Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with epilepsy. It is thought that SUDEP most commonly ensues from cardiac or respiratory consequences of a seizure. Serotonin (5-HT) is a key regulator of breathing, can modulate cardiac function, and is involved in modulation of seizure frequency and severity. 5-HT dysfunction has been implicated in the pathophysiology of SUDEP. With the aid of a mouse model in which nearly all 5-HT neurons have been genetically deleted (Lmx1b^f/f/p), we have previously shown that 5-HT neuron absence contributes to seizure severity and seizure-related death. Here we investigated whether pharmacologic manipulation of the 5-HT system could affect respiratory arrest and death. Methods: Seizures were induced via maximal electroshock (MES) in adult male wild-type (WT; 50 mA, 0.2 s, 60 Hz) and Lmx1b^f/f/p (30 mA, 0.2 s, 60 Hz) mice following pretreatment (i.p.; 0.1 ml; 30 min prior to MES) with vehicle; the selective serotonin reuptake inhibitor, fluoxetine; the 5-HT_2A/2C agonist, DOI; the 5-HT_2A agonist, TCB-2; the 5-HT_2C agonist, MK-212; or a combination of DOI preceded 20 minutes earlier by the 5-HT₂ antagonist, ketanserin or the 5-HT_2A antagonist, MDL 11,939 (n = 7 for each genotype/condition). These stimulus intensities were chosen for the given genotypes because they resulted in seizures of similar intensity and with similar mortality rates between the genotypes in preliminary studies. A subset of vehicle-treated WT and Lmx1b^f/f/p animals was mechanically ventilated (0.3 ml stroke volume; 150 breaths/minute) during the seizure. Seizure susceptibility, severity (extension-flexion ratio) and mortality, and presence and duration of respiratory arrest were assessed. Results: Seizures induced by MES following vehicle pretreatment were similar in intensity between genotypes and similar to those previously observed in our lab, and resulted in the same survival rate (28.6% for both genotypes). All WT and most (6/7) Lmx1b^f/f/p mice that were mechanically ventilated during the seizure survived (p < 0.05). Similarly, fluoxetine (20 mg/kg), DOI (0.3 mg/kg), or TCB-2 (3 mg/kg) pre-treatment prevented respiratory arrest and death in all WT (p < 0.05). DOI (1 mg/kg, but not 0.3 mg/kg) and TCB-2 (3 mg/kg) prevented death in most (6/7)