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The serotonin (5-HT) syndrome in man is a side-effect of drugs in over-dose that increase the synaptic 5-HT concentration or directly activate specific 5-HT receptors. It is characterized by a triad of signs including mental state alterations, neuromuscular excitation, and autonomic dysregulation. In mice, a set of behavioural and autonomic responses can be induced by the same serotonergic drugs as used in man.
The role of the 5-HT1A receptor for the 5-HT syndrome in mice has been extensively studied and responses like backward walking, flat body posture, forepaw treading, head weaving, hind limb abduction, Straub tail, Tremor and hypothermia have been attributed to 5-HT1A receptor activation. The role of the 5-HT2A receptor is less clear, and it has been mainly restricted to the induction of head twitches and hypothermia.
Hence, the aim of the present study was to define and differentiate the impact of the 5-HT2A and the 5-HT1A receptor for the different 5-HT responses. To that end, the effects of the full 5-HT1A receptor agonist 8-OH-DPAT and the partial 5-HT1A agonist buspirone as well as the 5-HT2A receptor agonist TCB-2 were investigated in male NMRI mice. The effects of the three compounds were compared with the effects induced by 5-HTP which increases the extracellular 5-HT content and therefore activates all 5-HT receptor subtypes.
In our study flat body posture, hind limb abduction, Straub tail, tremor, piloerection and decreased rearing were observed following the administration of 8-OH-DPAT. A similar set of responses were seen after treatment with 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 we also observed flat body
posture, hindlimb abduction, and piloerection, as well decreased numbers of rearings and defecation boli. To our knowledge such a broad spectrum of responses has not been previously demonstrated in mice after the activation of 5-HT2A receptors. Apart from the Straub tail response all previously described responses were induced by 5-HTP plus fore paw treading and hunched back.
In summary, the Straub tail response seems to be a specific sign for 5-HT1A receptor activation in NMRI mice. In addition, we demonstrated that the 5-HT2A receptor has more impact on the 5-HT syndrome than suggested. By inducing the broadest spectrum of signs, 5-HTP seems to be the most suitable compound as a positive control when investigating the 5-HT syndrome in mice.