Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control

• Published in: Translational psychiatry Vol. 3; no. 4; p. e243
• Main Authors: Kondo, M A, Tajinda, K, Colantuoni, C, Hiyama, H, Seshadri, S, Huang, B, Pou, S, Furukori, K, Hookway, C, Jaaro-Peled, H, Kano, S-i, Matsuoka, N, Harada, K, Ni, K, Pevsner, J, Sawa, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.04.2013; Nature Publishing Group
• Subjects: 631/337/641; 631/92/436/434; 692/699/476; Analysis of Variance; Animals; Antipsychotic Agents - pharmacology; Astrocytes - metabolism; Behavioral Sciences; Biological Psychology; Cell Cycle - drug effects; Dibenzothiazepines - pharmacology; Disease Models, Animal; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Gene Expression; Haloperidol - pharmacology; In Situ Hybridization; Male; Medicine; Medicine & Public Health; Methamphetamine - administration & dosage; Mice; Neurons - metabolism; Neurosciences; Oligodendroglia - metabolism; Original; original-article; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; Pharmacotherapy; Principal Component Analysis; Psychiatry; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Schizophrenia - chemically induced; Schizophrenia - metabolism; quetiapine; schizophrenia; cell cycle; mood disorders; neuroleptics; gene expression
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2013.19

Quetiapine is an atypical neuroleptic with a pharmacological profile distinct from classic neuroleptics that function primarily via blockade of dopamine D 2 receptors. In the United States, quetiapine is currently approved for treating patients with schizophrenia, major depression and bipolar I disorder. Despite its widespread use, its cellular effects remain elusive. To address possible mechanisms, we chronically treated mice with quetiapine, haloperidol or vehicle and examined quetiapine-specific gene expression change in the frontal cortex. Through microarray analysis, we observed that several groups of genes were differentially expressed upon exposure to quetiapine compared with haloperidol or vehicle; among them, Cdkn1a , the gene encoding p21, exhibited the greatest fold change relative to haloperidol. The quetiapine-induced downregulation of p21/ Cdkn1a was confirmed by real-time polymerase chain reaction and in situ hybridization. Consistent with single gene-level analyses, functional group analyses also indicated that gene sets associated with cell cycle/fate were differentially regulated in the quetiapine-treated group. In cortical cell cultures treated with quetiapine, p21/ Cdkn1a was significantly downregulated in oligodendrocyte precursor cells and neurons, but not in astrocytes. We propose that cell cycle-associated intervention by quetiapine in the frontal cortex may underlie a unique efficacy of quetiapine compared with typical neuroleptics.