The murine serotonin syndrome - Evaluation of responses to 5-HT-enhancing drugs in NMRI mice
The murine serotonin syndrome - Evaluation of responses to 5-HT-enhancing drugs in NMRI mice
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DOI：
10.1016/j.bbr.2014.04.033
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发表时间：
2015-01-15
影响因子：
2.7
通讯作者：
Bert, Bettina
中科院分区：
文献类型：
--
作者：
Haberzettl, Robert;Fink, Heidrun;Bert, Bettina
在人类中，摄取两种或两种以上5-羟色胺(5-羟色胺)增强药物的组合，但过量服用单一药物可引起严重的不良反应，这是5-羟色胺综合征(SS)的特征。在小鼠中，直接和间接5-羟色胺激动剂的急性给药也会导致行为和自主神经反应，但文献中认为不同的反应是必不可少的。为了检测不同作用机制的5-羟色胺增强剂诱导的常见行为SS反应，我们观察了5-羟色胺前体5-羟基-L色氨酸(5-HTP)、选择性5-羟色胺再摄取抑制剂(SSRI)氟西汀(Flx)和单胺氧化酶(MAO)抑制剂三羟丙胺(Tcp)对雄性NmR小鼠的影响。这些药物单独或联合使用，以研究相加效应或药物增强作用。此外，我们还比较了多巴胺、去甲肾上腺素和胆碱能激动剂阿朴吗啡(APO)、托莫西汀(ATO)和氧托莫林(OXO)对5-羟色胺的反应。我们的结果表明，所研究的5-羟色胺增强剂引起不同数量的伴随反应。以下五种反应在NMRI小鼠中持续且呈剂量依赖性地发生：扁平的身体姿势、后肢外展、竖立、震颤和后背变小。就像人类一样，5-羟色胺增强剂的组合会导致药物效应的增强。除扁平体位外，这些反应不是5-羟色胺能多动的特异性反应。这些结果表明，如果考虑到对5-羟色胺增强型药物的典型反应谱可能因药物和小鼠品系的不同而不同，并且一些反应也可能由激活其他传递系统引起，则NMRI小鼠的SS是一个适合进行临床前研究的动物模型。(C)2014年提交人。爱思唯尔出版公司(Elsevier B.V.)
In humans, the ingestion of the combination of two or more serotonin (5-HT)-enhancing drugs but also of a single drug in overdose can induce serious adverse effects, which are characteristics of the serotonin syndrome (SS). In mice, acute administration of direct and indirect 5-HT agonists also leads to behavioral and autonomic responses, but in literature different responses are thought to be essential. In order to detect common behavioral SS responses induced by 5-HT-enhancing drugs with different mechanisms of action, we investigated the effects of the 5-HT precursor 5-hydroxy-L-tryptophan (5-HTP), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX), and the monoaminooxidase (MAO) inhibitor tranylcypromine (TCP) in male NMRI mice. The drugs were administered alone or in combination to investigate additive effects or drug potentiation. Moreover, we compared the 5-HT responses to the effects induced by the dopamine, noradrenaline, and cholinergic agonists, apomorphine (APO), atomoxetine (ATO), and oxotremorine (OXO). Our results show that the studied 5-HT-enhancing drugs induced a different number of concomitant responses. The following five responses consistently and dose-dependently occurred in NMRI mice: flat body posture, hindlimb abduction, piloerection, tremor, and decreased rearings. Like in humans, the combination of 5-HT-enhancing drugs leads to a potentiation of drug effects. With the exception of flat body posture the responses are not specific for serotonergic hyperactivity. The findings demonstrate that the SS in NMRI mice is a suitable animal model for preclinical research, if it is taken into account that the spectrum of typical responses to 5-HT enhancing drugs may differ depending on drug and mouse strain and that some responses might be evoked by activation of other transmission systems, too. (C) 2014 The Authors. Published by Elsevier B.V.