The Effects of Chronic Amitriptyline on Zebrafish Behavior and Monoamine Neurochemistry
The Effects of Chronic Amitriptyline on Zebrafish Behavior and Monoamine Neurochemistry
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慢性阿米替林对斑马鱼行为和单胺神经化学的影响
作者：
D. Meshalkina;E. Kysil;K. Antonova;K. Demin;Tatiana O. Kolesnikova;S. L. Khatsko;R. Gainetdinov;P. Alekseeva;A. Kalueff
阿米替林是一种常用的三环类抗抑郁药（TCA），可抑制5-羟色胺和去甲肾上腺素再摄取。TCA的确切CNS作用仍然知之甚少，需要新的筛选方法和新的模式生物。斑马鱼（Danio rerio）正迅速成为包括阿米替林在内的抗抑郁药药理学研究的一种有前途的工具。在这里，我们研究了2周慢性暴露于10和50 μg/L阿米替林对斑马鱼行为和单胺神经递质的影响。总体而言，50 μg/L的药物在新的罐试验中引起明显的抗焦虑样作用（通过在顶部的更多时间、更少的过渡和更短的进入顶部的潜伏期进行评估）。与其他TCA一样，阿米替林降低了5-羟色胺的周转率，但也显著升高了全脑去甲肾上腺素和多巴胺水平。后一种效应以前在该模型中没有报道，并且伴随着酪氨酸羟化酶（儿茶酚胺生物合成的限速酶）的更高的脑表达，但多巴胺-β-羟化酶和单胺氧化酶（多巴胺代谢的酶）的表达不变。这种反应可能是阿米替林对多巴胺和去甲肾上腺素神经传递的慢性作用的基础，并有助于临床和动物模型中观察到的该药物的复杂CNS特征。总的来说，这些研究结果也证实了单胺调节在斑马鱼焦虑相关行为的调节中的重要作用，并支持这种生物体作为CNS药物筛选的有前途的体内模型的实用性。
Amitriptyline is a commonly used tricyclic antidepressant (TCA) inhibiting serotonin and norepinephrine reuptake. The exact CNS action of TCAs remains poorly understood, necessitating new screening approaches and novel model organisms. Zebrafish (Danio rerio) are rapidly emerging as a promising tool for pharmacological research of antidepressants, including amitriptyline. Here, we examine the effects of chronic 2-week exposure to 10 and 50 μg/L amitriptyline on zebrafish behavior and monoamine neurotransmitters. Overall, the drug at 50 μg/L evoked pronounced anxiolytic-like effects in the novel tank test (assessed by more time in top, fewer transition and shorter latency to enter the top). Like other TCAs, amitriptyline reduced serotonin turnover, but also significantly elevated whole-brain norepinephrine and dopamine levels. The latter effect was not reported in this model previously, and accompanied higher brain expression of tyrosine hydroxylase (a rate-limiting enzyme of catecholamine biosynthesis), but unaltered expression of dopamine-β-hydroxylase and monoamine oxidase (the enzymes of dopamine metabolism). This response may underlie chronic amitriptyline action on dopamine and norepinephrine neurotransmission, and contribute to the complex CNS profile of this drug observed both clinically and in animal models. Collectively, these findings also confirm the important role of monoamine modulation in the regulation of anxiety-related behavior in zebrafish, and support the utility of this organism as a promising in-vivo model for CNS drug screening.
影响因子：
13.8
作者：
Kalueff, Allan V.;Stewart, Adam Michael;Gerlai, Robert
通讯作者：
Gerlai, Robert
阿米替林是一种 TrkA 和 TrkB 受体激动剂，可促进 TrkA/TrkB 异二聚化并具有有效的神经营养活性。
影响因子：
--
作者：
Jang SW;Liu X;Chan CB;Weinshenker D;Hall RA;Xiao G;Ye K
通讯作者：
Ye K
影响因子：
5
作者：
Tatsumi, M;Groshan, K;Richelson, E
通讯作者：
Richelson, E