The CRF₁ receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: comparison with paroxetine and D-cycloserine.

Abstract

RATIONALE:

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.

OBJECTIVES:

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: J Philbert, C Belzung, G Griebel
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 228 Issue 1 Pg. 97-107 (Jul 2013) ISSN: 1432-2072 [Electronic] Germany
• PMID: 23407783 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydrocarbons, Halogenated
• Receptors, Corticotropin-Releasing Hormone
• SSR125543
• Serotonin Uptake Inhibitors
• Thiazines
• Paroxetine
• CRF receptor type 1
• Cycloserine

Topics

• Animals
• Behavior, Animal (drug effects)
• Cognition Disorders (drug therapy, etiology)
• Cycloserine (pharmacology)
• Electroshock
• Hippocampus (drug effects, pathology)
• Hydrocarbons, Halogenated (pharmacology)
• Male
• Mice
• Paroxetine (pharmacology)
• Receptors, Corticotropin-Releasing Hormone (antagonists & inhibitors)
• Selective Serotonin Reuptake Inhibitors (pharmacology)
• Stress, Psychological (complications, drug therapy)
• Thiazines (pharmacology)
• Time Factors