Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory

Neurobiol Learn Mem. 2011 May;95(4):453-60. doi: 10.1016/j.nlm.2011.02.006. Epub 2011 Feb 17.


Background: The pharmacology of traumatic memory extinction has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders, including post-traumatic stress disorder (PTSD). Here we examine the role of endogenous glucocorticoids in traumatic memory extinction.

Methods: Male C57BL/6J mice were injected with corticosterone (10 mg/kg, i.p.) or metyrapone (50 mg/kg, s.c.) during re-activation of a contextual fear memory, and compared to vehicle groups (N=10-12 per group). To ensure that metyrapone was blocking corticosterone synthesis, we measured corticosterone levels following re-activation of a fear memory in metyrapone- and vehicle-treated animals.

Results: Corticosterone administration following extinction trials caused a long-lasting inhibition of the original fear memory trace. In contrast, blockade of corticosteroid synthesis with metyrapone prior to extinction trials enhanced retrieval and prevented extinction of context-dependent fear responses in mice. Further behavioral analysis suggested that the metyrapone enhancement of retrieval and prevention of extinction were not due to non-specific alterations in locomotor or anxiety-like behavior. In addition, the inhibition of extinction by metyrapone was rescued by exogenous administration of corticosterone following extinction trials. Finally, we confirmed that the rise in corticosterone during re-activation of a contextual fear memory was blocked by metyrapone.

Conclusions: We demonstrate that extinction of a classical contextual fear memory is dependent on endogenous glucocorticoid synthesis during re-activation of a fear memory. Our data suggest that decreased glucocorticoids during fear memory re-activation may contribute to the inability to extinguish a fear memory, thus contributing to one of the core symptoms of PTSD.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites / pharmacology
  • Association Learning / drug effects
  • Association Learning / physiology*
  • Conditioning, Classical / physiology
  • Corticosterone / antagonists & inhibitors
  • Corticosterone / physiology*
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Fear*
  • Inhibition, Psychological
  • Male
  • Memory / drug effects
  • Memory / physiology*
  • Metyrapone / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Naphthalenes
  • Oxepins


  • 1-phenyl-1,4-epoxy-1H,4H-naphtho(1,8-de)(1,2)dioxepin
  • Antimetabolites
  • Naphthalenes
  • Oxepins
  • Corticosterone
  • Metyrapone