Psychological stress increases hippocampal mineralocorticoid receptor levels: involvement of corticotropin-releasing hormone.
We investigated whether acute stressors regulate functional properties of the hippocampal mineralocorticoid receptor (MR), which acts inhibitory on hypothalamic-pituitary-adrenocortical activity. Exposure of rats to forced swimming or novelty evoked a significant rise in density of MR immunoreactivity in all hippocampal subfields after 24 hr, whereas exposure to a cold environment was ineffective. Time course analysis revealed that the effect of forced swimming on MR peaked at 24 hr and returned to control levels between 24 and 48 hr. In pyramidal neurons of CA2 and CA3, marked rises were already observed after 8 hr. Radioligand binding assays showed that corticotropin-releasing hormone (CRH) injected intracerebroventricularly into adrenalectomized rats also produced a rise in hippocampal MR levels; an effect for which the presence of corticosterone, but not dexamethasone, at the time of injection was a prerequisite. Moreover, pretreatment with the CRH receptor antagonist (d-Phe(12),Nle(21,38),alpha-Me-Leu(37))-CRH(12-41) blocked the effect of forced swimming on hippocampal MR levels. To investigate whether the rise in MR levels had any functional consequences for HPA regulation, 24 hr after forced swimming, a challenge test with the MR antagonist RU 28318 was conducted. The forced swimming exposed rats showed an enhanced MR-mediated inhibition of HPA activity. This study identifies CRH as an important regulator of MR, a pathway with marked consequence for HPA axis regulation. We conclude that the interaction between CRH and MR presents a novel mechanism involved in the adaptation of the brain to psychologically stressful events.
Gesing
A
A
Max Planck Institute of Psychiatry, Section of Neuropsychopharmacology, 80804 Munich, Germany.
Bilang-Bleuel
A
A
Droste
S K
SK
Linthorst
A C
AC
Holsboer
F
F
Reul
J M
JM
D000315:Adrenalectomy; D000818:Animals; D003080:Cold Temperature; D003345:Corticosterone / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004777:Environment; D005938:Glucocorticoids / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013315:Stress, Psychological / Q000503:physiopathology*; D013550:Swimming
D005938:Glucocorticoids; C083591:H-R corticotropin-releasing factor (12-41), Phe(12)-Nle(21,38), C(alpha-MeLeu(37))-; D000451:Mineralocorticoid Receptor Antagonists; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; C113202:phenylalanyl corticotropin-releasing factor (12-41); D013148:Spironolactone; C041006:RU 28318; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone