Stress-Induced Sensitization of the Hypothalamic-Pituitary Adrenal Axis Is Associated with Alterations of Hypothalamic and Pituitary Gene Expression

Abstract

We have previously reported that inescapable tail shock (IS) produces persistent changes in hypothalamic-pituitary-adrenal (HPA) axis function. These changes are manifest as an elevation in basal corticosterone (CORT) levels, a sensitization of adrenocorticotropin hormone (ACTH) and CORT responses to subsequent challenge, and a failure of dexamethasone to suppress both the ACTH and CORT responses to a subsequent challenge. The experiments presented here examine IS-induced alterations in the responsiveness of the HPA axis, particularly at the level of the anterior pituitary. The data presented show that adrenalectomy does not abolish the IS-induced sensitization of the HPA axis, suggesting that the sensitization is not solely caused by a defect in glucocorticoid negative feedback. Analysis of gene expression in the anterior pituitary revealed that IS exposure persistently elevated basal levels of proopiomelanocortin (POMC; the precursor to ACTH) mRNA and sensitized the POMC hnRNA and c-fos mRNA response to a subsequent challenge. Analysis of gene expression in the parvocellular division of the paraventricular nucleus of the hypothalamus (pPVN) after IS exposure revealed that basal levels of corticotropin-releasing hormone (CRH) mature mRNA are elevated and the c-fos mRNA response to a subsequent challenge is enhanced. Finally, a blunted in vitro ACTH response to CRH challenge is observed after IS exposure. These data suggest that the ultimate source of the IS-induced sensitization is not the anterior pituitary and implicate an increased drive on the anterior pituitary from the pPVN.

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

“…The long-lasting effect of a single exposure to stress on ACTH has also been reported in others studies (Johnson et al 2002a, Armario et al 2004, O'Connor et al 2004, and effects on basal Crh mRNA levels in the PVN and increased stressinduced Fos mRNA in the PVN have been described 24 h after exposure to an acute inescapable shock (O'Connor et al 2004).…”

Long-term neuroendocrine and behavioural effects of a single exposure to stress in adult animals

“…Whether this resistance to dexamethasone was the result of impaired effectiveness of negative feedback mechanisms or it was secondary to enhanced stimulatory inputs to the HPA axis is unclear at present. These authors have also described important changes in the HPA axis on the day after shock, which may contribute to the enhanced responsiveness (O'Connor et al, 2004): basal levels of mRNA for CRF in the PVN and for POMC in the anterior pituitary were elevated. In addition, when the animals were exposed to a novel environment they showed a greater induction of c-fos in the PVN and of c-fos and hnRNA for POMC in the anterior pituitary, strongly suggesting that exacerbated pituitary responsiveness to the novel environment was derived by the PVN.…”

Regulation of Proopiomelanocortin Gene Transcription during Single and Repeated Immobilization Stress

“…In general, it is believed that pituitary ACTH responses to exogenous hypothalamic secretagogues, such as CRH and/or AVP, are of normal or slightly reduced amplitudes during chronic stress [6]. O’Connor et al[ 16] recently showed that inescapable tail shock produces persistent changes in the HPA axis function, including elevated basal CRH mRNA in the PVN and POMC mRNA in the AP with sensitization of the POMC hnRNA response to a subsequent challenge. Since the in vitro ACTH response to CRH challenge was blunted, they suggested that an increased hypothalamic drive was involved in the sensitization of the pituitary-adrenocortical axis.…”