1. ¹Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, Minneapolis, MN, USA
2. ²Department of Biochemistry and Biophysics, Center for Functional Genomics, University of Rochester School of Medicine, Rochester, NY, USA
3. ³Biomedical Genomics Center, University of Minnesota, Minneapolis, MN, USA
4. ⁴Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
5. ⁵Fukuda Initiative Research Unit, RIKEN, Wako, Saitama, Japan

Correspondence: Dr SH Fatemi, Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, MMC 392, 420 Delaware Street SE, Minneapolis, MN 55455, USA. Tel: +1 612 626 3633; Fax: +1 612 624 8935; E-mail: fatem002@umn.edu

Received 16 May 2005; Revised 17 October 2005; Accepted 24 October 2005; Published online 11 January 2006.

Abstract

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.