This research will systematically document changes in stress responsiveness induced by ethanol exposure, either in utero or in adulthood, and will investigate mechanisms that might mediate these changes. 1. Fetal alcohol exposure (FAE). Our working hypothesis is that pituitary-adrenal hyperresponsiveness and deficits in recovery following stress which have been observed in FAE animals result from ethanol-induced deficits in feedback control of the hypothalamo-pituitary-adrenal (HPA) axis. HPA function in FAE animals will be explored at multiple levels: 1) by both challenging and inhibiting the system, and 2) by examining hormonal responsiveness in parallel experiments both in vivo and in vitro. The role of hippocampal glucocorticoid receptors in mediating increased stress responsiveness of FAE animals will be studied by examining receptor occupancy under conditions of varying hormone levels, receptor plasticity (up-regulation following adrenalectomy [ADX]), and receptor down-regulation (during chronic stress or chronic corticoid administration). Possible deficits in feedback regulation at other levels of the HPA axis (hypothalamus, pituitary) will also be assessed. Sex differences in response will be examined in all studies. 2.Adult chronic alcoholism. Our working hypothesis is that chronic alcohol consumption, which consistently elevates basal corticoid levels in both animals and humans, will result in HPA hyperresponsiveness to stress. Chronic alcoholic males and females will be tested using acute and chronic stressors to determine HPA activation and recovery, and to examine HPA responsiveness both in vivo and in vitro. The role of hippocampal glucocorticoid receptors in mediating changes in stress responsiveness will be studied by examining receptor occupancy following acute and chronic stress and receptor plasticity (up-regulation following ADX). Possible deficits in feedback regulation at other levels of the HPA axis will also be examined. The ability to respond to stress is an important basic adaptive mechanism. Hyperresponsiveness or deficits in recovery following stress could have adverse physiological and behavioral consequences and thus impact negatively on health. The proposed research will have relevance to our understanding of sex differences in ethanol's effects, both in utero and in adulthood, on the adaptive function of the organism.