Stress, Feedback and Facilitation in the Hypothalamo‐Pituitary‐Adrenal Axis

Abstract

It has been obvious for at least 2 decades that there is a paradox that limits understanding of adrenocortical physiology. First, the hypothalamo-pituitary-adrenal (HPA) axis seems to be very sensitive to feedback inhibition by glucocorticoid hormones secreted from the adrenals. Second, stress, which causes ample adrenal steroid secretion, does not appear to inhibit subsequent activity in the HPA axis.Dallman and Jones worked on this problem in the 1970's (1). We showed that prolonged restraint stress of 90 min duration in rats did not inhibit the corticosterone (B) response to the subsequent mild stress of intraperitoneal injection. However, injection of adrenocorticotropin (ACTH) or B which mimicked the B response to restraint, did inhibit the B response to subsequent injection stress. We concluded that stress must induce a facilitatory effect on subsequent responses of the HPA axis to stress (1). Neither of us was satisfied with this entirely deductive approach, and in 1971, in collaboration with Vernikos, we filled a notebook with our unsuccessful attempts to show direct evidence for stressinduced facilitation, studying rats 1 to 2 days after bilateral adrenalectomy and bioassay of ACTH. The results were uninterpretable; we know now that this is because of the extreme disequilibrium in central components of the HPA axis that occurs during the first days after adrenalectomy with removal of the feedback signal.Recently, our laboratory has made considerable progress in making sense of the apparent paradox by reexamining all three aspects of this problem: the effect of chronic stress on function of the HPA axis (2-4); the sensitivity of the adrenocortical system of the intact rat to passive elevation in circulating B (5); and finding direct evidence for a facilitatory effect of stress on some aspects of subsequent activity in the HPA axis (6). The results of these studies have led us to a new understanding of the control of the HPA axis. It seems appropriate for the third Mortyn Jones Memorial Lecture to describe the highlights of these studies. The results of our work, and that of others, in rats, also appear to apply to man, and may be of utility to the understanding of adrenocortical function under normal circumstances as well as in disease . Some characteristics of the HPA axis and corticosteroid feedbackFour major characteristics of activity in the adrenocortical system are shown schematically in Fig. 1. Understanding of these, and the fact that they interact, is critical to the understanding of the whole HPA axis, the design of experiments, and the prediction of outcomes.There is a marked circadian rhythm in basal activity of the HPA axis which informs all other functional aspects of the system (Fig. 1~) . Mean 24 h basal plasma B levels in rats average -5 pg/dl (7). Basal activity during the trough of the rhythm results from constitutive secretory activity of the pituitary and adrenal components of the system without hypothalamic input; basal activity during the peak of the rhythm requires input from the h...

The role of the posterior medial bed nucleus of the stria terminalis in modulating hypothalamic–pituitary–adrenocortical axis responsiveness to acute and chronic stress

“…Chronic stress exposure also elevated plasma ACTH levels in the sham rats, consistent with previous studies of chronic stress facilitation of responses to novel stressors (Dallman et al, 1992;Hauger et al, 1990). However, in contrast to the corticosterone data, CVS exposure did not further elevate the ACTH response in rats with lesions.…”

“…Whereas a trend was observed in the sham-lesion CVS group, post-hoc analysis did not reveal significant increases in corticosterone relative to respective non-CVS controls at any time point. Nonetheless, it should be noted that the results remain consistent with stress facilitation in this group, as previous studies note that maintained responsiveness reflects the ability to overcome the cumulative impact of chronic stress-induced increases in glucocorticoid exposure (Dallman et al, 1992). The magnitude of the facilitation effect in BSTpm lesion groups appears to be a summation of the effects of lesion and CVS, being additive rather than synergistic in nature.…”

“…Post-hoc analyses indicated that the posterior BST lesions potentiated plasma ACTH levels compared to respective sham control levels at the 20-min time point regardless of CVS exposure (p < 0.05). Exposure to CVS elevated ACTH levels at the 20-min time point of 'CVS' shams compared to 'No CVS' shams (p < 0.05), consistent with HPA axis facilitation (Armario et al, 1985;Bhatnagar and Dallman, 1998;Bhatnagar and Vining, 2003;Dallman et al, 1992;Hauger et al, 1990;Kiss and Aguilera, 1993a;Ostrander et al, 2006). Lesions enhanced the integrated plasma ACTH response to restraint ( Figure 3C) (F 1,33 = 13.55; p < 0.05) regardless of CVS exposure (p < 0.05).…”

“…Chronic exposure to homotypic stressors typically engender some degree of HPA axis habituation (Dhabhar et al, 1997;Odio and Brodish, 1989;Pitman et al, 1988;Viau and Sawchenko, 2002). However, despite the presence of an enhanced glucocorticoid feedback signals, HPA responses to new stressors are either maintained or augmented following chronic stress a process known as stress facilitation (Armario et al, 1985;Bhatnagar and Dallman, 1998;Bhatnagar and Vining, 2003;Dallman et al, 1992;Hauger et al, 1990;Kiss and Aguilera, 1993;Ostrander et al, 2006). Additionally, chronic stress is implicated in the dysregulation of glucocorticoid secretion that is associated with many disease states such as depression, post-traumatic stress disorder (PTSD) and other anxiety disorders (see (Gold and Chrousos, 2002)).…”

Biphasic Effects of Adrenal Steroids on Learned Helplessness Behavior Induced by Inescapable Shock

“…MR and GR mediate different aspects of corticosterone (CS) action: for example, hippocampal MR is responsible for the maintenance of stability in the stress response system throughout the circadian cycle (Ratka et al, 1989;Dallman et al, 1992), whereas GR facilitates the recovery of the system after the exposure to a stressful stimulus (de Kloet et al, 1988). Moreover, the activation of MR in neurons from the hippocampal CA1 region stabilizes local excitability while it is reduced by GR activation .…”