Abstract
Converging evidence points at hypothalamus-pituitary-adrenal (HPA) axis hyperactivity and neuroinflammation as important factors involved in the etiopathogenesis of major depressive disorder (MDD) and in therapeutic efficacy of antidepressants. In this study, we examined the molecular effects associated with a response to a week-long treatment with escitalopram in the chronic escape deficit (CED) model, a validated model of depression based on the induction of an escape deficit after exposure of rats to an unavoidable stress. We confirmed our previous result that a treatment with escitalopram (10mg/kg) was effective after 7days in reverting the stress-induced escape deficit in approximately 50% of the animals, separating responders from non-responders. Expression of markers of HPA axis functionality as well as several inflammatory mediators were evaluated in the hypothalamus, a key structure integrating signals from the neuro, immune, endocrine systems. In the hypothalamus of responder animals we observed a decrease in the expression of CRH and its receptors and an increase in GR protein in total and nuclear extracts; this effect was accompanied by a significant decrease in circulating corticosterone in the same cohort. Hypothalamic IL-1β and TNFα expression were increased in stressed animals, while CXCL2, IL-6, and ADAM17 mRNA levels were decreased in escitalopram treated rats regardless of the treatment response. These data suggest that efficacy of a one week treatment with escitalopram may be partially mediated by a decrease HPA axis activity, while in the hypothalamus the drug-induced effects on the expression of immune modulators did not correlate with the behavioural outcome.
Highlights
Understanding the neurobiological basis of major depressive disorder (MDD) and the mechanisms behind the efficacy of antidepressant strategies is a pressing need for the scientific community worldwide.One of the most reliable reported neurobiological alterations in MDD is impaired hypothalamus-pituitary-adrenal (HPA) axis functionality: HPA axis hyperactivity, glucocorticoid (GC) insensitivity and CRH overexpression in the hypothalamus or the cerebrospinal fluid have been reported in depressed patients (Sanders and Nemeroff, 2016), and similar effects were observed in preclinical studies in animal models of depression (Wang et al, 2008)
To investigate the molecular mechanism behind the therapeutic efficacy of antidepressants, we examined the different molecular effects associated with a response to a week-long treatment with escitalopram in the chronic escape deficit (CED) model of depression on two key elements known to be altered in MDD: HPA axis functionality and cytokine production within the central nervous system (CNS)
The CED model allowed us to evaluate the molecular effects elicited by a seven-day exposure to escitalopram in two populations that responded to or not to the treatment
Summary
One of the most reliable reported neurobiological alterations in MDD is impaired hypothalamus-pituitary-adrenal (HPA) axis functionality: HPA axis hyperactivity, glucocorticoid (GC) insensitivity and CRH overexpression in the hypothalamus or the cerebrospinal fluid have been reported in depressed patients (Sanders and Nemeroff, 2016), and similar effects were observed in preclinical studies in animal models of depression (Wang et al, 2008). Elevated levels of inflammatory markers have been reported in peripheral blood and spinal fluid of depressed patients (Köhler et al, 2017), while a variety of pro- and anti-inflammatory cytokines were altered in the frontal cortex of subjects with MDD (Shelton et al, 2011). Chronic behavioural models possess a great potential to help elucidate and overcome these important limitations of antidepressant treatment because on one side they more closely mimic the delayed pharmacological response observed in patients (O’Leary and Cryan, 2013), and in some of them, like the chronic unpredictable stress and chronic social defeat, is possible to separate rodents into bimodal subpopulations that respond or not to traditional antidepressant treatments (Willner and Belzung, 2015)
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