title: Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment.
abstract: Disruptions of biological rhythms are known to be associated with depressive disorders, suggesting that abnormalities in the molecular clock may contribute to the development of these disorders. These mechanisms have been extensively characterized in the suprachiasmatic nucleus, but little is know about the role exerted by individual clock genes in brain structures that are important for depressive disorders. Using the chronic mild stress model we found a significant reduction of BMAL1 and CLOCK protein levels in the nuclear compartment of the prefrontal cortex of CMS rats, which was paralleled by a down-regulation of the expression of several target genes, including Pers and Crys but also Reverbβ and Pparα. Interestingly, chronic treatment with the multi receptor modulator lurasidone (3mg/kg for 5 weeks) was able to normalize the molecular changes induced by CMS exposure in prefrontal cortex, but it was also able to regulate some of these genes within the hippocampus. We believe that changes in clock genes expression after CMS exposure may contribute to the disturbances associated with depressive disorders and that the ability of chronic lurasidone to normalize such alterations may be relevant for its therapeutic properties in ameliorating functions that are deteriorated in patients with major depression and other stress-related disorders.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Savino
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Papp
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Molteni
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. Electronic address: M.Riva@unimi.it.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D000069056:Lurasidone Hydrochloride / Q000494:pharmacology*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D014150:Antipsychotic Agents; D056925:Circadian Rhythm Signaling Peptides and Proteins; D065127:Dopamine D2 Receptor Antagonists; D012333:RNA, Messenger; D058830:Serotonin 5-HT2 Receptor Antagonists; D000069056:Lurasidone Hydrochloride