title: Role of 5-HT(1A)- and 5-HT(2A) receptors for the murine model of the serotonin syndrome.
abstract: BACKGROUND
  The serotonin (5-HT) syndrome (SS) in man covers side effects of drugs in over dose that increase synaptic 5-HT concentration or directly activate 5-HT receptors. The SS is characterized by mental state alterations, neuromuscular excitation, and autonomic dysregulation. In mice, a set of behavioral and autonomic responses can be induced by the same serotonergic drugs as in man. The role of the 5-HT1A receptor for the murine SS has been extensively studied and several responses have been attributed to 5-HT1A receptor activation. So far, 5-HT2A receptor activation is thought to induce head twitches and hypothermia. The aim of this study is to define the impact of the 5-HT2A and the 5-HT1A receptor for different SS-like responses.
  
  
  METHODS
  The effects of the full 5-HT1A receptor agonist 8-OH-DPAT, the partial 5-HT1A agonist buspirone, and the 5-HT2A receptor agonist TCB-2 were investigated in male NMRI mice. The responses were compared with the effects induced by the 5-HT precursor 5-HTP.
  
  
  RESULTS
  Flat body posture, hindlimb abduction, Straub tail, tremor, piloerection and decreased rearing were observed after 8-OH-DPAT treatment. A similar set of responses was seen after administration of buspirone. However, the Straub tail response did not occur, probably due to the lower efficacy of buspirone at postsynaptic 5-HT1A receptors. As expected, TCB-2 induced head twitches, but also evoked flat body posture, hindlimb abduction, and piloerection, and decreased the numbers of rearings and defecation boli.
  
  
  CONCLUSIONS
  The Straub tail response seems to be a specific sign for postsynaptic 5-HT1A receptor activation. In addition, the 5-HT2A receptor has more impact on the 5-HT syndrome than previously suggested. By inducing the broadest spectrum of signs, 5-HTP seems to be suitable as a positive control when investigating the 5-HT syndrome in mice. In summary, the murine model of the SS is a valid tool for preclinical studies to screen drugs and drug combinations for the risk to cause an SS in man.
authors.affiliation: Institute of Pharmacology and Toxicology, Dept. of Veterinary Medicine, Freie Universität Berlin, Koserstrasse 20, 14195 Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Haberzettl
authors.affiliation: Institute of Pharmacology and Toxicology, Dept. of Veterinary Medicine, Freie Universität Berlin, Koserstrasse 20, 14195 Berlin, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Fink
authors.affiliation: Institute of Pharmacology and Toxicology, Dept. of Veterinary Medicine, Freie Universität Berlin, Koserstrasse 20, 14195 Berlin, Germany. Electronic address: bettina.bert@fu-berlin.de.
authors.forename: Bettina
authors.initials: B
authors.lastname: Bert
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D002065:Buspirone / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D008744:Methylamines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D020230:Serotonin Syndrome / Q000139:chemically induced / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C514172:(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine; D001643:Bridged Bicyclo Compounds; D008744:Methylamines; D044402:Receptor, Serotonin, 5-HT2A; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002065:Buspirone
keywords: 5-HT; 5-HT(1A) receptor; 5-HT(2A) receptor; 8-OH-DPAT; Buspirone; Mice; Serotonin; Serotonin syndrome; TCB-2