A comparison of midazolam and dexmedetomidine for the recovery of serotonin syndrome in rats

Serotonin syndrome is a drug-related toxicity caused by excess serotonin within the central nervous system. We recently encountered a case of serotonin syndrome that developed in the early postoperative period that was successfully treated with intravenous dexmedetomidine. Although the prescriptive literature has commonly recommended sedation with benzodiazepines for controlling agitation in serotonin syndrome, the effectiveness of dexmedetomidine has also been reported in several clinical conditions. In the present study, we conducted a reverse translational experiment to compare the efficacy of dexmedetomidine and midazolam, at equi-sedative doses, on serotonergic toxicity-like responses in rats. Animals were subcutaneously injected with 0.75 mg/kg 8-OH-DPAT, a full 5-HT_1A agonist. 8-OH-DPAT-treated rats showed serotonin syndrome-like behaviors (low body posture, forepaw treading), hyperlocomotion, and decreased body temperature, which were completely inhibited by pretreatment with WAY 100635, a selective 5-HT_1A antagonist (n = 8). Intramuscular injection of midazolam (1.0 mg/kg) or dexmedetomidine (0.01 mg/kg), which comparably induced observable signs of sedation, was tested in the present study. Concomitant treatment with midazolam significantly attenuated the hyperlocomotion, but failed to affect traditional serotonin syndrome behaviors and body temperature in 8-OH-DPAT-treated rats (n = 8). On the other hand, concomitant treatment with dexmedetomidine significantly attenuated all of these parameters (n = 8). The present case and related reverse translational experiment demonstrate that dexmedetomidine may be more beneficial for the treatment of serotonin syndrome compared to the current recommended treatment with benzodiazepines.