title: The CRF₁ receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: comparison with paroxetine and D-cycloserine.
abstract: BACKGROUND
  The selective CRF1 (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus.
  
  
  OBJECTIVE
  The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD.
  
  
  METHODS
  Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study.
  
  
  RESULTS
  Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine.
  
  
  CONCLUSIONS
  These findings confirm that the CRF1 receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress.
authors: Sanofi, Exploratory Unit, 1, Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France.
authors: J
authors: J
authors: Philbert
authors: C
authors: C
authors: Belzung
authors: G
authors: G
authors: Griebel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D003523:Cycloserine / Q000494:pharmacology; D004597:Electroshock; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D008297:Male; D051379:Mice; D017374:Paroxetine / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy*; D013843:Thiazines / Q000494:pharmacology*; D013997:Time Factors; D000099052:CRF Receptor, Type 1
chemical_list: D003523:Cycloserine; D006846:Hydrocarbons, Halogenated; D017374:Paroxetine; D018019:Receptors, Corticotropin-Releasing Hormone; D017367:Selective Serotonin Reuptake Inhibitors; D013843:Thiazines; D000099052:CRF Receptor, Type 1; C502407:SSR125543