Inhibiting 11β-hydroxysteroid dehydrogenase type 1 prevents stress effects on hippocampal synaptic plasticity and impairs contextual fear conditioning.
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.
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
R Angela
RA
Sarabdjitsingh
Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands.
Ming
M
Zhou
MRC Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom; Endocrinology Unit, BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
Joyce L W
JL
Yau
MRC Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom; Endocrinology Unit, BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
Scott P
SP
Webster
MRC Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom; Endocrinology Unit, BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
Brian R
BR
Walker
MRC Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom; Endocrinology Unit, BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
Jonathan R
JR
Seckl
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
Marian
M
Joëls
Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands. Electronic address: h.krugers@uva.nl.
Harm J
HJ
Krugers
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000161:Acoustic Stimulation / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D003463:Cues; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005239:Fear / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000209:etiology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D013315:Stress, Psychological / Q000097:blood / Q000150:complications* / Q000473:pathology / Q000517:prevention & control; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*
C000601250:(4-(2-chlorophenyl-4-fluoro-1-piperidinyl)(5-(1H-pyrazol-4-yl)-3-thienyl)methanone; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone
Corticosterone; Fear conditioning; Long-term potentiation; Memory; Stress