Selective Blockade of the Mineralocorticoid Receptor Impairs Hypothalamic‐Pituitary‐Adrenal Axis Expression of Habituation

Abstract

The present study investigated the role of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in the expression of habituation of the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Male rats were restrained for 1 h per day for six consecutive days. On day 6, 1 h prior to restraint stress, both restraint-naive and repeatedly restrained rats were injected s.c. with either vehicle (propylene glycol) or one of three corticosteroid receptor antagonist treatments: selective MR antagonist (RU28318 or spironolactone), selective GR antagonist (RU40555), or both MR and GR antagonists combined (RU28318+RU40555). Blood samples were collected for corticosterone measurement at the beginning of stress, during stress, and 1 h after stress termination. Repeated restraint stress produced signi®cant habituation of corticosterone responses. Acute treatment with the combined MR and GR antagonists prevented the expression of habituation. When tested alone, the MR antagonist also blocked the expression of corticosterone-response habituation, whereas the GR antagonist had no effect. Neither the MR, nor the GR antagonists alone, signi®cantly altered the corticosterone response to restraint in rats exposed to restraint for the ®rst time. The ®nal experiment examined the corticosterone response to a corticotropin releasing hormone (CRH, 3 mg/kg i.p.) challenge. Neither previous exposure to restraint or acute pretreatment with the combined MR and GR antagonists (RU28318+RU40555) altered the corticosterone response to CRH challenge. This result indicates that the expression of habituation and its blockade by corticosteroid receptor antagonists is not a result of altered pituitary-adrenal response to CRH. Overall, this study suggests that MR plays an important role in constraining the HPA axis response to restraint stress in restraint-habituated rats. The dependence of the HPA axis on MR-mediated corticosteroid negative feedback during acute stress may be an important mechanism that helps maximize the expression of stress habituation and thereby minimize exposure of target tissues to corticosteroids in the context of repeated stress.Repeated exposure to stress often leads to adaptation within stress response systems that is evident by a change in the magnitude of subsequent elicited stress responses. In some cases, repeated stress leads to an enhanced or sensitized stress response and in other cases it leads to a blunted or habituated stress response (1, 2). Although some of the conditions that lead to stress response sensitization or habituation have been characterized, there is very little understanding of the mechanisms responsible for this adaptation. We have studied a stress habituation paradigm in which rats were repeatedly exposed to restraint stress. Our studies focused on the hypothalamic-pituitary-adrenal (HPA) axis as a stress response system by which to monitor the habituation process (3, 4). For the studies reported here, we considered the possibility that corticosterone negative feedback p...

Effect of vasopressin 1b receptor blockade on the hypothalamic–pituitary–adrenal response of chronically stressed rats to a heterotypic stressor

“…This hypothesis is supported by the evidence that blockade of central mineralocorticoid receptors can prevent habituation of the corticosterone response to repeated restraint (Cole et al 2000). Our data suggest that the effects of AVPR1B antagonist and chronic stress .…”

Adaptation to intermittent stress promotes maintenance of β-cell compensation: comparison with food restriction

“…The corticosterone responses to restraint stress were elevated for the first 4 wk, after which responses habituated. Thus, intermittent exposure to restraint stress for an extended time causes habituation of corticosterone responses as is commonly seen with repeated exposure to the same type of stress (2,15,33,34,65). However, we (5) have previously shown that this is accompanied by sustained reductions in food intake and inhibition of growth hormone, illustrating persistent effects of chronic stress independent of corticosterone responses.…”

Chronic mild stress decreases survival, but not proliferation, of new-born cells in adult rat hippocampus

“…Interestingly, the present results raise the possibility of a habituation of the hypothalmo-pituitaryadrenal (HPA) axis in response to repeated mild stress. The habituation of HPA axis activation has been previously shown after repeated exposure to restraint (Hauger et al, 1990;Cole et al, 2000), cold (Bhatnagar et al, 1995), noise (Armario et al, 1986), water immersion (De Boer et al, 1990), and repeated handling (Dobrakovova et al, 1993).…”