GLUCOCORTICOIDS REGULATE HIPPOCAMPAL 11-BETA-HYDROXYSTEROID DEHYDROGENASE-ACTIVITY AND GENE-EXPRESSION IN-VIVO IN THE RAT

Chronic glucocorticoid excess or deficiency is associated with hippoca mpal dysfunction and neuronal death. 11 beta-hydroxysteroid dehydrogen ase (11 beta-OHSD), which catalyses the reversible conversion of corti costerone to inactive 11-dehydrocorticosterone, regulates glucocortico id access to receptors in the kidney and liver in vivo. The enzyme is also present in the hippocampus where it might modulate glucocorticoid action. We examined the effects of corticosteroid manipulations on hi ppocampal and peripheral 11 beta-OHSD. In the hippocampus, chronic adr enalectomy (10 days) had no effect on 11 beta-OHSD activity, compared to sham-operated controls. Treatment of adrenalectomized animals with dexamethasone (200 mu g/kg.day(-1)), but not aldosterone (20 mu g/kg.d ay(-1)), for 10 days significantly increased hippocampal 11 beta-OHSD activity compared with sham or adrenalectomized rats (22% and 23% rise respectively, P < 0.05). These effects reflect changes in transcripti on of the liver-type 11 beta-OHSD gene, with dexamethasone significant ly increasing 11 beta-OHSD mRNA expression in the hippocampus compared with sham or adrenalectomized animals (32% and 70% higher respectivel y, P<0.05). In the liver, adrenalectomy significantly reduced 11 beta- OHSD activity (16% lower), which was restored to sham levels by dexame thasone, but not aldosterone. Similar trends were seen in 11 beta-OHSD mRNA expression, although these did not reach significance. None of t he manipulations altered 11 beta-OHSD activity or mRNA expression in t he kidney. The hippocampal effects of dexamethasone were similar to th ose of chronic stress (arthritis) which increased 11 beta-OHSD activit y (20% rise, P < 0.05), although this was not reflected at the level o f mRNA. Thus, hippocampal (and hepatic, but not renal) 11 beta-OHSD ap pears to be regulated by chronic glucocorticoid manipulations and stre ss. Hippocampal 11 beta-OHSD may thus ensure optimal long-term cortico sterone exposure of glucocorticoid-sensitive neurons.