In humans, the ingestion of the combination of two or more
serotonin (5-HT)-enhancing drugs but also of a single
drug in overdose can induce serious adverse effects, which are characteristics of the
serotonin syndrome (SS). In mice, acute administration of direct and indirect
5-HT agonists also leads to behavioral and autonomic responses, but in literature different responses are thought to be essential. In order to detect common behavioral SS responses induced by 5-HT-enhancing drugs with different mechanisms of action, we investigated the effects of the
5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), the
selective serotonin reuptake inhibitor (SSRI)
fluoxetine (FLX), and the monoaminooxidase (
MAO) inhibitor tranylcypromine (TCP) in male NMRI mice. The drugs were administered alone or in combination to investigate additive effects or drug potentiation. Moreover, we compared the
5-HT responses to the effects induced by the
dopamine,
noradrenaline, and
cholinergic agonists,
apomorphine (APO),
atomoxetine (ATO), and
oxotremorine (OXO). Our results show that the studied 5-HT-enhancing drugs induced a different number of concomitant responses. The following five responses consistently and dose-dependently occurred in NMRI mice: flat body posture, hindlimb abduction, piloerection,
tremor, and decreased rearings. Like in humans, the combination of 5-HT-enhancing drugs leads to a potentiation of
drug effects. With the exception of flat body posture the responses are not specific for serotonergic hyperactivity. The findings demonstrate that the SS in NMRI mice is a suitable animal model for preclinical research, if it is taken into account that the spectrum of typical responses to
5-HT enhancing drugs may differ depending on
drug and mouse strain and that some responses might be evoked by activation of other transmission systems, too.