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.
Highlights
Understanding the molecular mechanisms that underlie the pathophysiology of major mental illnesses, such as schizophrenia and depression, is very important
The aim of this study was to identify novel pathways potentially involved in schizophrenia and/or mood disorders by investigating quetiapine, but not haloperidol, induced molecular expression changes in the frontal cortex
Our in situ hybridization results indicate that the change seems to occur at least in deep layer neurons in the adult brain, and systematic analysis of cell culture indicate that quetiapine significantly downregulates the expression of Cdkn1a in oligodendrocyte precursor cells (OPCs) and primary neurons, but not in astrocytes
Summary
Understanding the molecular mechanisms that underlie the pathophysiology of major mental illnesses, such as schizophrenia and depression, is very important. Neuroleptics have been in clinical use for schizophrenia since the 1950s.3 The hallmark of these first-generation drugs, including haloperidol and chlorpromazine, is antagonism of the dopamine D2 receptor.[4,5,6] Since the late 1980s, the so-called atypical neuroleptics, such as clozapine, have been introduced. Among the atypical neuroleptics that share a high affinity for serotonin (5-HT2A) but a relatively low affinity for dopamine (D2) receptors, quetiapine has a further unique profile with a high affinity for histamine (H1) and a1-adrenergic receptors.[14,15] It is not well understood how the interplay of quetiapine’s various receptor-binding activities affects molecular pathways and translates to clinical efficacy. It seems necessary to look beyond the effects of the individual receptors within quetiapine’s known receptor-binding profile to understand its overall therapeutic mechanism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
