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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >The CRF 1 receptor antagonist SSR125543 attenuates long-term cognitive deficit induced by acute inescapable stress in mice, independently from the hypothalamic pituitary adrenal axis
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The CRF 1 receptor antagonist SSR125543 attenuates long-term cognitive deficit induced by acute inescapable stress in mice, independently from the hypothalamic pituitary adrenal axis

机译：CRF 1受体拮抗剂SSR125543减轻小鼠急性不可避免的应激诱导的长期认知功能障碍，独立于下丘脑垂体肾上腺轴

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摘要

The selective antagonist at the CRF 1 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 CRF 1 receptors may play a role in these effects.
机译：在许多动物模型中，CRF 1受体的选择性拮抗剂SSR125543已显示出产生抗焦虑作用。本研究的目的是验证这些作用是否由下丘脑垂体肾上腺（HPA）轴的作用介导。在创伤后应激障碍的小鼠模型中评估了SSR125543的作用。动物接受了两次不可避免的电击（1.5 mA / 2 s）。两周后，将它们置于休克环境中，并通过酶免疫法测定粪便和血浆皮质酮水平。在以3、10和30 mg / kg的SSR125543或以20 mg / kg的帕罗西汀（i.p.）给药后，使用目标识别任务评估了他们的认知表现。为了评估HPA轴对药物作用的影响，将另一组动物接受相同的程序和药物治疗，但用地塞米松治疗以钝化HPA轴。与对照动物相比，压力小鼠在再次暴露于环境后具有较高的皮质酮水平，并且显示出受损的认知能力。不论HPA轴是否钝化，通过SSR125543使应激小鼠的皮质酮水平恢复正常，并且通过SSR125543和帕罗西汀明显减轻认知障碍。这些发现证实SSR125543能够减轻压力暴露的有害影响。重要的是，观察到这些作用仍存在于地塞米松治疗的小鼠中，这表明该作用不一定涉及垂体-肾上腺轴阻滞，从而表明垂体外CRF 1受体可能在这些作用中起作用。

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