Traditional monoaminergic treatments of depression frequently exhibit suboptimal tolerability and effectiveness. The 'short' (s) allele variant of 5-HTTLPR is known to compromise transcriptional efficacy of the serotonin transporter (5-HTT) and can reduce treatment response to traditional antidepressants (e.g. selective serotonin reuptake inhibitors or SSRIs). This study sought to establish the 5-HTT knock-out (KO) line as a mouse model of SSRI-resistant depression and assess its response to a novel glutamatergic antidepressant, ketamine, a non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonist. Following acute antidepressant treatment, 5-HTT KO mice and wild-type (WT) controls were subjected to the forced-swim test (FST), one of the most widely used techniques to detect acute antidepressant response. As hypothesised, when assessed 30 min after administration in the FST, the SSRI sertraline (20 mg/kg, i.p.) produced antidepressant-like effects in WT control but not in 5-HTT KO mice. In contrast, ketamine (20 mg/kg, i.p.) induced antidepressant-like effects in both genotypes. 5-HTT KO mice also exhibited a reduced locomotor response to both MK-801 (another NMDAR antagonist) and ketamine, and reduced GluN2A protein levels in the hippocampus, suggesting glutamatergic dysfunction in this model. These results highlight the utility of 5-HTT KO mice as a relevant model of SSRI-resistant depression and demonstrate that ketamine can produce acute antidepressant-like effects in conditions of 5-HTT deficiency. These findings extend existing literature that indicates ketamine is effective in ameliorating symptoms of treatment-resistant depression and may have implications for understanding the cellular and molecular mechanisms underlying the antidepressant effects of ketamine.

中文翻译：

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氯胺酮在血清素能功能障碍小鼠模型中的抗抑郁样作用。

传统的抑郁症单胺疗法经常表现出次佳的耐受性和有效性。已知5-HTTLPR的“短”等位基因变异会损害5-羟色胺转运蛋白（5-HTT）的转录功效，并会降低对传统抗抑郁药（例如选择性5-羟色胺再摄取抑制剂或SSRI）的治疗反应。这项研究试图建立5-HTT敲除（KO）品系作为SSRI抗性抑郁症的小鼠模型，并评估其对新型谷氨酸能抗抑郁药氯胺酮（一种非竞争性N-甲基-d-天冬氨酸受体）的反应（ NMDAR）拮抗剂。急性抗抑郁药治疗后，对5-HTT KO小鼠和野生型（WT）对照进行强迫游泳试验（FST），这是检测急性抗抑郁药反应最广泛的技术之一。假设 当在FST中给药30分钟后评估时，SSRI舍曲林（20 mg / kg，ip）在WT对照中产生抗抑郁样作用，但在5-HTT KO小鼠中不产生。相反，氯胺酮（20 mg / kg，腹膜内）在两种基因型中均可诱导抗抑郁样作用。5-HTT KO小鼠还表现出对MK-801（另一种NMDAR拮抗剂）和氯胺酮的运动反应降低，海马中GluN2A蛋白水平降低，表明该模型存在谷氨酸能功能障碍。这些结果突出了5-HTT KO小鼠作为抗SSRI抑郁症的相关模型的效用，并证明氯胺酮可以在5-HTT缺乏的情况下产生急性抗抑郁样作用。