Serotonin 5-HT receptors play a critical role in the action of fenfluramine to block seizure-induced sudden death in a mouse model of SUDEP.

RATIONALE

Our previous study showed that the recently approved anticonvulsant drug, fenfluramine, which enhances the release of serotonin (5-hydroxytryptamine, 5-HT) in the brain, prevents seizure-induced respiratory arrest (S-IRA) in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). The present study examined the role of 5-HT receptor subtypes in mediating the effect of this agent by combined administration of fenfluramine with selective 5-HT receptor antagonists prior to seizure in DBA/1 mice.

METHODS

Fenfluramine (15 mg/kg, i.p.) was administered to primed DBA/1 mice, and audiogenic seizure (Sz) was induced 16 h later. Thirty min prior to Sz induction a selective antagonist acting on 5-HT, 5-HT, 5-HT 5-HT, 5-HT, 5-HT or 5-HT receptors at a sub-toxic dose was administered, and changes in seizure-induced behaviors were evaluated. Follow-up studies examined the effect of administration of a 5-HT receptor agonist, BIMU 8, as well as the effect of co-administration of ineffective doses of fenfluramine and BIMU-8 on Sz behaviors.

RESULTS

The 5-HT antagonist (GR125487) was the only 5-HT receptor antagonist that was able to reverse the action of fenfluramine to block Sz and S-IRA. Treatment with the 5-HT receptor agonist (BIMU-8), or co-administration of ineffective doses of BIMU-8 and fenfluramine significantly reduced the incidence of S-IRA and tonic Sz in DBA/1 mice. The antagonists for 5-HT, 5-HT 5-HT, and 5-HT receptors did not significantly affect the action of fenfluramine. However, the 5-HT and the 5-HT antagonists enhanced the anticonvulsant effects of fenfluramine.

CONCLUSIONS

These findings suggest that the action of fenfluramine to prevent seizure-induced sudden death in DBA/1 mice is mediated primarily by activation of 5-HT receptors. These studies are the first to indicate the therapeutic potential of 5-HT receptor agonists either alone or in combination with fenfluramine for preventing SUDEP. Enhancement of the anticonvulsant effect of fenfluramine by 5-HT and 5-HT antagonists may involve presynaptic actions of these antagonists. Thus, the Sz and S-IRA blocking actions of fenfluramine involve complex interactions with several 5-HT receptor subtypes. These data also provide further support for the serotonin hypothesis of SUDEP.