Role of 5-HT1A- and 5-HT2A receptors for the murine model of the serotonin syndrome

Introduction: 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. Discussion: 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. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.