Blunted neuroendocrine responses to stress are reported in lactating females after exposure to various stressors. However, many of the stimuli used in these studies have little ethological relevance for maternal protection of the litter in a threatening environment. The question that arises is whether the relevance of the stressor to the infant is critical in the 'gating' of the neuroendocrine response. We hypothesized that the presence of pups with their mothers at the time of exposure to an intruder or a predator odour is an effective way to increase the emotional salience of the psychological stressor, thus eliminating the stress hyporesponsiveness in lactating females. We first compared neuroendocrine responses [corticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN) and central nucleus of the amygdala (CeA), plasma adrenocorticotropic hormone (ACTH) and corticosterone] between early (EL, PPD3-5), late (LL, PPD 15) lactating and virgin (V) females to a male intruder in the home cage. We next investigated the effect of pups' presence at the time of stressor exposure on the magnitude of the hormonal response to a male intruder in the home cage or to a predator odour (fox urine) in a novel environment. In the male intruder paradigm, levels of CRF mRNA expression in the PVN and CeA were lower in LL compared to EL or V females and plasma ACTH and corticosterone secretion was not as elevated in LL compared to EL females. Aggression towards the intruder was high in EL females in the presence of their pups and a positive correlation was found with the integrated ACTH response. Aggression rapidly declined after pup separation (2.5 h or 48 h) or in LL nursing females. In EL females, the presence of the pups with their mothers (EL + pups) at the time of stress significantly increased plasma ACTH and corticosterone responses to either male intruder or predator odour compared to EL females without their pups for 2.5 h or 48 h (EL - pups). Plasma ACTH response to fox urine in EL + pups females was comparable to that of virgin females, suggesting that increasing the salience of emotionally relevant stimuli by keeping the pups present in the cage could eliminate the hyporesponsiveness detected for EL females without their pups. These studies indicate the critical role of the pups in modulating the maternal response to stressors that represent a threat for the litter. We hypothesize that the amygdala, because of its ability to process olfactory stimuli and stimuli with affective properties, might play an essential role in 'gating' the neuroendocrine response to stress during lactation.