The hypothalamic-pituitary-adrenal (HPA) axis is normally quiescent during the stress-hyporesponsive period (SHRP) from day 4-14 in infant rats. However, maternal deprivation (DEP) can disinhibit the HPA axis, thus enabling neonatal rats to respond to mild stressors. In an effort to understand how DEP may alter HPA axis sensitivity, we used in situ hybridization to measure changes in the expression of stress-responsive genes in the brains of neonatal rats. Despite the minimal HPA axis response in nondeprived rats during the SHRP (postnatal day 12), the mild stress of a saline injection significantly increased messenger RNA levels of two immediate-early genes (IEGs), c-fos and NGFI-B, in the hypothalamic paraventricular nucleus (PVN) and in the cerebral cortex. Following 24 h of DEP, the induction of IEGs in response to stress was greatly potentiated in the PVN of P12 neonates. In contrast, DEP attenuated the effects of stress on IEG induction in rats that had matured beyond the SHRP (P20). Surprisingly, DEP decreased basal levels of CRH messenger RNA in the PVN at P12 and P20. Thus the SHRP most accurately refers to HPA axis insensitivity to stress because the brain itself readily responds to stress as evidenced by the induction of IEGs.