A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats

Abstract

Aberrant glucocorticoid secretion is implicated in the pathophysiology of stress-related disorders (i.e., depression, anxiety). Glucocorticoids exert biological effects via mineralocorticoid (MR) and glucocorticoid (GR) receptors. Previous data from our laboratory indicate that GR antagonism/modulation (i.e., mifepristone, CORT 108297) regulate endocrine, behavioral, and central stress responses. Because of the dynamic interplay between MR and GR on HPA axis regulation and emotionality, compounds targeting both receptors are of interest for stress-related pathology. We investigated the effects of CORT 118335 (a dual selective GR modulator/MR antagonist) on endocrine, behavioral, and central (c-Fos) stress responses in male rats. Rats were treated for five days with CORT 118335, imipramine (positive control), or vehicle and exposed to restraint or forced swim stress (FST). CORT 118335 dampened corticosterone responses to both stressors, without a concomitant antidepressant-like effect in the FST. Imipramine decreased corticosterone responses to restraint stress; however, the antidepressant-like effect of imipramine in the FST was independent of circulating glucocorticoids. These findings indicate dissociation between endocrine and behavioral stress responses in the FST. CORT 118335 decreased c-Fos expression only in the CA1 division of the hippocampus. Imipramine decreased c-Fos expression in the basolateral amygdala and CA1 and CA3 divisions of the hippocampus. Overall, the data indicate differential effects of CORT 118335 and imipramine on stress-induced neuronal activity invarious brain regions. The data also highlight acomplex relationship between neuronal activation instress and mood regulatory brain regions and the ensuing impact on endocrine and behavioral stress responses.

Resetting the Stress System with a Mifepristone Challenge

“…However, upon repeated high-dose MIF (200 mg/kg) daily administration, the circadian- and stress-induced HPA-axis activity are abolished. This apparent GR agonism of MIF upon repeated administration was previously also reported (Havel et al 1996 ; Wulsin et al 2010 ; van der Veen et al 2013 ; Solomon et al 2014 ; van den Heuvel et al 2016 ; Nguyen et al 2017 , 2018 ; Kroon et al 2018 ); however, with the lower doses in these studies, stress responsivity was attenuated rather than abolished (see also Fig. 5 ).…”

“…Fourth, repeated daily administration for 5 days up to three weeks revealed an unexpected apparent GR agonism of MIF and blocked basal and stress-induced HPA-axis activity in rodents (Havel et al 1996 ; Wulsin et al 2010 ; van der Veen et al 2013 ). Similar GR agonism rather than antagonism was noted with the novel selective GR modulators C-108297, C-125281, and the GR modulator/MR antagonist C-118335 (Solomon et al 2014 ; Nguyen et al 2017 ; Kroon et al 2018 ; Van den Heuvel et al 2016 ). Repeated MIF treatment caused a differential pattern of activation and inhibition of central inputs to the PVN, as judged from c-FOS activation (Wulsin et al 2010 ).…”

MR/GR Signaling in the Brain during the Stress Response

“…Alternatively, the glucocorticoid/progesterone antagonist mifepristone is applied for treatment of hyperglycemia in patients suffering from Cushing's syndrome [116]. Recently, selective GR modulators (SGRMs) became available that can target metabolism but do not show side effects on pituitary ACTH release [117][118][119].…”

Psychosocial-Stress, Liver Regeneration and Weight Gain: a Conspicuous Pathophysiological Triad

“…In recent years, the role of stress mediators in the liver pathophysiology has gained a new dimension [8, 10, 11]. Deviant increase in glucocorticoids following stress-arousal influences both food consumption and energy expenditure [12, 13]. Studies in human subjects strongly suggest a correlation between prolonged elevation of circulating glucocorticoids and weight gain [14].…”