The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test

Abstract

Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10 mg/kg), CORT 108297 (30 mg/kg and 60 mg/kg), imipramine (10mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.

RU486 Reverses Emotional Disorders by Influencing Astrocytes and Endoplasmic Reticulum Stress in Chronic Restraint Stress Challenged Rats

“…Glucocorticoids exert their biological effects by binding glucocorticoid receptors [18, 19]. One of the putative mechanisms involved in these changes could be excessive activation of glucocorticoid receptors under stressful conditions [20]. The CRS procedure is a good method to establish the animal anxiety model for analyzing cellular and molecular mechanisms underlying the pathophysiology of mental diseases, and for exploring potential treatments for mood disorders [13].…”

Adolescent chronic stress causes hypothalamo–pituitary–adrenocortical hypo-responsiveness and depression-like behavior in adult female rats

“…Corticosterone (CORT) and adrenocorticotropin hormone (ACTH) levels were measured by radioimmunoassay as previously described (Ostrander et al, 2006; Solomon et al, 2014; Wulsin et al, 2010). CORT concentration was determined using 125 I RIA kits (MP Biomedicals Inc., Orangerburg NY).…”

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

“…For example, mifepristone, a non-selective GR antagonist, inhibits HPA axis activity, resulting in an initial suppression of corticosterone stress responses [10,11]. However, in these same studies, mifepristone consistently impairs the glucocorticoid-mediated feedback.…”

“…Because complete GR antagonism may pose some adverse consequences, GR modulators, such as CORT 108297 with tissue-specific agonistic and antagonistic activity have been developed. Unlike mifepristone, CORT 108297 suppresses HPA axis stress responses without impairing HPA axis shut off [11,12]. Interestingly, the tricyclic antidepressant imipramine is associated with HPA axis attenuation [13–15] and can similarly attenuate corticosterone stress responses [11].…”