title: The corticotropin-releasing factor 1 receptor antagonist, SSR125543, and the vasopressin 1b receptor antagonist, SSR149415, prevent stress-induced cognitive impairment in mice.
abstract: The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animals. In the present study, their effects on stress-induced deficit in cognitive performances as assessed in a modified object recognition test were investigated in mice. The object recognition task measures the ability of a mouse to remember an object it has previously explored in a learning trial. During this acquisition session, the mouse was stressed by the presence of a pair of rats under the grid floor of the apparatus. One hour later, it was placed again in the environment with the known and a novel object, but in the absence of the rats. While non-exposed mice spent more time exploring the new object, mice that had been exposed to the rats during acquisition failed to discriminate between the known and the new object during retrieval. This cognitive impairment in stressed mice was prevented by the administration of SSR149415 (10 mg/kg, ip), SSR125543 (10 mg/kg, ip) and the selective serotonin reuptake inhibitor, fluoxetine (10 mg/kg, ip). Under similar conditions, the cognitive enhancer donepezil (1 mg/kg, ip) failed to reverse object recognition deficit. These results indicate that the effects of SSR149415 and SSR125543 in the modified object recognition test, in stressed mice, involve the ability of mice to cope with stress rather than an effect on cognition per se. Together, these data suggest that SSR149415 and SSR125543 may be of interest to reduce the cognitive deficits following exposure to stress-related events, such as acute stress disorder.
authors.affiliation: Sanofi-Aventis, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Urani
authors.forename: Julie
authors.initials: J
authors.lastname: Philbert
authors.forename: Caroline
authors.initials: C
authors.lastname: Cohen
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013315:Stress, Psychological; D013843:Thiazines / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
chemical_list: C456029:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide; D065092:Antidiuretic Hormone Receptor Antagonists; D006846:Hydrocarbons, Halogenated; D007211:Indoles; D011759:Pyrrolidines; D018019:Receptors, Corticotropin-Releasing Hormone; C502407:SSR125543; D013843:Thiazines; D000099052:CRF Receptor, Type 1