title: Implication of 5-HT(2B) receptors in the serotonin syndrome.
abstract: 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.
authors.affiliation: INSERM UMR-S 839, Université Pierre et Marie Curie, Institut du Fer à Moulin, 17 rue du Fer à Moulin, F75005 Paris, France.
authors.forename: Silvina Laura
authors.initials: SL
authors.lastname: Diaz
authors.forename: Luc
authors.initials: L
authors.lastname: Maroteaux
mesh_terms: D006916:5-Hydroxytryptophan / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D011743:Pyrimidines / Q000633:toxicity; D011897:Random Allocation; D044302:Receptor, Serotonin, 5-HT1B / Q000737:chemistry; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000097:blood; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use; D058826:Serotonin 5-HT2 Receptor Agonists / Q000627:therapeutic use; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000633:toxicity; D017366:Serotonin Receptor Agonists / Q000633:toxicity; D020230:Serotonin Syndrome / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D006916:5-Hydroxytryptophan; D011743:Pyrimidines; D044302:Receptor, Serotonin, 5-HT1B; D044403:Receptor, Serotonin, 5-HT2B; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine