Implication of 5-HT2B receptors in the serotonin syndrome

NEUROPHARMACOLOGY

卷:61

Article

Diaz, Silvina Laura¹  Maroteaux, Luc¹ 

[1] Univ Paris 06, INSERM, UMR S 839, Inst Fer Moulin, F-75005 Paris, France

关键词: 5-HT2B receptor;    Serotonin syndrome;    SSRI antidepressants;    Forced swimming test;    Mice;   

DOI  :  10.1016/j.neuropharm.2011.01.025

来源: Elsevier

【 摘 要 】

The serotonin (5-HT) syndrome occurs in humans after antidepressant overdose or combination of drugs inducing a massive increase in extracellular 5-HT. Several 5-HT receptors are known to participate in this syndrome in humans and animal models. The 5-HT2B receptor has been proposed as a positive modulator of serotonergic activity, but whether it is involved in 5-HT syndrome has not yet been studied. We analyzed here, a putative role of 5-HT2B receptors in this disorder by forced swimming test (FST) and behavioral assessment in the open field. In FST, genetic (5-HT2B-/- mice) or pharmacological (antagonist RS127445 at 0.5 mg/kg) ablation of 5-HT2B receptors facilitated selective 5-HT reuptake inhibitors (SSRI)-induced increase of immobility time as well as expression of other symptoms related to 5-HT syndrome like hind limb abduction and Straub tail. Increase in immobility was also developed in FST by both wild type (WT) and mice after the administration of 5-HT1A, 5-HT2A or 5-HT2C receptor agonists, 8-0H-DPAT (5 mg/kg), DOI (1 mg/kg), or WAY161503 (5 mg/kg), respectively. In contrast, the 5-HT2B receptor agonist BW723C86 (3 mg/kg) or 5-HT-Hi receptor agonist CGS12066A (2 mg/kg) decreased immobility time in both genotypes. The 5-HT syndrome induced by fluoxetine at high doses was blocked in WT and 5-HT2B-/- mice by administration of 5-HTIA and 5-HTK receptor antagonists (WAY100635 0.5 mg/kg and 5B242084 0.5 mg/kg) but not by the 5-HT2A receptor antagonist MDL100907 (1 mg/kg). By behavioral assessment, we confirmed that 5-HT2B-/- mice were more prone to develop 5-HT syndrome symptoms after administration of high dose of SSRIs or the precursor 5-Hydroxytryptophan, 5-HIP, even if increases in 5-HT plasma levels were similar in both genotypes. This evidence suggests that the presence of 5-HT2B receptors hinders acute 5-HT toxicity once high levels of 5-HT are attained. Therefore, differential agonism/antagonism of 5-HT receptors should be considered in the search of therapeutic targets for treating this serious disorder. This article is part of a Special Issue entitled 'Serotonin: The New Wave'. C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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