Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is a rare but devastating event in human epilepsy. Two hypotheses for the causation of SUDEP have been proposed, cardiac and respiratory malfunction. Little progress in preventing SUDEP has been achieved because there is no accepted animal model. DBA/2 mice have been proposed as a model of SUDEP, since these mice exhibit respiratory arrest (RA)-based death, following tonic audiogenic seizures (AGS) (Venit et al., Epilepsia 45:993-996, 2004; Tupal & Faingold, Epilepsia 47:21-26, 2006). RA can be prevented in DBA/2 mice by increasing 5-HT availability (Tupal & Faingold, 2006). Methods: We examined the effects of intraperitoneal (ip) injection of agents that enhance 5-HT neurotransmission on susceptibility of DBA/2 mice to AGS and RA. This involved injection of selective 5-HT receptor agonists. These agents included a 5-HT_2B/2C receptor agonist, mCPP [1-(3-chloro-phenyl)-piperazine dihydro-chloride] (2-3 mg/kg) and a 5-HT_2C receptor agonist, RO 60-0175 [(S)-2-chloro-5-fluoro-indol-1-yl)-1-methylethylamine fumarate] (5-40 mg/kg). Seizures were initiated by an electrical bell at an intensity of 122 dB SPL (max. 60 sec). Most (>90%) DBA/2 mice can be resuscitated for subsequent tests in the same animal. However, a disadvantage of DBA/2 mice as a SUDEP model is that these mice have a short time period during which they exhibit RA, because they exhibit progressive hearing loss and lose RA susceptibility as seizure severity declines. Therefore, we examined the effects of auditory stimulation (parameters listed above) in a closely-related mouse strain, DBA/1, which was thought not to be susceptible to AGS. We also examined the effects of fluoxetine (ip), a selective 5-HT re-uptake inhibitor on DBA/1 mice. Results: The results indicate that mCPP (3 mg/kg i.p.) reduced AGS severity, and blocked RA, and RO 60-0175 (20 mg/kg i.p.) also reduced AGS severity and blocked RA in DBA/2 mice. DBA/1 mice were surprisingly susceptible to AGS followed by RA. The duration of AGS plus RA susceptibility in DBA/1 mice (~4 wks) also greatly exceeded that of DBA/2 mice (~1 wk). DBA/1 mice often did not initially exhibit RA, but after 2-3 stimulus exposures most DBA/1 mice began to exhibit AGS with RA consistently. Fluoxetine exerted an anticonvulsant effect in DBA/1 mice. The fluoxetine dose required to suppress seizures in DBA/1 mice (45 mg/kg) exceeded that in DBA/2 mice (25 mg/kg). Block of RA alone (with tonic seizures remaining) occurred in a number of DBA/1 mice with 40-50 mg/kg doses of fluoxetine. Conclusions: These findings extend previous results that indicate enhancement of 5-HT neurotransmission in DBA/2 mice prevents SUDEP, based on the effectiveness of the selective 5-HT agonists in blocking RA and reducing AGS severity. Our findings also suggest that DBA/1 mice may be a useful SUDEP model. DBA/1 mice exhibit seizures followed by RA with the advantage that they are also useful for chronic SUDEP prevention studies because they exhibit seizures with RA for an extended time period. (Support: Citizens United for Research in Epilepsy Interdisciplinary Res. Award)