Some molecular effectors of antidepressant action of quetiapine revealed by DNA microarray in the frontal cortex of anhedonic rats.
OBJECTIVE
We have previously demonstrated that quetiapine (QTP) had antidepressant-like action by using the chronic mild stress (CMS) paradigm, an animal model of human depression. The aim of this study was to investigate the molecular mechanism(s) of QTP antidepressant effect by coupling the CMS protocol with Affymetrix microarray technology to screen the entire rat genome for gene changes in the frontal cortex.


RESULTS
The genes regulated by the administration of CMS whose transcription was reversed by chronic QTP treatment (2 mg/kg/day) were 42 (23 upregulated and 19 downregulated). The transcripts that showed no significant altered expression levels in anhedonic rats but were regulated by the administration of QTP were 19 (nine upregulated and 10 downregulated). On the whole, the action of QTP prevented the stress-induced impairment of some processes involved in central nervous system development or having a crucial role for viability of neural cells and cell-cell communications, like regulation of signal transduction, inorganic cation transport, membrane organization, and neurite morphogenesis. For 11 genes (Ptgs2, Gad1, Plcb1, Camk2a, Homer1, Senp2, Junb, Nfib, Hes5, Capon, and Marcks), significant differential expressions were confirmed by real-time reverse-transcriptase polymerase chain reaction.


CONCLUSIONS
We have shown that chronic QTP treatment prevented anhedonia and reversed, at least in part, the changes of gene expression induced by CMS in the rat frontal cortex. We have also identified and confirmed by two different methods that 11 genes, representing molecular targets of QTP, are presumably the effectors of its clinical efficacy.
Orsetti
Marco
M
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche (DiSCAFF), Università del Piemonte Orientale A. Avogadro, Novara, Italy. orsetti@pharm.unipmn.it
Di Brisco
Fabio
F
Rinaldi
Maurizio
M
Dallorto
Dario
D
Ghi
Piera
P
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects*; D003987:Dibenzothiazepines / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010597:Pharmacogenetics / Q000379:methods; D000069348:Quetiapine Fumarate; D051381:Rats; D017208:Rats, Wistar; D013315:Stress, Psychological; D013395:Sucrose / Q000494:pharmacology
D000928:Antidepressive Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D013395:Sucrose