Fatemi S Hossein, Reutiman Teri J, Folsom Timothy D, Bell Christopher, Nos Lisa, Fried Peter, Pearce David A, Singh Sushmita, Siderovski David P, Willard Francis S, Fukuda Mitsunori
Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Neuropsychopharmacology. 2006 Sep;31(9):1888-99. doi: 10.1038/sj.npp.1301002. Epub 2006 Jan 11.
Recent emerging biochemical data indicate that several important neuroregulatory genes and proteins may be involved in the etiology of schizophrenia and bipolar disorder. Additionally, the same genes appear to be targets of several psychotropic medications that are used to treat these disorders. Recent DNA microarray studies show that genes involved in synaptic neurotransmission, signal transduction, and glutamate/GABA regulation may be differentially regulated in brains of subjects with schizophrenia. We hypothesized that chronic administration of olanzapine to rats would alter expression of various genes that may be involved in the etiology of schizophrenia and mood disorders. Rats were administered olanzapine (N=20, 2 mg/kg/day) or sterile saline intraperitoneally (N=20) daily for 21 days. Control and olanzapine-treated frontal cortices were analyzed using cDNA microarray technology. The results showed significant downregulation of 31 genes and upregulation of 38 genes by greater than two-fold in the drug-treated brains vs controls. Our results provide evidence for altered regulation of genes involved with signal transduction and cell communication, metabolism and energy pathways, transport, immune response, nucleic acid metabolism, and neuronal growth factors. Real-time quantitative RT-PCR analysis verified the direction and magnitude of change in six genes of interest: calbindin 3, homer 1, regulator of G-protein signaling (RGS) 2, pyruvate kinase, Reelin and insulin 2. Western blotting showed significant upregulation in protein products for Reelin 410 and Reelin 180 kDa and downregulation for NMDA3B and RGS2. Our results show for the first time that olanzapine causes changes in levels of several important genes that may be involved in the etiology and treatment of schizophrenia and other psychiatric disorders.
最近新出现的生化数据表明，几种重要的神经调节基因和蛋白质可能参与了精神分裂症和双相情感障碍的病因。此外，这些相同的基因似乎是用于治疗这些疾病的几种精神药物的靶点。最近的DNA微阵列研究表明，参与突触神经传递、信号转导以及谷氨酸/γ-氨基丁酸调节的基因在精神分裂症患者的大脑中可能受到不同程度的调节。我们假设，对大鼠长期给予奥氮平会改变各种可能参与精神分裂症和情绪障碍病因的基因的表达。将大鼠分为两组，每组20只，一组每天腹腔注射奥氮平（2mg/kg/天），另一组每天腹腔注射无菌生理盐水，持续21天。使用cDNA微阵列技术分析对照组和奥氮平处理组大鼠的额叶皮质。结果显示，与对照组相比，药物处理组大脑中有31个基因显著下调，38个基因上调超过两倍。我们的结果为涉及信号转导、细胞通讯、代谢和能量途径、转运、免疫反应、核酸代谢以及神经元生长因子的基因调节改变提供了证据。实时定量逆转录-聚合酶链反应分析验证了六个感兴趣基因的变化方向和幅度：钙结合蛋白3、荷马1、G蛋白信号调节因子（RGS）2、丙酮酸激酶、Reelin和胰岛素2。蛋白质印迹法显示，Reelin 410和180kDa蛋白产物显著上调，N-甲基-D-天冬氨酸受体3B（NMDA3B）和RGS2下调。我们的结果首次表明，奥氮平会导致几种可能参与精神分裂症和其他精神疾病病因及治疗的重要基因水平发生变化。
