title: Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory.
abstract: 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.
authors.affiliation: Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave., St. John's, Newfoundland A1B3X9, Canada. jblundell@mun.ca
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Blundell
authors.forename: Cory A
authors.initials: CA
authors.lastname: Blaiss
authors.forename: Diane C
authors.initials: DC
authors.lastname: Lagace
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Eisch
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001245:Association Learning / Q000187:drug effects / Q000502:physiology*; D003214:Conditioning, Classical / Q000502:physiology; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear; D007266:Inhibition, Psychological; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes; D010082:Oxepins
chemical_list: C461941:1-phenyl-1,4-epoxy-1H,4H-naphtho(1,8-de)(1,2)dioxepin; D000963:Antimetabolites; D009281:Naphthalenes; D010082:Oxepins; D003345:Corticosterone; D008797:Metyrapone