11 beta-Hydroxysteroid dehydrogenase activity in the hippocampus: Implications for in vivo corticosterone receptor binding and cell nuclear retention

In this study a possible role of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) in altering the access of corticosteroids to their receptors in the hippocampus is investigated. In vitro, oxidation of corticosterone to 11-dehydrocorticosterone (11-DHC) was demonstrated in hippocampal homogenates. Glycyrrhetinic acid (GE) and carbenoxolone (CBX) were potent inhibitors of 11 beta-HSD activity and did not display affinity for mineralocorticoid (MRs) nor glucocorticoid receptors (GRs). Intracerebroventricular injection of CBX in vivo (ED(50) similar to 30 mu g) decreased oxidative activity in hippocampal homogenates, as demonstrated in vitro. In vitro, in hippocampal slices, cell nuclear retention of tritiated corticosterone, but not aldosterone, was markedly enhanced in the presence of GE, which at a concentration of 20 nM was found to inhibit 11 beta-HSD activity by about 50% in the intact cell preparation. In contrast to the effect on in vitro cell nuclear uptake, in vivo autoradiography revealed that retention of corticosterone in the hippocampal cell nuclei was not affected after intracerebroventricular treatment with CBX. We conclude that hippocampal 11 beta-HSD activity does not alter binding of low amounts of corticosterone to MRs in vivo, but we cannot exclude that the enzyme may modulate access to corticosteroid receptors under certain circumstances.