Effects of a non-competitive N-methyl-D-aspartate (NMDA) antagonist, tiletamine, in adult zebrafish
Effects of a non-competitive N-methyl-D-aspartate (NMDA) antagonist, tiletamine, in adult zebrafish
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DOI：
10.1016/j.ntt.2016.11.009
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发表时间：
2017-01-01
影响因子：
2.9
通讯作者：
Kalueff, Allan V.
中科院分区：
文献类型：
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作者：
Kolesnikova, Tatiana O.;Khatsko, Sergey L.;Kalueff, Allan V.
Tiletamine 是一种非竞争性 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂，与氯胺酮和苯环己哌啶在化学上相关。替来他明是一种常见的兽用麻醉药，目前在美国属于三级管制物质。该化合物对人类和动物具有镇静作用，在临床上也具有滥用潜力、毒性和解离性致幻特性。然而，替来他明的神经营养特性仍然知之甚少，需要新的模型和体内筛选，包括非哺乳动物物种。斑马鱼 (Danio rerio) 正迅速成为筛选各种 CNS 药物（包括作用于 NMDA 受体的药物）的流行模型生物。在这里，我们研究了 1、5 和 10 mg/L 替来他明对成年斑马鱼的急性行为影响。在标准新型水箱测试中，在 1 mg/L 替来他明中浸泡 20 分钟，与对照斑马鱼（接受 0.1% DMSO 媒介物）相比，除了顶部入口减少外，没有产生明显差异。相比之下，5 mg/L 和 10 mg/L 的替来他明对斑马鱼产生了强烈的剂量依赖性镇静作用（也使它们的肤色变深，类似于氯胺酮和五氯苯酚）。气相色谱/质谱 (GC/MS) 分析显示对照组和 1 mg/L 组中没有替来他明峰，但在斑马鱼脑样本中检测到 5 和 10 mg/L 替来他明峰。总之，这些发现证明了替来他明对斑马鱼具有强大的神经营养作用，以及它们对该药物的高度敏感性。我们的研究结果还支持以鱼类为基础的水生筛选在研究体内 NMDA 拮抗剂的神经活性特性方面的应用不断增长。 (C) 2016 年，爱思唯尔公司出版
Tiletamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist chemically related to ketamine and phencyclidine. A common veterinary anesthetic drug, tiletamine is currently a Schedule III controlled substance in USA. This compound exerts sedative effects in humans and animals, also having an abuse potential, toxicity and dissociative hallucinogenic properties clinically. However, the neurotropic profile of tiletamine remains poorly understood, necessitating novel models and in-vivo screens, including non-mammalian species. Zebrafish (Danio rerio) are rapidly becoming a popular model organism for screening various CNS drugs, including those acting at NMDA receptors. Here, we investigated acute behavioral effects of 1, 5 and 10 mg/L of tiletamine on adult zebrafish. In the standard novel tank test, a 20-min immersion in 1 mg/L of tiletamine produced no overt differences from control zebrafish (receiving 0.1% DMSO vehicle), except for reduced top entries. In contrast, tiletamine at 5 and 10 mg/L exerted robust dose-dependent sedative effects in zebrafish (also darkening their skin coloration, similar to ketamine and PCP). Gas chromatography/mass spectrometry (GC/MS) analyses revealed no tiletamine peaks in control and 1 mg/L groups, but detected tiletamine peaks in zebrafish brain samples at 5 and 10 mg/L. Together, these findings demonstrate potent neurotropic effects of tiletamine in zebrafish, and their high sensitivity to this drug. Our findings also support the growing utility of fish-based aquatic screens for studying neuroactive properties of NMDA antagonists in-vivo. (C) 2016 Published by Elsevier Inc.