CRH deficiency impairs but does not block pituitary-adrenal responses to diverse stressors

We have previously observed significant, albeit decreased, corticosterone r esponses to restraint stress in corticotropin releasing hormone (CRH)-defic ient (knockout, CRH KO) mice. Because different stressors have been shown t o engage different populations of hypophysiotropic neurons, we have used hy poglycemia and hypovolemia to test whether CRH-independent pituitary-adrena l activation is evoked by stimuli other than restraint. Insulin injection i n fasted CRH KO mice elicited increases in corticosterone that were markedl y lower than those in wild type but marginally significant relative to corr esponding KO controls. Consistent with impaired adrenocortical function, hy poglycemia-induced epinephrine secretion was reduced in female CRH KO mice. Hypovolemia produced by retro-orbital bleeding also significantly elevated corticosterone in CRH KO mice. In contrast to significant stress-induced i ncreases in corticotropin (ACTH) in wild-type mice, those in CRH KO mice we re slight, transient and difficult to detect without frequent sampling. Res traint-induced interleukin-6 (IL-6) levels were similar between wild-type a nd CRH KO mice, arguing against compensatory changes in IL-6 responses to r estraint due to CRH deficiency. CRH infusion enhanced adrenocortical respon ses to restraint independently of effects on basal corticosterone levels, s uggesting that pituitary-adrenal activity is augmented by factors besides C RH during stress. We conclude that although stress-induced pituitary-adrena l activity does not require acute increases in CRH, CRH is required to supp ort the normal amplitude of adrenocortical axis responsiveness to other end ocrine or neural factors during stress. Copyright (C) 2000 S. Karger AG, Ba sel.