Response of Htr3a knockout mice to antidepressant treatment and chronic stress
Response of Htr3a knockout mice to antidepressant treatment and chronic stress
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DOI：
10.1111/bph.13857
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发表时间：
2017-08-01
影响因子：
7.3
通讯作者：
Lanfumey, Laurence
中科院分区：
文献类型：
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作者：
Martin, Vincent;Riffaud, Armance;Lanfumey, Laurence
背景和目的最近有人提出，5-HT 3受体阻断剂可增强选择性5-HT（5-羟色胺）再摄取抑制剂（SSRI）抗抑郁药，并可逆转啮齿动物中应激诱导的缺陷。我们用缺乏5-HT 3受体的小鼠（Htr 3a KO）和它们的野生型（WT）对照以评估它们在与焦虑和抑郁相关的行为范例中的反应。小鼠进行了研究基础，抗抑郁治疗和慢性社会失败stress（CSDS）conditions.KEY结果在基础条件下，Htr 3a基因敲除小鼠显示抗焦虑和抗抑郁样行为在高架十字迷宫，社会互动和强迫游泳试验（FST），但表现为WT小鼠在急性西酞普兰在FST。然而，在这些相同的测试中，氟西汀在Htr 3a KO小鼠中的作用减弱。在体外电生理范例中，低剂量西酞普兰治疗仅在Htr 3a KO的中缝背核中触发5-HT 1A受体脱敏，尽管高剂量脱敏的5-HT 1A自身受体在Htr 3a KO和WT小鼠中的功能相同，这表明当5-HT 3受体失活时，西酞普兰在较低剂量下可能变得有效。此外，Htr 3a的缺失阻断了CSDS诱导的两个参与氧化应激的基因CaMKIIa和SOD 1表达的改变。结论和意义综合起来，这些数据表明，Htr 3a的缺失促进了SSRI的疗效，并防止了应激诱导的有害作用的发生，这表明5-HT 3受体可能是治疗应激相关疾病的一个有趣的靶点。
BACKGROUND AND PURPOSE It has recently been suggested that 5-HT3 receptor blockade enhances the efficacy of selective 5-HT (serotonin) reuptake inhibitor (SSRI) antidepressants and may reverse stress-induced deficits in rodents.EXPERIMENTAL APPROACH To further explore this hypothesis, we used mice lacking the 5-HT3 receptor (Htr3a KO) and their wild-type (WT) controls to assess their response in behavioural paradigms relevant to anxiety and depression. Mice were studied under basal, antidepressant treatments and chronic social defeat stress (CSDS) conditions.KEY RESULTS In basal conditions, Htr3a KO mice displayed anxiolytic- and antidepressant-like behaviours in the elevated plus maze, the social interaction and the forced swim tests (FST), but behaved as WT mice in response to acute citalopram in the FST. However, the effects of fluoxetine were blunted in Htr3a KO mice in these same tests. In an in vitro electrophysiological paradigm, a low-dose citalopram treatment triggered 5-HT1A receptor desensitization only in the dorsal raphe nucleus of Htr3a KO, although a high dose desensitized 5-HT1A autoreceptor function equally in Htr3a KO and WT mice, suggesting that citalopram may become effective at lower doses when 5-HT3 receptors are inactivated. In addition, Htr3a deletion blocked CSDS-induced modification in the cortical expression of two genes involved in oxidative stress, CaMKIIa and SOD1.CONCLUSIONS AND IMPLICATIONS Taken together, these data show that Htr3a deletion promotes SSRI efficacy and prevents the occurrence of stress-induced deleterious effects, suggesting that the 5-HT3 receptor may represent an interesting target for the treatment of stress-related disorders.