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CRF-R1 Antagonist Treatment Exacerbates Circadian Corticosterone Secretion under Chronic Stress, but Preserves HPA Feedback Sensitivity

1
UMR1253, iBrain, Université de Tours, Inserm, 37200 Tours, France
2
EUK-CVL, Université d’Orléans, 45100 Orléans, France
3
Department of Biomedical Sciences/Biochemistry, University of Veterinary Medicine, 1210 Vienna, Austria
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Yasumasa Ikeda
Pharmaceutics 2021, 13(12), 2114; https://doi.org/10.3390/pharmaceutics13122114
Received: 3 November 2021 / Revised: 1 December 2021 / Accepted: 4 December 2021 / Published: 8 December 2021
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. View Full-Text
Keywords: CRF; CRF receptor type 1 antagonist; HPA axis; glucocorticoids; chronic stress; antidepressant; anxiety; depression CRF; CRF receptor type 1 antagonist; HPA axis; glucocorticoids; chronic stress; antidepressant; anxiety; depression
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MDPI and ACS Style

Ibarguen-Vargas, Y.; Leman, S.; Palme, R.; Belzung, C.; Surget, A. CRF-R1 Antagonist Treatment Exacerbates Circadian Corticosterone Secretion under Chronic Stress, but Preserves HPA Feedback Sensitivity. Pharmaceutics 2021, 13, 2114. https://doi.org/10.3390/pharmaceutics13122114

AMA Style

Ibarguen-Vargas Y, Leman S, Palme R, Belzung C, Surget A. CRF-R1 Antagonist Treatment Exacerbates Circadian Corticosterone Secretion under Chronic Stress, but Preserves HPA Feedback Sensitivity. Pharmaceutics. 2021; 13(12):2114. https://doi.org/10.3390/pharmaceutics13122114

Chicago/Turabian Style

Ibarguen-Vargas, Yadira, Samuel Leman, Rupert Palme, Catherine Belzung, and Alexandre Surget. 2021. "CRF-R1 Antagonist Treatment Exacerbates Circadian Corticosterone Secretion under Chronic Stress, but Preserves HPA Feedback Sensitivity" Pharmaceutics 13, no. 12: 2114. https://doi.org/10.3390/pharmaceutics13122114

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