Adrenergic α2 receptors are implicated in seizure-induced respiratory arrest in DBA/1 mice

[摘要] Aims: Sudden unexpected death in epilepsy (SUDEP) is a serious and underestimated public health burden. Both clinical and animal studies show that seizure-induced respiratory arrest (S-IRA) is the primary cause of death in SUDEP. Our previous studies demonstrated that atomoxetine, a norepinephrine reuptake inhibitor (NRI), suppresses S-IRA in DBA/1 mice, suggesting that noradrenergic neurotransmission modulates S-IRA. However, it remains unclear which adrenoceptors are implicated in S-IRA in DBA/1 mice. Materials and methods: Naive DBA/1 mice exhibit a low incidence of S-IRA, but after primed by acoustic stimulation, they become consistently susceptible to S-IRA. Atomoxetine, adrenoceptor agonists, antagonists or vehicle was intraperitoneally (i.p.) administered alone or in combination, and the effects of drug treatments on S IRA incidence and seizure behaviors were examined. Key findings: The incidence of S-IRA in primed DBA/1 mice was significantly reduced by clonidine, an alpha 2 adrenoceptor agonist, as compared with that of the vehicle control. However, compared with the vehicle control, S-IRA was not altered by cirazoline, an alpha 1 agonist. Consistent with previous reports, atomoxetine reduced S-IRA in primed DBA/1 mice. The suppressing effect of atomoxetine on S-IRA was prevented by injection of an alpha 2 adrenoceptor antagonist, yohimbine or atipamezole, but not by prazosin, an alpha 1 antagonist. Administration of alpha 1 or alpha 2 antagonists alone did not promote the incidence of S-IRA in nonprimed DBA/1 mice. Significance: These data demonstrate that noradrenergic neurotransmission modulates S-IRA predominantly via alpha 2 adrenoceptors in DBA/1 mice, indicating that selective activation of alpha 2 adrenoceptors can potentially prevent SUDEP.

[发布日期] 2021-11-01

[关键词] SUDEP;Noradrenergic neurotransmission;Atomoxetine;Clonidine;Yohimbine;Prazosin