Changes in intensity of serotonin syndrome caused by adverse interaction between monoamine oxidase inhibitors and serotonin reuptake blockers.
Changes in intensity of serotonin syndrome caused by adverse interaction between monoamine oxidase inhibitors and serotonin reuptake blockers.
复制标题
单胺氧化酶抑制剂和血清素再摄取阻滞剂之间的不良相互作用引起血清素综合征强度的变化。
DOI：
10.1038/npp.2014.49
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Ma,Zhiyuan
中科院分区：
文献类型：
--
作者：
Tao,Rui;Rudacille,Mary;Zhang,Gongliang;Ma,Zhiyuan
单胺氧化酶（MAOIs）抑制剂和选择性5-羟色胺（5-HT）再摄取（SSRIs）抑制剂之间的药物相互作用可诱导5-羟色胺综合征，通常为轻度，但偶尔为重度。然而，很少有人知道负责综合征的诱导和强化的神经机制。在这项研究中，我们假设综合征的诱导和强度利用两种不同但相互关联的机制。5-羟色胺综合征是由大脑中过量的5-HT引起的（突触前机制），而综合征的强度归因于涉及5-HT 2A和NMDA受体的神经回路（突触后机制）。为了验证这一假设，基础5-HT流出和突触后电路的MAOI clorgyline预处理3，6或13天，每天一次，在大鼠中被显著改变。通过测量5-HT外排、神经肌肉活动和对氯吉兰联合SSRI帕罗西汀激发注射反应的体核温度来估计综合征强度。结果表明，5-羟色胺综合征的发病是由5-羟色胺流出超过10倍以上的基线，证实了突触前假说。神经肌肉和身体核心温度异常，否则药物幼稚大鼠轻度，显着加剧到严重的水平，每天氯吉林预处理3和6天，但在大鼠预处理13天。M100907和MK-801可阻断这种增强效应，提示证候强度的变化是通过5-HT 2A和NMDA受体参与的回路介导的。因此，我们得出结论，MAOI的预处理改变了突触后回路的活动，这是负责症状强度的变化。
Drug interaction between inhibitors of monoamine oxidase (MAOIs) and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake (SSRIs) induces serotonin syndrome, which is usually mild but occasionally severe in intensity. However, little is known about neural mechanisms responsible for the syndrome induction and intensification. In this study, we hypothesized that the syndrome induction and intensity utilize two different but inter-related mechanisms. Serotonin syndrome is elicited by excessive 5-HT in the brain (presynaptic mechanism), whereas syndrome intensity is attributed to neural circuits involving 5-HT 2A and NMDA receptors (postsynaptic mechanism). To test this hypothesis, basal 5-HT efflux and postsynaptic circuits were pharmacologically altered in rats by once daily pretreatment of the MAOI clorgyline for 3, 6, or 13 days. Syndrome intensity was estimated by measuring 5-HT efflux, neuromuscular activity, and body-core temperature in response to challenge injection of clorgyline combined with the SSRI paroxetine. Results showed that the onset of serotonin syndrome is caused by 5-HT efflux exceeding 10-fold above baseline, confirming the presynaptic hypothesis. The neuromuscular and body-core temperature abnormalities, which were otherwise mild in drug-naive rats, were significantly intensified to a severe level in rats pretreated with daily clorgyline for 3 and 6 days but not in rats pretreated for 13 days. The intensified effect was blocked by M100907 and MK-801, suggesting that variation in syndrome intensity was mediated through a 5-HT 2A and NMDA receptor-engaged circuit. Therefore, we concluded that pretreatments of MAOI pharmacologically alter the activity of postsynaptic circuits, which is responsible for changes in syndrome intensity.