Inhibiting 11β-hydroxysteroid dehydrogenase type 1 prevents stress effects on hippocampal synaptic plasticity and impairs contextual fear conditioning

Abstract 11β-Hydroxysteroid dehydrogenase type 1 (11β−HSD1) catalyzes intracellular regeneration of corticosterone and cortisol, thereby enhancing glucocorticoid action. Inhibition of 11β−HSD1 reverses the deficits in cognition with aging, a state of elevated glucocorticoid levels. However, any impact of 11β−HSD1 inhibition during high glucocorticoid states in younger animals is unknown. Here we examined whether a single injection of the selective 11β−HSD1 inhibitor UE2316 modifies the effect of stress on hippocampal long-term potentiation and fear conditioning, a learning paradigm that is strongly modulated by glucocorticoids. We found that novelty stress suppresses hippocampal synaptic potentiation. This effect was completely prevented by administration of UE2316 one hour before stress exposure. A single injection of UE2316 also impaired contextual, but not tone-cue-fear conditioning. These observations suggest that local metabolism of glucocorticoids is relevant for the outcome of stress effects on hippocampal synaptic plasticity and contextual fear conditioning. Selective 11β−HSD1 inhibitors may be an interesting new approach to the prevention of trauma-associated psychopathology.