Intracellular regeneration of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD)-1 plays a key role in regulation of the hypothalamic-pituitary-adrenal axis: Analysis of 11 beta-HSD-1-deficient mice

11 beta -Hydroxysteroid dehydrogenases (11 beta -HSDs) catalyze interconver sion of active corticosterone and inert 11-dehydrocorticosterone, thus regu lating glucocorticoid access to intracellular receptors in vivo. 11 beta -H SD type 1 is a reductase, locally regenerating active glucocorticoids. To e xplore the role of this isozyme in the brain, we examined hypothalamic-pitu itary-adrenal axis (HPA) regulation in mice homozygous for a targeted disru ption of the 11 beta -HSD-1 gene. 11 beta -HSD-1-deficient mice showed elev ated plasma corticosterone and ACTH levels at the diurnal nadir, with a pro longed corticosterone peak, suggesting abnormal HPA control and enhanced ci rcadian HPA drive. Despite elevated corticosterone levels, several hippocam pal and hypothalamic glucocorticoid-sensitive messenger RNAs were normally expressed in 11 beta -HSD-1-deficient mice, implying reduced effective gluc ocorticoid activity within neurons. 11 beta -HSD-1-deficient mice showed ex aggerated ACTH and corticosterone responses to restraint stress, with a del ayed fall after stress, suggesting diminished glucocorticoid feedback. Inde ed, 11 beta -HSD-1-deficient mice were less sensitive to exogenous cortisol suppression of HPA activation. Thus 11 beta -HSD-1 amplifies glucocorticoi d feedback on the HPA axis and is an important regulator of neuronal glucoc orticoid exposure under both basal and stress conditions in vivo.