The murine serotonin syndrome – Evaluation of responses to 5-HT-enhancing drugs in NMRI mice

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.