Assessment of 5-hydroxytryptamine efflux in rat brain during a mild, moderate and severe serotonin-toxicity syndrome.
Assessment of 5-hydroxytryptamine efflux in rat brain during a mild, moderate and severe serotonin-toxicity syndrome.
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DOI：
10.1016/j.ejphar.2009.05.008
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发表时间：
2009-08-01
影响因子：
5
通讯作者：
Tao R
中科院分区：
文献类型：
--
作者：
Zhang G;Krishnamoorthy S;Ma Z;Vukovich NP;Huang X;Tao R
5-羟色胺（5-HT）毒性综合征是一种由5-HT过度外排引起的医源性脑功能障碍，近年来随着5-HT能抗抑郁药的使用而受到广泛关注。然而，细胞外5-HT升高到毒性水平的综合征的神经机制仍有待确定。本研究的目的是检验细胞外5-HT是由两个组件流出负责不同方面的综合征的假设。第一组实验是通过测量神经肌肉体征、身体核心温度和死亡率的变化来描述该综合征。我们的研究结果表明，综合征的严重程度可以分为轻度，中度和重度水平。第二组实验是确定诱导每个水平的综合征的细胞外5-HT的阈值。我们的研究结果表明，轻度综合征增加了11倍，重度综合征增加了55倍以上。在最后一系列实验中，5-HT的过度增加被5-HT 2A受体拮抗剂赛庚啶和酮色林以及NMDA受体拮抗剂（+）-MK-801分为主要和次要成分流出。我们的研究结果表明，主要成分外排是由直接药物作用于5-HT的生物合成和代谢途径和次级外排归因于间接药物作用于正反馈电路，涉及5-HT 2A和NMDA受体。总之，原发性外排可能是诱发综合征的初始原因，而继发性外排可能涉及综合征的恶化。
Serotonin (5-hydroxytryptamine; 5-HT)-toxicity syndrome, an iatrogenic brain disorder induced by excessive efflux of 5-HT, has received much attention because of increasing incidents of serotonergic antidepressants. However, the neural mechanism by which extracellular 5-HT is elevated to a toxic level for the syndrome remains to be determined. The goal of the present study was to test the hypothesis that extracellular 5-HT is composed of two component effluxes responsible for distinct aspects of the syndrome. The first set of experiments was to characterize the syndrome by measuring changes in neuromuscular signs, body-core temperature and mortality rate. Our results indicate that the syndrome severity can be categorized into mild, moderate and severe levels. The second set of experiments was to determine a threshold of extracellular 5-HT for induction of each level of the syndrome. Our results demonstrate that there were an 11-fold increase in the mild syndrome and an over 55-fold increase in the severe syndrome. In the last series of experiments, the excessive increases in 5-HT were pharmacologically separated into primary and secondary component effluxes with the 5-HT2A receptor antagonists cyproheptadine and ketanserin and NMDA receptor antagonist (+)-MK-801. Our results suggest primary component efflux was caused by direct drug effects on 5-HT biosynthetic and metabolic pathways and secondary efflux ascribed to indirect drug effect on a positive feedback circuit involving 5-HT2A and NMDA receptors. In summary, the primary efflux could be an initial cause for the induction of the syndrome while the secondary efflux might involve deterioration of the syndrome.
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影响因子：
5
作者：
GOBBI, M;FRITTOLI, E;MENNINI, T
通讯作者：
MENNINI, T
影响因子：
--
作者：
Aghajanian, GK;Marek, GJ
通讯作者：
Marek, GJ
影响因子：
4.7
作者：
GRAHAMESMITH, DG
通讯作者：
GRAHAMESMITH, DG
影响因子：
6.1
作者：
HJORTH, S;SHARP, T
通讯作者：
SHARP, T
DOI：
10.1152/ajpregu.1998.274.5.r1260
发表时间：
1998-05-01
影响因子：
2.8
作者：
Lin, MT;Tsay, HJ;Chueh, FY
通讯作者：
Chueh, FY