Facilitation of feedback inhibition through blockade of glucocorticoid receptors in the hippocampus.
In the present study the effects of intracerebroventricular (i.c.v.) and intrahippocampal administration of corticosteroid antagonists on basal hypothalamic-pituitary-adrenal (HPA) activity around the diurnal peak were compared in male Wistar rats. In two separate experiments the glucocorticoid receptor (GR) antagonist RU 38486 and the mineralocorticoid receptor (MR) antagonist RU 28318 were tested. One hour after GR antagonist injection, significant increases in plasma ACTH and corticosterone levels were observed in the i.c.v. treated rats, when compared to vehicle. In contrast, a significant decrease in ACTH levels, and a slight, but non-significant decrease in corticosterone concentrations were attained one hour after intrahippocampal injection of the GR antagonist. Injection of the MR antagonist, on the other hand, resulted in enhanced ACTH and corticosterone levels irrespective of the site of injection. These findings suggest that negative feedback inhibition at the circadian peak involves hippocampal MRs and extrahippocampal (hypothalamic) GRs. The latter feedback inhibition overrides a positive feedback influence exerted by endogenous corticosteroids through hippocampal GRs.
van Haarst
A D
AD
Division of Medical Pharmacology, Leiden-Amsterdam Center for Drug Research, The Netherlands.
Oitzl
M S
MS
de Kloet
E R
ER
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007276:Injections, Intraventricular; D008297:Male; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D013148:Spironolactone; D015735:Mifepristone; C041006:RU 28318; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone