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Glucocorticoid Receptor Blockade Disinhibits Pituitary-Adrenal Activity during the Stress Hyporesponsive Period of the Mouse

Leiden-Amsterdam Center for Drug Research/Leiden University Medical Center (M.S., M.S.O., M.v.d.M., E.R.d.K.), Leiden University, 2300RA Leiden, The Netherlands; Max Planck Institute for Psychiatry (M.S., M.B.M., F.H.), 80804 Munich, Germany; Department of Psychiatry (S.L.), University of California, Davis, California 95616

Address all correspondence and requests for reprints to: Dr. Mathias Schmidt, Max Planck Institute of Psychiatry, Molecular Stress Physiology, Kraepelinstrasse 2–10, 80804 München, Germany. E-mail: mschmidt{at}mpipsykl.mpg.de.

During postnatal development, mice undergo a period of reduced responsiveness of the pituitary-adrenal axis, the stress hyporesponsive period (SHRP), which is largely under control of maternal signals. The present study was designed to test the hypothesis that this quiescence in hypothalamic-pituitary-adrenal (HPA) activity is mediated by glucocorticoid feedback. For this purpose, the role of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in control of HPA activity was examined during the SHRP and in response to 24 h of maternal deprivation. Nondeprived or deprived (24 h) CD1 mice on postnatal d 8 were injected sc at 16 and 8 h before testing with the MR antagonist RU28318 or the GR antagonist RU38486. The results showed that, in nondeprived mice, blockade of GR rather than MR triggered a profound increase in anterior pituitary proopiomelanocortin mRNA, circulating ACTH, and corticosterone concentrations. In contrast, CRH mRNA in hypothalamus and GR mRNA in hippocampus and hypothalamus were decreased. Blockade of the GR during the deprivation period amplified the rise in corticosterone induced by maternal deprivation, whereas it reversed the deprivation effect on the other HPA markers, leading to profound increases in plasma ACTH, proopiomelanocortin mRNA expression in the anterior pituitary, CRH mRNA expression in the paraventricular nucleus, and MR mRNA expression in the hippocampus, but not in GR mRNA expression in the hippocampus and paraventricular nucleus. In conclusion, the data suggest that control of postnatal pituitary-adrenal activity during the SHRP involves GR-mediated feedback in the anterior pituitary, which is further potentiated in the absence of the mother.

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