ABSTRACT
OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Although the mechanisms for SUDEP are incompletely understood, seizure-induced respiratory arrest (S-IRA) has been strongly and consistently implicated. A body of evidence indicates that serotonin (5-HT), a modulator of breathing, plays a critical role in SUDEP. Because the 5-HT and norepinephrine (NE) systems interact in many biologic processes and NE is known to modulate breathing and seizures, we hypothesized that NE may play a role in S-IRA and SUDEP. METHODS: We examined the effects of pharmacologic manipulation of 5-HT and NE on S-IRA and death following maximal electroshock (MES)-induced seizures in adult wild-type (WT) mice, genetically 5-HT neuron-deficient (Lmx1bf/f/p ) mice, and chemically NE neuron-deficient mice. Mice were treated with pharmacologic agents targeting the serotonergic and noradrenergic systems and subjected to seizure induction via MES while breathing was measured via whole-body plethysmography. RESULTS: S-IRA and death was reduced in WT mice with NE reuptake inhibitors (NRIs), reboxetine and atomoxetine, selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the dual 5-HT/NE reuptake inhibitor (SNRI), duloxetine. S-IRA and death was also reduced in Lmx1bf/f/p mice with reboxetine and fluoxetine. The protective effects of the reuptake inhibitors were prevented by the α1 antagonist, prazosin. Citalopram did not reduce S-IRA and death in NE neuron-deficient mice. SIGNIFICANCE: These data suggest that 5-HT and NE critically interact in the modulation of breathing following a seizure and potentially inform preventive strategies for SUDEP.
