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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.
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.
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.
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.