Conditional Feedback in the Hypothalamic- Pituitary-Adrenal Axis

Up to this point, glucocorticoid feedback properties have been discussed with respect to the normal unstressed organism. Under conditions of persistent or chronic stress, the axis appears to change, and sensitivity to the feedback action of corticosteroids is slightly to markedly reduced.

Thus, under chronic stress, mean daily plasma corticosteroid concentrations increase, frequently only because circadian trough levels are elevated but occasionally because there are major stressor-induced elevations throughout the circadian cycle. With chronic stress, the degree of the inhibition of stimulated ACTH secretion by exogenous (or endogenously secreted) glucocorticoids is decreased.

In rats, chronic stress often stimulates increased expression of AVP in CRH-synthesizing neurons, thus providing a means for amplifying the corticotroph response to the CRH and AVP secreted. However, it also appears that neural sites upstream from the final hypothalamic CRH and AVP motor neurons of the HPA axis are less sensitive to corticosteroid feedback.

A decreased number of GRs has been reported, primarily in hippocampus, after many chronic stressors and after treatment with exogenous glucocorticoids, suggesting that one mechanism of reduced feedback sensitivity may reside in GR downregulation. This is not the only explanation for reduced feedback sensitivity during chronic stress, however, because there are several examples in which both MR and GR numbers are normal throughout brain but glucocorticoid feedback insensitivity is found.

Because the strength of inputs to the CRH and AVP cells stimulates dose-related output, it is likely that, although corticosteroid dose-related functions are occurring normally under chronic stress conditions, the level of input to the CRH and AVP cells increases. Thus, normal responsivity in the HPA axis is maintained, whereas the apparent feedback efficacy of glucocorticoids is reduced. It does appear that new stimuli presented to chronically stressed animals causes facilitated responses in the central neural pathways to the CRH and AVP neurons.

The result of the apparent decrease in glucocorticoid feedback under conditions of chronic stimulation of the HPA axis is that there is dampening of the response to the ongoing stimulus but full or even exaggerated responsiveness to a new and different stimulus. Both effects are useful - the degree of hyperglucocorticoidism is limited by ongoing glucocorticoid feedback, but the organism is still capable of responding to a new stimulus that may demand a momentary shot of the hormones for optimal response.