. Results. Administration of raclopride or clozapine reversed either an amphetamine or a ketamine-induced PPI deficit, as had the novel mood stabilizer lamotrigine in previous studies. In contrast, the PPI deficit of the mGluR5 KO mice was not altered by administration of raclopride, clozapine, or lamotrigine. The serotonin(2A) antagonist M100,907 was also ineffective in reversing the mGluR5 KO deficit in PPI. Conclusions. Most of the compounds examined ameliorated at least a subset of pharmacologically induced PPI deficits. That none of the antipsychotic treatments attenuated the PPI deficit in the mGluR5 KO mice indicates that this model is not predictive of known treatments for schizophrenia, but does not preclude a role for the mGluR5 receptor in schizophrenia or other psychiatric disorders.