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

R. Angela Sarabdjitsingh, Ming Zhou, Joyce L. W. Yau, Scott P. Webster, Brian R. Walker, Jonathan R. Seckl, Marian Joels, Harm J. Krugers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)

Abstract

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes intracellular regeneration of corticosterone and cortisol, thereby enhancing glucocorticoid action. Inhibition of 11 beta-HSD1 reverses the deficits in cognition with aging, a state of elevated glucocorticoid levels. However, any impact of 11 beta-HSD1 inhibition during high glucocorticoid states in younger animals is unknown. Here we examined whether a single injection of the selective 11 beta-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 11 beta-HSD1 inhibitors may be an interesting new approach to the prevention of trauma-associated psychopathology. (C) 2014 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)231-236
Number of pages6
JournalNeuropharmacology
Volume81
DOIs
Publication statusPublished - Jun-2014
Externally publishedYes

Keywords

  • Stress
  • Corticosterone
  • Long-term potentiation
  • Fear conditioning
  • Memory
  • LONG-TERM DEPRESSION
  • GLUCOCORTICOID-RECEPTOR
  • SPATIAL MEMORY
  • MOUSE HIPPOCAMPUS
  • CORTICOSTERONE
  • BRAIN
  • POTENTIATION
  • MICE
  • MODULATION
  • ACTIVATION

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