Corticosterone exposure augments sensitivity to the behavioral and neuroplastic effects of fluoxetine in C57BL/6 mice.
Corticosterone exposure augments sensitivity to the behavioral and neuroplastic effects of fluoxetine in C57BL/6 mice.
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DOI：
10.1016/j.ynstr.2015.12.005
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发表时间：
2016-06
影响因子：
5
通讯作者：
Lucki I
中科院分区：
文献类型：
--
作者：
Robinson SA;Brookshire BR;Lucki I
遗传背景和预先存在的压力在抗抑郁药物的作用中起着关键作用。目前的研究表明，暴露于应激激素皮质酮（CORT）后，C57 BL/6小鼠（一种通常对这些作用有抵抗力的品系）长期接受氟西汀治疗后，出现了行为和神经原性效应。成年雄性小鼠皮下植入21天缓释CORT丸粒（10 mg）或安慰剂，然后用5 mg/kg氟西汀（b.i.d.，i.p.）或生理盐水14天。然后评估动物在新奇诱导的摄食量减少（NIH）试验中的接近行为、海马细胞增殖、皮质类固醇受体表达和CORT血浆水平。CORT与氟西汀联合治疗显著降低了NIH测试新环境中的接近行为，并增加了海马细胞增殖，而氟西汀单独给药无效。单独给予CORT并不改变新环境中的接近行为，并引起细胞增殖的较小增加。肾上腺切除术阻断了CORT效应，可能是由于肾上腺反馈增加。CORT处理动物的细胞增殖与盐皮质激素受体mRNA表达降低相关，但与糖皮质激素受体mRNA表达无关。尽管宣传颗粒可持续释放CORT 21天，但植入后1天血浆CORT水平升高，但在7天或更长时间间隔测量时并不持续。然而，在氟西汀治疗后，短暂的CORT增加足以诱导长期的行为和分子变化。这些研究需要进一步研究糖皮质激素和环境应激作为抗抑郁药反应的连续促进剂的作用，特别是对于治疗抵抗的患者。C57 BL/6 J小鼠对慢性氟西汀的行为和神经原性影响无反应。CORT减少焦虑行为，增加海马神经元再生对氟西汀的反应。CORT颗粒不能有效维持升高的血浆CORT水平。
Both genetic background and pre-existing stress play critical roles in the effects of antidepressant drugs. The current studies showed this principal by demonstrating that exposure to the stress hormone corticosterone (CORT) allowed behavioral and neurogenic effects to emerge following chronic treatment with fluoxetine of C57BL/6 mice, a strain ordinarily resistant to these effects. Adult male mice were implanted subcutaneously with 21-day slow-release CORT pellets (10 mg) or placebo and then co-treated with 5 mg/kg fluoxetine (b.i.d., i.p.) or saline for 14 days. Animals were then assessed for approach behavior in the novelty-induced hypophagia (NIH) test, hippocampal cell proliferation, corticosteroid receptor expression, and CORT plasma levels. Co-treatment of CORT with fluoxetine significantly reduced approach behavior in the novel environment of the NIH test and increased hippocampal cell proliferation whereas fluoxetine given alone was ineffective. CORT given alone did not alter approach behavior in the novel environment and caused a smaller increase of cell proliferation. The CORT effect was blocked by adrenalectomy and was likely due to increased adrenal feedback. Cell proliferation in CORT-treated animals was associated with reduced mineralocorticoid, but not glucocorticoid, receptor mRNA expression. Although the pellets were advertised to release CORT for 21 days, plasma CORT levels were increased at 1 day after implantation but were not sustained when measured at 7 days or longer intervals. Nevertheless, the transient CORT increase was sufficient to induce long-lasting behavioral and molecular changes when followed by fluoxetine treatment. These studies warrant further investigation into the role of glucocorticoids and environmental stress as adjunctive facilitators of the response to antidepressants, especially for treatment-resistant patients. C57BL/6J mice are not responsive to behavioral and neurogenic effects of chronic fluoxetine. CORT reduced anxiogenic behavior, increased hippocampal neurogenesis in response to fluoxetine. CORT pellets are not effective in sustaining elevated plasma CORT levels.