Circadian activity of the hypothalamic–pituitary–adrenal axis is differentially affected in the rat chronic mild stress model of depression

Abstract

The altered activity of the hypothalamic-pituitary-adrenal (HPA) axis is often observed in stress-related disorders. According to the literature, about 60% of patients with major depressive disorder elicit high levels of cortisol. It is still unclear why high cortisol levels are not observed in all patients. In this study, we used the chronic mild stress (CMS) rat model of depression, which is based on continuous exposure to unpredictable stressors, to track longitudinal changes in HPA function using fecal corticosterone metabolites (FCM) as a read out. The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Our results show (1) a disturbance in diurnal corticosterone rhythm measured as fluctuations of the diurnal FCM peak, (2) differences in corticosterone levels between stress-susceptible and stress-resilient animals, (3) recovery of diurnal corticosterone rhythm after 8 weeks of CMS, and (4) alterations in sensitivity to dexamethasone in negative feedback regulation of corticosterone secretion during the time course of CMS. Thus, a disruption of HPA axis circadian rhythmicity coincides with the initial state in the development of depression-like behavior. This chronobiological abnormality, as well as the hypersecretion of corticosterone, is state, rather than trait, dependent.

Chronic selective serotonin reuptake inhibition modulates endothelial dysfunction and oxidative state in rat chronic mild stress model of depression

“…In accordance with our previous studies (4,8,12,14,39,41,57), exposure to CMS induced anhedonic-like behavior, in about one-third of the rat population. The CMS-susceptible rats reduced their sucrose intake by 36 Ϯ 2% (n ϭ 26) (Fig.…”

“…Food and water were available ad libitum, except when food and/or water deprivation was applied as a stressor. The standard 12:12-h light-dark cycle (light phase 0600 -1800) was only changed in the course of the stress exposure (14,33,39). The weight of a subgroup of rats was obtained regularly throughout the study.…”

“…The baseline sucrose consumption was measured during 3 wk. Then rats were divided into two groups, where one group was exposed to CMS for 8 wk and the other remained unchallenged (3,7,8,13,14,33,34,36,41,42,57 SCT. SCT measures the sucrose intake of individual rats during 1-h exposure to a bottle with 1.5% sucrose solution.…”

“…The CMS paradigm originally involved a large group of rats whose hedonic state was analyzed after the first 4 wk of stress (3,14,33,57). Rats exposed to CMS showed differential stress susceptibility with ϳ50% being anhedonic, while others were either resilient (no change in sucrose intake) or reduced their sucrose intake Ͻ30% (61,70,71).…”

Using Rodent Models to Simulate Stress of Physiologically Relevant Severity: When, Why and How

“…The diurnal rhythm for corticosterone for example is only regular from about day 30-32 in rats (Allen and Kendall, 1967). Also, circadian rhythms are affected by many stress-related disorders -in this context, a chronic mild stress model of depression has been shown to cause fluctuations in corticosterone rhythm which only normalised after 8 weeks of chronic mild stress, and which was dependent on resilience of animals exposed to stress (Christiansen et al, 2012).…”