CRH deficiency impairs but does not block pituitary-adrenal responses to diverse stressors.
We have previously observed significant, albeit decreased, corticosterone responses to restraint stress in corticotropin releasing hormone (CRH)-deficient (knockout, CRH KO) mice. Because different stressors have been shown to engage different populations of hypophysiotropic neurons, we have used hypoglycemia and hypovolemia to test whether CRH-independent pituitary-adrenal activation is evoked by stimuli other than restraint. Insulin injection in fasted CRH KO mice elicited increases in corticosterone that were markedly lower than those in wild type but marginally significant relative to corresponding KO controls. Consistent with impaired adrenocortical function, hypoglycemia-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 increases in corticotropin (ACTH) in wild-type mice, those in CRH KO mice were slight, transient and difficult to detect without frequent sampling. Restraint-induced interleukin-6 (IL-6) levels were similar between wild-type and CRH KO mice, arguing against compensatory changes in IL-6 responses to restraint due to CRH deficiency. CRH infusion enhanced adrenocortical responses to restraint independently of effects on basal corticosterone levels, suggesting that pituitary-adrenal activity is augmented by factors besides CRH during stress. We conclude that although stress-induced pituitary-adrenal activity does not require acute increases in CRH, CRH is required to support the normal amplitude of adrenocortical axis responsiveness to other endocrine or neural factors during stress.
Jacobson
L
L
Division of Endocrinology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Muglia
L J
LJ
Weninger
S C
SC
Pacák
K
K
Majzoub
J A
JA
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001786:Blood Glucose; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics* / Q000494:pharmacology; D004837:Epinephrine / Q000097:blood; D005215:Fasting / Q000502:physiology; D005260:Female; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020896:Hypovolemia / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013312:Stress, Physiological / Q000503:physiopathology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D015850:Interleukin-6; D011994:Recombinant Proteins; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D004837:Epinephrine