Antidepressant-like effects of the glucocorticoid receptor antagonist RU-43044 are associated with changes in prefrontal dopamine in mouse models of depression
Antidepressant-like effects of the glucocorticoid receptor antagonist RU-43044 are associated with changes in prefrontal dopamine in mouse models of depression
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DOI：
10.1016/j.neuropharm.2008.08.026
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发表时间：
2008-12-01
影响因子：
4.7
通讯作者：
Matsuda, Toshio
中科院分区：
文献类型：
--
作者：
Ago, Yukio;Arikawa, Shinsuke;Matsuda, Toshio
慢性皮质酮和隔离饲养模式可能提供可靠的抑郁症小鼠模型。利用这些模型，本研究考察了特异性糖皮质激素受体拮抗剂RU-43044是否具有抗抑郁样作用，并研究了前额叶神经传递在行为效应中的可能作用。在强迫游泳和悬尾试验中，长期给予皮质酮和隔离饲养增加了静止时间。用RU-43044亚慢性治疗可减少慢性皮质酮治疗和隔离饲养小鼠在强迫游泳试验中的不动时间，但对对照组小鼠无此作用。慢性皮质酮降低皮质糖皮质激素受体水平，应激诱导血浆皮质酮水平升高，阻断血浆皮质酮对地塞米松的反应，而分离饲养未引起糖皮质激素受体系统的任何变化。慢性皮质酮和分离饲养均显著增加高K+诱导的前额皮质多巴胺释放，但不增加血清素释放。亚慢性RU-43044逆转慢性皮质酮治疗和隔离饲养小鼠前额皮质多巴胺释放的增强。这些结果表明，慢性皮质酮和隔离饲养分别增加糖皮质激素受体依赖和独立方式的抑郁样行为，而RU-43044可能通过抑制这些小鼠模型中增强的前额叶多巴胺能神经传递而表现出抗抑郁样作用。(C) 2008 Elsevier Ltd版权所有。
Chronic corticosterone and isolation rearing paradigms may provide reliable mouse models of depression. Using these models, the present study examined if the specific glucocorticoid receptor antagonist, RU-43044, has an antidepressant-like effect, and Studied the possible role of prefrontal neurotransmission on the behavioral effects. Chronic administration of corticosterone and isolation rearing increased the immobility time in the forced swim and tail suspension tests. Subchronic treatment with RU-43044 decreased the immobility time in the forced swim test in chronic corticosterone-treated and isolation-reared mice, but not the control mice. Chronic corticosterone decreased the levels of cortical glucocorticoid receptors and stress-induced increases in plasma corticosterone levels, and blocked the response of plasma corticosterone to dexamethasone, while isolation rearing did not cause any changes in the glucocorticoid receptor system. Both chronic corticosterone and isolation rearing markedly increased high K+-induced dopamine release, but not serotonin release, in the prefrontal cortex. Subchronic RU-43044 reversed the enhanced release of dopamine in the prefrontal cortex of chronic corticosterone-treated and isolation-reared mice. These results Suggest that chronic corticosterone and isolation rearing increase the depressive-like behavior in glucocorticoid receptor-dependent and independent manners, respectively, and that RU-43044 shows an antidepressant-like effect, probably via an inhibition of enhanced prefrontal dopaminergic neurotransmission in these mouse models. (C) 2008 Elsevier Ltd. All rights reserved.