Acute Glucocorticoid Pretreatment Suppresses Stress‐Induced Hypothalamic‐Pituitary‐Adrenal Axis Hormone Secretion and Expression of Corticotropin‐Releasing Hormone hnRNA but Does Not Affect c‐fos mRNA or Fos Protein Expression in the Paraventricular Nucleus of the Hypothalamus

Abstract

Corticosterone regulates both basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity in a negative-feedback fashion. However, the cellular and molecular mechanisms of this negative feedback have yet to be explicitly characterized. By comparing stress-induced c-fos and corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus (PVN), we may be able to determine whether acute glucocorticoid treatment affects the net neural excitatory input to the PVN (represented primarily by c-fos mRNA expression) or directly affects the ability of cells in the PVN to respond to that input (represented primarily by CRH hnRNA expression). In the following studies, we observed the effect of acute glucocorticoid (RU28362) treatment on subsequent HPA axis reactivity by measuring stress-induced plasma hormone concentration [corticosterone and adrenocorticotropic hormone (ACTH)] and gene expression (c-fos and CRH) in the PVN. First, we examined the dose-response relationship between systemically administered RU28362 (1-150 microg/kg, i.p) and suppression of the stress-induced corticosterone response. We then confirmed central nervous system access of the maximally suppressive dose of RU28362 (150 microg/kg) by an ex vivo radioligand binding assay. RU28362 selectively occupied the majority of glucocorticoid receptors in the hippocampus and hypothalamus while having no effect on mineralocorticoid receptors. In separate studies, RU28362 (150 microg/kg) and corticosterone (5 mg/kg) were injected i.p. 1 h before restraint stress. Compared to vehicle-treated controls, rats treated with RU28362 and corticosterone had substantially blunted stress-induced corticosterone and ACTH production, respectively. Furthermore, treatment with RU28362 significantly blunted stress-induced CRH hnRNA expression in the PVN. By contrast, neither RU28362 nor corticosterone treatment had an effect on stress-induced neuronal activation as measured by c-fos mRNA and its protein product in the PVN. This dissociation between c-fos and CRH gene expression suggests that glucocorticoid suppression of HPA activity within this time-frame is not a result of decreased excitatory neural input to the PVN, but instead depends on some direct effect of RU28362 on cells intrinsic to the HPA axis.

Angiotensin II AT1 receptor blockade prevents the hypothalamic corticotropin-releasing factor response to isolation stress

“…This is important to preserve homeostasis, limiting the duration and magnitude of the HPA axis response during stress (Aguilera, 1994;McEwen, 1998;Itoi et al, 1998;Ma and Aguilera, 1999a, b;Ginsberg et al, 2003). Activation of intracellular feedback mechanisms, such as cAMP-mediated repression of CRF transcription, may contribute to limiting the CRF response (Shepard et al, 2005).…”

“…Increased brain AT 1 receptor activity, such as that present in genetic hypertension (Saavedra et al, 1986), may mediate the pathological, long term stimulation of the HPA axis during stress characteristic of genetically hypertensive rats (Horie et al, 1991). Excessive central AT 1 receptor activation may decrease the efficiency of glucocorticoid feedback and may be a factor involved in the maintenance of sustained HPA axis activity in the presence of stress-induced hypercorticism (Itoi et al, 1998;Ma et al, 2001;Ginsberg et al, 2003). Whether such a mechanism plays a role in the development of stress-induced disorders, and whether centrally-acting AT 1 receptor antagonists should be considered as therapeutic anti-stress compounds remain open questions.…”

Role of Glucocorticoids and cAMP-Mediated Repression in Limiting Corticotropin-Releasing Hormone Transcription during Stress

“…Studies in rats have shown that elevated levels of circulating glucocorticoids decrease basal levels of CRH transcription (Itoi et al, 1998;Ma et al, 2001;Ginsberg et al, 2003) and CRH mRNA levels in the PVN (Jingami et al, 1985;Sawchenko, 1987;Lightman and Young, 1989;Swanson and Simmons, 1989). However, although some observations suggest that glucocorticoids limit the stress response (Kovacs and Sawchenko, 1996), others show a lack of effect of glucocorticoids or even a facilitation of the CRH transcriptional response to stress (Ma and Aguilera, 1999b;Watts and Sanchez-Watts, 2002).…”

“…Glucocorticoids reduce basal levels of CRH transcription and CRH mRNA levels in the paraventricular nucleus (PVN) (Itoi et al, 1998;Ma and Aguilera, 1999a,b;Ginsberg et al, 2003) and are a likely candidate for limiting CRH transcription during stress. However, variations in plasma glucocorticoids cannot always explain changes in HPA axis activity.…”

Stress-Induced c-Fos Expression is Differentially Modulated by Dexamethasone, Diazepam and Imipramine

“…The expression of cFos as a consequence of stress is the result of a complex interaction of pathways of cellular activation, and the effect of dexamethasone depends on the neurochemical identity of different cell type groups (eg, monoaminergic), the nature of the challenge (kind of stress), and the dose of corticosteroid among other factors (Li and Sawchenko, 1998;Ginsberg et al, 2003). Furthermore, not all corticosteroid-sensitive cells groups respond similarly to the manipulation of the levels of glucocorticoids (Li and Sawchenko, 1998).…”