%0 Journal Article %T Implication of 5-HT(2B) receptors in the serotonin syndrome. %+ Institut du Fer à Moulin %A Diaz, Silvina Laura %A Maroteaux, Luc %< avec comité de lecture %@ 0028-3908 %J Neuropharmacology %I Elsevier %V 61 %N 3 %P 495-502 %8 2011-09 %D 2011 %R 10.1016/j.neuropharm.2011.01.025 %M 21277875 %K 5-HT2B receptor %K serotonin syndrome %K SSRI antidepressants %K forced swimming test %K mice %Z Life Sciences [q-bio]/Biochemistry, Molecular BiologyJournal articles %X 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-HT(2B) 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-HT(2B) receptors in this disorder by forced swimming test (FST) and behavioral assessment in the open field. In FST, genetic (5-HT(2B)(-/-) mice) or pharmacological (antagonist RS127445 at 0.5 mg/kg) ablation of 5-HT(2B) 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 5-HT(2B)(-/-) mice after the administration of 5-HT(1A), 5-HT(2A) or 5-HT(2C) receptor agonists, 8-OH-DPAT (5 mg/kg), DOI (1 mg/kg), or WAY161503 (5 mg/kg), respectively. In contrast, the 5-HT(2B) receptor agonist BW723C86 (3 mg/kg) or 5-HT(1B) 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-HT(2B)(-/-) mice by administration of 5-HT(1A) and 5-HT(2C) receptor antagonists (WAY100635 0.5 mg/kg and SB242084 0.5 mg/kg) but not by the 5-HT(2A) receptor antagonist MDL100907 (1 mg/kg). By behavioral assessment, we confirmed that 5-HT(2B)(-/-) mice were more prone to develop 5-HT syndrome symptoms after administration of high dose of SSRIs or the 5-HT precursor 5-Hydroxytryptophan, 5-HTP, even if increases in 5-HT plasma levels were similar in both genotypes. This evidence suggests that the presence of 5-HT(2B) 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. %G English %2 https://inserm.hal.science/inserm-00561473/document %2 https://inserm.hal.science/inserm-00561473/file/NEUROPHARM-S-10-00594.fdf %L inserm-00561473 %U https://inserm.hal.science/inserm-00561473 %~ INSERM %~ UPMC %~ IFM %~ UPMC_POLE_4 %~ SORBONNE-UNIVERSITE %~ SU-SCIENCES %~ SU-TI %~ ANR %~ ALLIANCE-SU