title: Comparative gene expression study of the chronic exposure to clozapine and haloperidol in rat frontal cortex.
abstract: 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.
authors.affiliation: Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, United States. fatem002@umn.edu
authors.forename: S Hossein
authors.initials: SH
authors.lastname: Fatemi
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Folsom
authors.forename: Teri J
authors.initials: TJ
authors.lastname: Reutiman
authors.forename: Jessica
authors.initials: J
authors.lastname: Novak
authors.forename: Rachelanne H
authors.initials: RH
authors.lastname: Engel
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; C494813:Bcl2l1 protein, rat; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C489215:Opcml protein, rat; D012333:RNA, Messenger; D051020:bcl-X Protein; D002394:Catechol O-Methyltransferase; D003024:Clozapine; D006220:Haloperidol