Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice

Purpose: Sudden unexpected death in epilepsy (SUDEP) is a serious concern for epilepsy patients. DBA/2 mice are proposed as a SUDEP model, because these mice exhibit respiratory arrest (RA) after audiogenic seizures (AGSs), and RA is also implicated in human SUDEP. Respiratory mechanisms are modulated, in part, by serotonin. Therefore we evaluated the effects of serotoninergic agents on RA incidence in DBA/2 mice. Methods: DBA/2 mice (75%) exhibited AGS and RA, and similar to 99% of animals could be resuscitated. The mice exhibiting RA were given a selective serotonin reuptake inhibitor, fluoxetine, 24 h after the initial AGS, and RA susceptibility was evaluated 30 min later. Ten percent of DBA/2 mice exhibited tonic hindlimb extension (TE) without RA, and a serotonin antagonist (cyproheptadine) was administered to these mice. Results: Fluoxetine (15-25 mg/kg, i.p.) significantly reduced the incidence of RA in DBA/2 mice after AGSs, and this effect was reversible by 72 h. Only the 25-mg/kg dose reduced AGS severity. In mice exhibiting TE without RA, the incidence of RA was significantly increased 30 min after cyproheptadine (1-2 mg/kg i.p.). Most of these mice exhibited AGSs without RA again by 72 h. Conclusions: These findings indicate that fluoxetine reduced RA in DBA/2 mice at doses that did not reduce seizure severity. Because DBA/2 mice are a proposed model for human SUDEP, these data support evaluation of fluoxetine for SUDEP prevention in the patient population most susceptible to SUDEP. The data raise concern about the use of serotonin antagonists in this patient population.