The responsiveness of the neonatal hypothalamus-pituitary-adrenal (HPA) axis to stress has been though to be impaired or diminished during the first 2 weeks of life. Although we previously found full responsiveness of the hypothalamus-pituitary unit to adrenalectomy in young rats [days (d) 5-10], we failed to measure a significant increase in ACTH 10 min after ether administration until d14 of age. These studies were, therefore, designed to test the functional activation of the HPA axis after a single or repeated exposures to stress. Both qualitative (time-course, stressor-specific, circadian) and quantitative changes in the ACTH and corticosterone (B) responses to various stressors were tested during the first 10 days of life. Exposure to 3 min of ether vapor increased ACTH and B secretion (P < 0.05-0.01) in 1-, 5-, and 10-d-old rats, with an increasing amplitude of both ACTH and B responses as a function of age. Peak secretion of ACTH occurred 5 min after the onset of stress (122 +/- 3.8 to 359 +/- 54 pg/ml on d1-10), while the time of maximal B increased as a function of age. Other stressors, such as maternal separation (12 h), cold (4 C; 60 min), or histamine injection (4 mg/kg BW, ip), provoked significant and stressor-specific ACTH and B responses in 10-d-old rats. Histamine administration increased ACTH secretion above that of vehicle-injected rats, with a peak of secretion 15 min after drug injection (272 +/- 29 vs. 127 +/- 8 pg/ml; P < 0.01). Histamine-induced B secretion peaked at 60 min (3.7 +/- 0.5-mu-g/dl). In contrast to early responses observed after ether, separation, or histamine stress, cold stress in 10-d-old pups caused a large ACTH and B release 4 h after the onset of cold compared to that in maternally deprived pups [ACTH: cold, 457 +/- 61 pg/ml; separated, 150 +/- 14 (P < 0.01); B: cold, 3.3 +/- 0.4-mu-g/dl; separated, 1.8 +/- 0.2 (P < 0.05)]. We did not detect morning-evening (AM-PM) differences in either the pattern or the magnitude of the ACTH or B response to maternal separation or cold stress. Suppression of cold-induced ACTH release by B injection (1 mg/kg BW) 2 h before stress was observed until 4 h after stress in the AM and PM, whereas when given after cold, B was less effective in the PM than in the AM at preventing the rise in ACTH levels observed at 4 h. The hypothalamic arginine vasopressin content decreased (P < 0.01) after cold stress, while the CRF content was not altered compared to those in separated pups. However, B treatment 2 h before cold produced significant (P < 0.01) accumulation of CRF content in cold-exposed pups compared to untreated stressed rats. Repeated stimulation (ether stress or CRF administration) in 10-d-old pups caused further increases in plasma ACTH and B concentrations. This was observed after a second 3-min exposure to ether whether the interval between the two stressors was 5 min, 1 h, or 4 h or when synthetic CRF was injected 5 min after ether exposure. Our results demonstrate that the functional capacity of the HPA axis to respond to a variety of stressors is present throughout neonatal life. However, the magnitude of the responses varies with developmental age, and the pattern as well as the kinetics of the response are stressor specific. Furthermore, the pituitary adrenocortical system is not limited in its capacity to respond to repeated stimulation by either stress or CRF administration. Thus, a developmental increase in the capacity for pituitary and adrenal components of the system to respond to stress is observed in neonates, rather than an impairment in central motor components controlling HPA axis activity.
