Although the stimulative effects on the normal behaviors of fish posed by ketamine (KET) were well‐studied, the adverse effects on the behavioral functions induced by KET at nighttime were unknown. Here, we used zebrafish larvae as a model exposed to KET (10, 50, 100, and 250 ng/L) at environmental levels for 21 days. The behavioral functions at nighttime, morphological changes during exposure stage, and alterations on the associated genes transcriptional levels of fish were determined. The difficultly initiating sleep was found in the fish exposed to KET, while the sleep duration of the animals was at the normal levels in exposure groups. The significant suppressions of the developmentally relevant genes, including bmp2, bmp4, and pth2ra were consistent with the developmental abnormalities of fish found in exposure groups. Moreover, the expression of γ‐aminobutyric acid (GABA) receptor increased and melatonin (MTN) receptor decreased while the levels of GABA and MTN remained unchanged after exposure, by gene expression analysis and molecular docking. In addition, the transcriptional expression of apoptotic genes, including tp53, aifm1, and casp6, was significantly upregulated by KET. After a 7‐day recovery, the insomnia‐like behaviors (shorter sleep duration) were observed in zebrafish from the 250 ng/L‐KET group. Accordingly, the adverse outcome pathway framework of KET was constructed by prognostic assessment of zebrafish larvae. This study suggested that the adverse outcomes of KET on the sleep health of organisms at environmentally relevant concentrations should be concerned.

中文翻译：

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氯胺酮在环境相关浓度下通过介导 GABA 能突触诱导斑马鱼出现失眠样症状

尽管氯胺酮 (KET) 对鱼类正常行为的刺激作用已得到充分研究，但 KET 在夜间对鱼类行为功能的不利影响尚不清楚。在这里，我们使用斑马鱼幼虫作为模型，在环境水平下暴露于 KET（10、50、100 和 250 ng/L）21 天。测定了鱼类夜间的行为功能、暴露阶段的形态变化以及相关基因转录水平的变化。暴露于KET的鱼发现入睡困难，而暴露组动物的睡眠持续时间处于正常水平。发育相关基因的显着抑制，包括图像格式2,图像格式4， 和pth2ra与暴露组中发现的鱼类发育异常一致。此外，通过基因表达分析和分子对接，暴露后γ-氨基丁酸（GABA）受体的表达增加，褪黑激素（MTN）受体的表达减少，而GABA和MTN的水平保持不变。此外，凋亡基因的转录表达，包括TP53,aifm1， 和半胱氨酸蛋白酶6，被 KET 显着上调。恢复 7 天后，在 250 ng/L-KET 组的斑马鱼中观察到类似失眠的行为（睡眠时间较短）。因此，通过对斑马鱼幼虫的预后评估构建了 KET 的不良结果通路框架。这项研究表明，应关注环境相关浓度下的 KET 对生物体睡眠健康的不利影响。