Abstract
Despite promising initial reports, corticotropin-releasing factor receptor type-1 (CRF-R1) antagonists have mostly failed to display efficacy in clinical trials for anxiety or depression. Rather than broad-spectrum antidepressant/anxiolytic-like drugs, they may represent an ‘antistress’ solution for single stressful situations or for patients with chronic stress conditions. However, the impact of prolonged CRF-R1 antagonist treatments on the hypothalamic–pituitary–adrenal (HPA) axis under chronic stress conditions remained to be characterized. Hence, our study investigated whether a chronic CRF-R1 antagonist (crinecerfont, formerly known as SSR125543, 20 mg·kg−1·day−1 ip, 5 weeks) would alter HPA axis basal circadian activity and negative feedback sensitivity in mice exposed to either control or chronic stress conditions (unpredictable chronic mild stress, UCMS, 7 weeks), through measures of fecal corticosterone metabolites, plasma corticosterone, and dexamethasone suppression test. Despite preserving HPA axis parameters in control non-stressed mice, the 5-week crinercerfont treatment improved the negative feedback sensitivity in chronically stressed mice, but paradoxically exacerbated their basal corticosterone secretion nearly all along the circadian cycle. The capacity of chronic CRF-R1 antagonists to improve the HPA negative feedback in UCMS argues in favor of a potential therapeutic benefit against stress-related conditions. However, the treatment-related overactivation of HPA circadian activity in UCMS raise questions about possible physiological outcomes with long-standing treatments under ongoing chronic stress.
Highlights
The identification of pharmacological targets capable of tuning hypothalamic-pituitaryadrenal (HPA) axis activity has been at the forefront of many research and development strategies against chronic stress, anxiety, and depression over the past decades
(1) CRF release is the primary step toward HPA axis activation and glucocorticoid releases; (2) the CRF system exhibits alterations in depressed patients including higher CRF expressions in the brain [1,2,3,4]; (3) the CRF system involves forebrain modules, including amygdala and prefrontal cortex [5,6], which can coordinate behavioral responses to stress-associated stimuli and activate hypothalamic neurons upstream to HPA axis; and (4) intracerebral CRF administration or overexpression in rodents induce physiological and behavioral phenotypes that are reminiscent of anxiety and depressive
Pharmaceutics 2021, 13, 2114 disorders [7]. These results indicate that CRF dysfunctions may drive symptomatology and HPA axis abnormalities in stress-related disorders and that glucocorticoid excess may be the downstream reverberation of an altered CRF system
Summary
The identification of pharmacological targets capable of tuning hypothalamic-pituitaryadrenal (HPA) axis activity has been at the forefront of many research and development strategies against chronic stress, anxiety, and depression over the past decades. These results indicate that CRF dysfunctions may drive symptomatology and HPA axis abnormalities in stress-related disorders and that glucocorticoid excess may be the downstream reverberation of an altered CRF system Within this framework, research efforts converged to develop CRF receptor antagonists, focusing mainly on the CRF receptor type 1 (CRF-R1) that mediates ACTH releases and promotes anxiety-related behaviors in forebrain areas [8]. Despite high translational expectations and an initial promising result [17], all subsequent clinical trials failed to successfully complete double-blind, placebo-controlled studies for anxiety and depressive disorders, mainly for adverse liver effects or lack of efficacy; see [18] for review It is, critical to reassess the medical scopes of the CRF-R1 antagonists and to define realistic avenues for their potential therapeutic uses in stress-related conditions. Previous studies showed that chronic treatments with crinecerfont improve physical and behavioral alterations in UCMS [10,15,22,26,27,28], but none of these studies determined the outcomes of such chronic treatments on the HPA axis under chronic stress conditions
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