The effect of chronic treatment with lurasidone on rat liver cytochrome P450 expression and activity in the chronic mild stress (CMS) model of depression

Abstract

Recent studies indicated an important role of the monoaminergic nervous systems (dopaminergic, noradrenergic and serotonergic systems) and stress in the regulation of cytochrome P450 (CYP) expression and activity in the liver. The aim of our present research was to determine the effect of the novel atypical neuroleptic drug with antidepressant properties lurasidone, on the expression (mRNA and protein level) and activity of liver CYP isoforms involved in the metabolism of drugs and endogenous steroids, in the chronic mild stress (CMS) model of depression. Male Wistar rats were subjected to CMS for 7 weeks. Lurasidone (3 mg/kg p.o./day) was administered to non-stressed or stressed animals for 5 weeks (weeks 3-7 of CMS). It has been found that 1) CMS moderately affects cytochrome P450 (CYP2B, CYP2C11 and CYP3A) and its effects are different from those observed after other kinds of psychological stress, such as repeated restraint stress (RS) or early-life maternal deprivation (MD); 2) chronic lurasidone influences the expression and/or activity of CYP2B, CYP2C11 and CYP3A isoforms; 3) CMS modifies the action of lurasidone on cytochrome P450 expression and function, leading to different effects of the neuroleptic in non-stressed and stressed rats. Based on the obtained results, it can be suggested that the metabolism of endogenous substrates (e.g. steroids) and drugs, catalyzed by the isoforms CYP2B, CYP2C11 or CYP3A may proceed at a different rate in the two groups of animals (non-stressed and stressed) in the rat CMS model.