Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia; Melbourne School of Psychological Science, University of Melbourne, Parkville, Australia.
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia.
Neuropharmacology. 2020 May 15;168:107998. doi: 10.1016/j.neuropharm.2020.107998. Epub 2020 Feb 12.
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. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
传统的单胺能治疗抑郁症的方法常常表现出不尽人意的耐受性和疗效。5-HTTLPR 的“短”（s）等位基因变体已知会影响 5-羟色胺转运体（5-HTT）的转录功效，并可能降低传统抗抑郁药（例如选择性 5-羟色胺再摄取抑制剂或 SSRIs）的治疗反应。本研究旨在建立 5-HTT 敲除（KO）系作为一种抗 SSRIs 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的反应，氯胺酮是一种非竞争性 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂。在急性抗抑郁治疗后，5-HTT KO 小鼠和野生型（WT）对照小鼠接受强迫游泳测试（FST），这是检测急性抗抑郁反应最广泛使用的技术之一。正如假设的那样，当在 FST 中给药后 30 分钟评估时，SSRIs 舍曲林（20mg/kg，ip）在 WT 对照中产生抗抑郁样作用，但在 5-HTT KO 小鼠中没有。相比之下，氯胺酮（20mg/kg，ip）在两种基因型中均诱导抗抑郁样作用。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减少，以及海马中的 GluN2A 蛋白水平降低，表明该模型中的谷氨酸能功能障碍。这些结果突出了 5-HTT KO 小鼠作为一种相关的抗 SSRIs 性抑郁症模型的实用性，并表明氯胺酮可以在 5-HTT 缺乏的情况下产生急性抗抑郁样作用。这些发现扩展了现有的文献，表明氯胺酮在改善治疗抵抗性抑郁症的症状方面有效，并且可能对理解氯胺酮抗抑郁作用的细胞和分子机制具有意义。本文是题为“血清素研究：跨越尺度和边界”的特刊的一部分。
