Anxiety is the most prevalent brain disorder and a common cause of human disability. Animal models are critical for understanding anxiety pathogenesis and its pharmacotherapy. The zebrafish (Danio rerio) is increasingly utilized as a powerful model organism in anxiety research and anxiolytic drug screening. High similarity between human, rodent and zebrafish molecular targets implies shared signaling pathways involved in anxiety pathogenesis. However, mounting evidence shows that zebrafish behavior can be modulated by drugs beyond conventional anxiolytics or anxiogenics. Furthermore, these effects may differ from human and/or rodent responses, as such ‘unconventional’ drugs may affect zebrafish behavior despite having no such profiles (or exerting opposite effects) in humans or rodents. Here, we discuss the effects of several putative unconventional anxiotropic drugs (aspirin, lysergic acid diethylamide (LSD), nicotine, naloxone and naltrexone) and their potential mechanisms of action in zebrafish. Emphasizing the growing utility of zebrafish models in CNS drug discovery, such unconventional anxiety pharmacology may provide important, evolutionarily relevant insights into complex regulation of anxiety in biological systems. Albeit seemingly complicating direct translation from zebrafish into clinical phenotypes, this knowledge may instead foster the development of novel CNS drugs, eventually facilitating innovative treatment of patients based on novel ‘unconventional’ targets identified in fish models.

焦虑是最普遍的脑部疾病，也是人类残疾的常见原因。动物模型对于理解焦虑的发病机制及其药物治疗至关重要。斑马鱼 ( Danio rerio) 在焦虑研究和抗焦虑药物筛选中越来越多地被用作强大的模型生物。人类、啮齿动物和斑马鱼分子靶点之间的高度相似性意味着参与焦虑发病机制的共同信号通路。然而，越来越多的证据表明，斑马鱼的行为可以通过常规抗焦虑药或抗焦虑药以外的药物进行调节。此外，这些影响可能与人类和/或啮齿动物的反应不同，因为这种“非常规”药物可能会影响斑马鱼的行为，尽管在人类或啮齿动物中没有这种特征（或产生相反的影响）。在这里，我们讨论了几种推定的非常规抗焦虑药物（阿司匹林、麦角酸二乙胺 (LSD)、尼古丁、纳洛酮和纳曲酮）的作用及其在斑马鱼中的潜在作用机制。强调斑马鱼模型在中枢神经系统药物发现中的日益增长的效用，这种非常规的焦虑药理学可能为生物系统中焦虑的复杂调节提供重要的、与进化相关的见解。尽管从斑马鱼到临床表型的直接转化看似复杂，但这种知识可能会促进新型 CNS 药物的开发，最终促进基于鱼类模型中发现的新型“非常规”靶点的患者创新治疗。