Glucocorticoids act upon the hypothalamus and pituitary to regulate both corticotropin-releasing factors and adrenocorticotropin (ACTH) in a classical negative feedback loop. There are two distinct receptor systems in the central nervous system for glucocorticoids: type I corticosterone/cortisol-preferring, predominantly hippocampal receptors, and type II dexamethasone-binding receptors with a much broader distribution. To determine the relative roles played by these two receptors in determining basal and stress-induced ACTH/cortisol levels in the sheep, we have conducted two series of experiments. In the first, we infused 4 sheep with cortisol (50 µg/h), or dexamethasone (20 µg/h) for 17 h, collected 10-min blood samples for 3 h for basal hormone levels, and then subjected the sheep to an audiovisual stress (barking dog), 10 µg of ovine corticotropin-releasing factor (oCRF) 1 h later, and 100 U of insulin another 2 h later. Dexamethasone reduced ACTH and cortisol levels, both basal and in response to stress; cortisol infusion had no effect on any parameters; oCRF did not raise ACTH levels. In the second experiment, cortisol (100 µg/h) alone was infused into 4 sheep for 17 h, and blood samples were collected for 3 h for basal hormone levels; this was followed by the injection of 10 µg oCRF, and 2 h later a barking dog was introduced into the sheep shed. Again, cortisol infusion did not affect basal ACTH or cortisol levels, though both cortisol-infused and control animals had ACTH responses to oCRF when it was not preceded by the audiovisual stress. ACTH and cortisol levels were higher in the 2 h following oCRF injection. Subsequent responses to the stress brought on by the dog were not altered. We conclude: (i) with the caveat that cortisol levels did not rise post-infusion, that negative feedback effects of glucocorticoids on the hypothalamo-pituitary adrenal axis in intact sheep are primarily via type II and not type I receptors; (ii) that physiologically induced elevations in cortisol are capable of inhibiting pituitary responsiveness to oCRF in the sheep via an intermediate duration (minutes-to-hours) feedback mechanism, and (iii) that oCRF may play a role in priming the hypothalamo-pituitary-adrenal axis.

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