During postnatal development mice undergo a period of reduced responsiveness of the pituitary-adrenal axis, the stress hypo-responsive period (SHRP), which is largely under control of maternal signals. The present study was designed to test the hypothesis that this quiescence in HPA activity is mediated by glucocorticoid feedback. For this purpose the role of mineralo- (MR) and glucocorticoid receptors (GR) in control of HPA activity was examined during the SHRP and in response to 24 h of maternal deprivation. Non-deprived or deprived (24 h) CD1 mice on postnatal day 8 were injected subcutaneously at 16 and 8 h before testing with the MR antagonist RU28318 or the GR antagonist RU38486. The results showed that in non-deprived mice blockade of GR rather than MR triggered a profound increase in anterior pituitary POMC 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, while it reversed the deprivation effect on the other HPA markers leading to profound increases in plasma ACTH, POMC mRNA expression in the anterior pituitary, CRH mRNA expression in the PVN and MR mRNA expression in the hippocampus, but not in GR mRNA expression in hippocampus and PVN. 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.