FEEDBACK AND FACILITATION IN THE ADRENOCORTICAL SYSTEM - UNMASKING FACILITATION BY PARTIAL INHIBITION OF THE GLUCOCORTICOID RESPONSE TO PRIOR STRESS

Previously stressed animals remain responsive to subsequent stressors, despite secreting an adequate corticosteroid signal during the first stress which should act to damp the response to a second stress. We have previously postulated that stress acts to facilitate subsequent responses in the adrenocortical system, and that this facilitation is balanced by the corticosteroid feedback signal. To test this hypothesis directly, we treated young male rats with cyanoketone (CK) to partially block the adrenal capacity to synthesize corticosterone (B). Subsequently, groups of CK- or vehicle (VEH)-treated rats were exposed to the FIRST stress of 30-min restraint with small blood samples collected at 0, 15, and 30 min. The FIRST stress was given to subgroups of rats 12, 9, 6, or 3 h before lights off (12 h) or lights on (24 h). At 12 or 24 h, rats were again restrained with blood samples at 0 ("basal") and 30 min (SECOND stress). Control groups were stressed for the first time when the experimental groups received their SECOND stress. Plasma ACTH and B concentrations were measured. Although in the absence of stress, basal B concentrations were normal in CK-treated compared to VEH-treated rats throughout the day, the B response to the FIRST stress was reduced by 60% in the CK- compared to the VEH-treated group. When the FIRST stress was performed during the time of lights on, "basal" plasma ACTH was elevated in CK groups at 12 h (lights off) compared to levels in both previously stressed VEH groups and unstressed CK controls. There was no difference at this time of day in the magnitude of the ACTH response to the SECOND stress in CK rats compared to that in CK rats receiving their only stress (controls) or that in VEH-treated rats receiving the SECOND stress. When first stress was performed during the time of lights off, "basal" plasma ACTH at 24 h (lights on) in CK and VEH rats were not different compared to levels in their respective unstressed controls. The ACTH response to the SECOND stress at 24 h was elevated in all previously stressed CK groups compared to that in either CK control or VEH groups. At neither time of day were SECOND stress ACTH concentrations in VEH rats different from those in control VEH rats. At 12 h (lights off), but not at 24 h (lights on), "basal" ACTH was significantly elevated in VEH rats above the unstressed VEH control values. We conclude from these experiments that 1) during at least a 12-h period, prior stress induces a facilitatory trace in central neural components of the adrenocortical system that causes an elevated ACTH response to the diurnal input at lights off; 2) because VEH groups were normoresponsive to stress at all times, the facilitatory signal imposed by the FIRST stress is balanced by the simultaneously secreted corticosteroid feedback signal, so that repeated stressors provoke repeated ACTH secretion of similar magnitude; 3) the stress-induced facilitatory trace observed in CK groups resides at a neural site that lies before the final hypothalamic neuroendocrine neurons, because the ACTH response to restraint stress was facilitated only at lights on, not at lights off. The results show that stress-induced facilitation of subsequently stimulated ACTH secretion explains the persistant normoresponsiveness of the mammalian adrenocortical system to repeated stress.