To determine the expression of glucocorticoid metabolizing and action genes in the hippocampus of fetal, neonatal, and adult sheep. pregnant ewes (or their fetuses) received intramuscular injections of saline or betamethasone (BETA, 0-5 ing/kg) at 104, 111, 118, and/or 125 days of gestation (dG). Hippocampal tissue was collected prior to (75, 84, and 101 dG), during (109 and 116 dG), or after (121, 132, and 146 dG; 6 and 12 postnatal weeks; 3-5 years of age) saline or BETA injections. Hippocampal glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and 11 beta-hydroxysteroid dehydrogenase (11 beta HSD)1 and 11 beta HSD2 mRNA levels were determined using qRT-PCR. Control animals late in gestation demonstrated a decrease in mPNA encoding GR and 11 beta HSD1, whereas 11 beta HSD2 was undetectable, consistent witha damping of the negative feedback influence of circulating or locally produced cortisol on the hypothalamic-pituitary-adrenal (HIIA) a-xis. BETA-administration had transient effects on fetal GR and MR, and early in postnatal life (12 weeks of age) 11 beta HSD1 mRNA was increased. Hippocampal MR, mRNA was elevated in adult offipring exposed to either one or four doses of maternal BETA (P<0.001). Four courses of maternal BETA increased 11 beta HSD2 (P<0.05) but not 11 beta HSD1 mRNA levels. Late in gestation a reduction in hippocampal GR and 11 beta HSD1 mRNA suggests lessening of glucocorticoid negative feedback, facilitating increased preterm HIIA activity and parturition. Adult offispring of BETA-treated mothers demonstrated increased MR and 11 beta HSD2 mRNA, therefore it appears that exposure of fetus to high levels of synthetic glucocorticoids may have long-lasting effects on the hippocampal expression of HPA-related genes into adulthood.