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.

Effect of lurasidone treatment on chronic mild stress-induced behavioural deficits in male rats: The potential role for glucocorticoid receptor signalling

“…Both stressed and control groups were further divided into two subgroups, and for subsequent five weeks, they received the administration of vehicle (1% hydroxyethylcellulose, oral gavage) or lurasidone (3 mg/kg, oral gavage; Sumitomo Dainippon Pharma Co. Ltd, Japan) once a day. The dose of lurasidone was chosen on the basis of our previous work that showed its effectiveness in normalising the behavioural and the molecular alterations due to CMS exposure (Calabrese et al, 2016; Luoni et al, 2015; Rossetti et al, 2018). The volume of all injections was 1 mL/kg.…”

Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone

“…We have previously shown that CMS is able to induce depressive-like behaviors such as anhedonia (Rossetti et al, 2016) as well as cognitive impairment (Calabrese et al, 2017), which are associated with alterations in key molecular players for psychiatric disorders (Luoni et al, 2014; Calabrese et al, 2016b; Molteni et al, 2016). We also investigated the effect of a chronic treatment with lurasidone in counteracting the CMS-induced alterations in rat hippocampus.…”

Transcriptome Analysis on Maternal Separation Rats With Depression-Related Manifestations Ameliorated by Electroacupuncture

“…Furthermore, the clock genes ( Arntl, Per2-3 ) of animals suffering from chronic mild stress (CMS) were strongly expressed in the PFC, but did not follow a circadian rhythm. The other study also found a reduction of the BMAL1 protein ( Arntl ) in the PFC of CMS rats (Calabrese et al, 2016; Christiansen et al, 2016). Consistent with our conclusions, one previous study reported EA can ameliorate the bowel dysfunction in spinal cord injury rats, and increase Per2 expression (Cheng et al, 2016).…”