Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, United States.
Schizophr Res. 2012 Feb;134(2-3):211-8. doi: 10.1016/j.schres.2011.11.013. Epub 2011 Dec 10.
Antipsychotic drugs (APDs) are effective in treating some of the positive and negative symptoms of schizophrenia. APDs take time to achieve a therapeutic effect which suggests that changes in gene expression are involved in their efficacy. We hypothesized that there would be altered expression of specific genes associated with the etiology or treatment of schizophrenia in frontal cortex of rats that received chronic treatment with a typical APD (haloperidol) vs. an atypical APD (clozapine). Rats were administered clozapine, haloperidol, or sterile saline intraperitoneally daily for 21days. Frontal cortices from clozapine-, haloperidol-, and saline-treated rats were dissected and subjected to microarray analysis. We observed a significant (1.5 fold, p<0.05) downregulation of 278 genes and upregulation of 73 genes in the clozapine-treated brains vs. controls and downregulation of 451 genes and upregulation of 115 genes in the haloperidol-treated brains vs. control. A total of 146 genes (130 downregulated and 16 upregulated) were significantly altered by both clozapine and haloperidol. These genes were classified by functional groups. qRT-PCR (quantitative real-time polymerase chain reaction) analysis verified the direction and magnitude of change for a group of nine genes significantly altered by clozapine and 11 genes significantly altered by haloperidol. Three genes verified by qRT-PCR were altered by both drugs: Bcl2-like 1 (Bcl2l1), catechol-O-methyltransferase (Comt), and opioid-binding protein/cell adhesion molecule-like (Opcml). Our results show that clozapine and haloperidol cause changes in levels of many important genes that may be involved in etiology and treatment of schizophrenia.
抗精神病药物（APD）在治疗精神分裂症的一些阳性和阴性症状方面有效。APD 需要时间才能达到治疗效果，这表明基因表达的变化与它们的疗效有关。我们假设，在接受典型 APD（氟哌啶醇）与非典型 APD（氯氮平）慢性治疗的大鼠的额叶皮层中，与精神分裂症的病因或治疗相关的特定基因会出现表达改变。大鼠每天通过腹膜内注射氯氮平、氟哌啶醇或无菌生理盐水进行治疗，共 21 天。从氯氮平、氟哌啶醇和生理盐水处理的大鼠的额叶皮层中取出并进行微阵列分析。我们观察到氯氮平处理的大脑与对照相比，有 278 个基因显著下调（1.5 倍，p<0.05），73 个基因上调，氟哌啶醇处理的大脑与对照相比，有 451 个基因下调，115 个基因上调。氯氮平和氟哌啶醇共改变了 146 个基因（130 个下调和 16 个上调）。这些基因按功能组分类。qRT-PCR（实时定量聚合酶链反应）分析验证了一组由氯氮平显著改变的 9 个基因和由氟哌啶醇显著改变的 11 个基因的变化方向和幅度。通过 qRT-PCR 验证的三个基因均由两种药物改变：Bcl2 样 1（Bcl2l1）、儿茶酚-O-甲基转移酶（Comt）和阿片结合蛋白/细胞粘附分子样（Opcml）。我们的结果表明，氯氮平和氟哌啶醇导致许多重要基因的水平发生变化，这些基因可能与精神分裂症的病因和治疗有关。
