The CRF₁ receptor antagonist SSR125543 attenuates long-term cognitive deficit induced by acute inescapable stress in mice, independently from the hypothalamic pituitary adrenal axis.
The selective antagonist at the CRF₁ receptor, SSR125543, has been shown to produce anxiolytic-like effects in a number of animal models. The aim of the present study was to verify whether these effects are mediated by an action on the hypothalamic pituitary adrenal (HPA) axis. SSR125543 effects were evaluated in a mouse model of post-traumatic stress disorder. Animals received two unavoidable electric foot-shocks (1.5 mA/2 s). Two weeks later they were placed in the shock context and fecal and plasma corticosterone levels were measured by enzyme-immunoassay. Their cognitive performances were evaluated using the object recognition task following administration of SSR125543 at 3, 10 and 30 mg/kg or paroxetine at 20 mg/kg (i.p.), used as positive control. To assess the involvement of the HPA axis in the drug effects, a separate group of animals was subjected to the same procedure and drug regimen, but was treated with dexamethasone to blunt the HPA axis. Stressed mice had higher levels of corticosterone following re-exposure to the context and displayed impaired cognitive performance as compared to control animals. Corticosterone levels were normalized in stressed mice by SSR125543 and the cognitive deficit was significantly attenuated by SSR125543 and paroxetine, whether the HPA axis was blunted or not. These findings confirm that SSR125543 is able to attenuate the deleterious effects of stressful exposure. Importantly, the observation that these effects were still present in dexamethasone-treated mice indicates that this action does not necessarily involve pituitary-adrenal axis blockade, thereby suggesting that extra-pituitary CRF₁ receptors may play a role in these effects.
Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
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Philbert
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Pichat
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Palme
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Belzung
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Griebel
D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000523:psychology*; D003345:Corticosterone / Q000032:analysis / Q000097:blood / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004597:Electroshock; D005243:Feces / Q000737:chemistry; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D051379:Mice; D017374:Paroxetine / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists*; D021641:Recognition, Psychology / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013315:Stress, Psychological / Q000150:complications / Q000523:psychology*; D013843:Thiazines / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
D003345:Corticosterone; D003907:Dexamethasone; D006846:Hydrocarbons, Halogenated; D017374:Paroxetine; D018019:Receptors, Corticotropin-Releasing Hormone; D017367:Selective Serotonin Reuptake Inhibitors; D013843:Thiazines; D000099052:CRF Receptor, Type 1; C502407:SSR125543