Studies on fast feedback mechanisms by endogenous glucocorticoids.

Negative feedback in the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoids has been well established, but it is still in doubt whether ACTH-releasing factor (CRF) activity in the hypothalamus is inhibited by endogenous glucocorticoids under conditions of stress. In our first experiment, CRF activity in the hypothalamus of rats was significantly increased, 2 min after onset of immobilization, for 2 min; a rapid drop of CRF activity followed immediately. On the other hand, the concentration of plasma corticosterone changed more slowly; it was increased at 5 min, and showed a progressive further increase until 17 min after the administration of the immobilization stress. A high plateau level persisted for the next 8 min, after which the concentration of plasma corticosterone fell, reaching the control level at 40 min. In order to test for negative feedback inhibition by endogenous glucocorticoids in the hypothalamic-pituitary-adrenal axis, a 2nd immunobilization stress was administered to rats 5 or 23 min after the 1st stress, and hypothalamic CRF activity and plasma corticosterone were examined after the 2nd stress. When the 2nd stress was applied 5 min after the start of the 1st stress, during the phase of a gradual increase of endogenous glucocorticoids, CRF activity was not increased 2 min after the 2nd stress. In contrast, an increase of CRF activity and plasma corticosterone was observed when the 2nd stress was administered 23 min after the onset of the 1st stress, during the phase of a high plateau level of endogenous plasma corticosterone. These data suggest that CRF activity in the hypothalamus is governed by a fast feedback, rate-sensitive mechanism.