title: The CRF₁ receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: comparison with paroxetine and d-cycloserine.
abstract: The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term behavioral and electrophysiological effects produced by traumatic stress exposure in mice. Sleep disturbances are one of the most commonly reported symptoms by people with post-traumatic stress disorder (PTSD). The present study aims at investigating whether SSR125543 (10 mg/kg/day/i.p. for 2 weeks) is able to attenuate sleep/wakefulness impairment induced by traumatic stress exposure in a model of PTSD in mice using electroencephalographic (EEG) analysis. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day/i.p.), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day/i.p.), two compounds which have demonstrated clinical efficacy against PTSD. Baseline EEG recording was performed in the home cage for 6h prior to the application of two electric foot-shocks of 1.5 mA. Drugs were administered from day 1 post-stress to the day preceding the second EEG recording session, performed 14 days later. Results showed that at day 14 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the occurrence of both non-rapid eye movement (NREM) sleep and wakefulness bouts. The duration of wakefulness, NREM and REM sleep were not significantly affected. The stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. These findings confirm further that the CRF₁ receptor antagonist SSR125543 is able to attenuate the deleterious effects of traumatic stress exposure.
authors.affiliation: Sanofi, Translational Sciences Unit, Chilly-Mazarin, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Philbert
authors.affiliation: Sanofi, Translational Sciences Unit, Chilly-Mazarin, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Beeské
authors.affiliation: INSERM U-930, Université François Rabelais Tours, UFR Sciences et Techniques, Parc Grandmont, Tours, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Belzung
authors.affiliation: Sanofi, Translational Sciences Unit, Chilly-Mazarin, France. Electronic address: guy.griebel@sanofi.com.
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003523:Cycloserine / Q000008:administration & dosage; D004195:Disease Models, Animal; D004569:Electroencephalography; D004597:Electroshock; D006846:Hydrocarbons, Halogenated / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D017374:Paroxetine / Q000008:administration & dosage; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D012890:Sleep / Q000187:drug effects; D012893:Sleep Wake Disorders / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013313:Stress Disorders, Post-Traumatic / Q000150:complications* / Q000503:physiopathology; D013315:Stress, Psychological / Q000150:complications* / Q000503:physiopathology; D013843:Thiazines / Q000008:administration & dosage*; D014851:Wakefulness / Q000187:drug effects; D000099052:CRF Receptor, Type 1
chemical_list: D003523:Cycloserine; D006846:Hydrocarbons, Halogenated; D017374:Paroxetine; D018019:Receptors, Corticotropin-Releasing Hormone; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; D013843:Thiazines; D000099052:CRF Receptor, Type 1; C502407:SSR125543
keywords: CRF(1) receptor antagonist; PTSD; Paroxetine; SSR125543; Sleep disturbances; Stress; d-Cycloserine