title: Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control.
abstract: Quetiapine is an atypical neuroleptic with a pharmacological profile distinct from classic neuroleptics that function primarily via blockade of dopamine D2 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Kondo
authors.forename: K
authors.initials: K
authors.lastname: Tajinda
authors.forename: C
authors.initials: C
authors.lastname: Colantuoni
authors.forename: H
authors.initials: H
authors.lastname: Hiyama
authors.forename: S
authors.initials: S
authors.lastname: Seshadri
authors.forename: B
authors.initials: B
authors.lastname: Huang
authors.forename: S
authors.initials: S
authors.lastname: Pou
authors.forename: K
authors.initials: K
authors.lastname: Furukori
authors.forename: C
authors.initials: C
authors.lastname: Hookway
authors.forename: H
authors.initials: H
authors.lastname: Jaaro-Peled
authors.forename: S-i
authors.initials: SI
authors.lastname: Kano
authors.forename: N
authors.initials: N
authors.lastname: Matsuoka
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: K
authors.initials: K
authors.lastname: Ni
authors.forename: J
authors.initials: J
authors.lastname: Pevsner
authors.forename: A
authors.initials: A
authors.lastname: Sawa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006220:Haloperidol / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage; D051379:Mice; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D025341:Principal Component Analysis; D000069348:Quetiapine Fumarate; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D008694:Methamphetamine; D054462:p21-Activated Kinases; D006220:Haloperidol
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