The development of pituitary-adrenal activity was examined in the offspring of rat dams fed a 5.0% w/v ethanol-containing liquid diet or pair-fed an isocaloric diet, as a nutritional control, from day 8 of gestation to parturition. Serum corticosterone responses of the pups to challenges with ethanol (1.5 g/kg) or morphine (3.0 mg/kg) were determined at 5, 7, 10, 12 and 18 days of age. The pituitary-adrenal axis of normal neonates was activated by the drugs at each age, with a characteristic biphasic developmental pattern in which a trough occurred at day 7. The overall pattern was unaffected by prenatal ethanol exposure or pair-feeding. However, both prenatal treatments intensified the trough. Already on day 5 and also on day 7, corticosterone responses of both the ethanol-exposed and pair-fed offspring to ethanol were significantly lower than responses of normal pups. Additionally, on day 7, ethanol-exposed offspring had significantly lower responses to ethanol than pair-fed offspring and significantly lower responses to morphine than normal pups. Thus, both the prenatal ethanol and pair-feeding treatments suppressed pituitary-adrenal responsiveness of 5 and 7 day-old neonates to the drug challenges. This is in marked contrast to our previous findings for adult prenatally ethanol-exposed offspring whose pituitary-adrenal responses to the same drugs, as well as to other stressors, are consistently enhanced in comparison to pair-fed derived rats, whose responses in adulthood no longer differ from normals.