5-HT receptors exert differential effects on seizure-induced respiratory arrest in DBA/1 mice

Abstract

Both clinical and animal studies demonstrated that seizure-induced respiratory arrest (S-IRA) contributes importantly to sudden unexpected death in epilepsy (SUDEP). It has been shown that enhancing serotonin (5-HT) function relieves S-IRA in animal models of SUDEP, including DBA/1 mice. Direct activation of 5-HT3 and 5-HT4 receptors suppresses S-IRA in DBA/1 mice, indicating that these receptors are involved in S-IRA. However, it remains unknown if other subtypes of 5-HT receptors are implicated in S-IRA in DBA/1 mice. In this study, we investigated the action of an agonist of the 5-HT1A (8-OH-DPAT), 5-HT2A (TCB-2), 5-HT2B (BW723C86), 5-HT2C (MK-212), 5-HT6 (WAY-208466) and 5-HT7 (LP-211) receptor on S-IRA in DBA/1 mice. An agonist of the 5-HT receptor or a vehicle was intraperitoneally administered 30 min prior to acoustic simulation, and the effect of each drug/vehicle on the incidence of S-IRA was videotaped for offline analysis. We found that the incidence of S-IRA was significantly reduced by TCB-2 at 10 mg/kg (30%, n = 10; p < 0.01, Fisher's exact test) but was not altered by other agonists compared with the corresponding vehicle controls in DBA/1 mice. Our data demonstrate that 5-HT2A receptors are implicated in S-IRA, and 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 receptors are not involved in S-IRA in DBA/1 mice.

Fig 1. Activating 5-HT_2A but not 5-HT_2B and 5-HT_2C receptors suppresses S-IRA in DBA/1 mice.

A) Systemic administration of the 5-HT_2A receptor agonist TCB-2 significantly reduced the incidence of S-IRA at 10 mg/kg compared with the vehicle control (dose zero). But, TCB-2 at 5 mg/kg or 1 mg/kg was ineffective in alleviating S-IRA. B, C) Injection of the 5-HT_2B receptor agonist BW723C86 at 2–10 mg/kg or 5-HT_2C receptor agonist MK-212 at 5–20 mg/kg exerted no effect on S-IRA compared with the corresponding vehicle control, respectively. ** p < 0.01: Significantly different from the vehicle control (dose zero) (Fisher’s exact test).

Fig 2. Stimulating the function of 5-HT_1A, 5-HT₆ and 5-HT₇ receptors engenders no effect on S-IRA in DBA/1 mice.

A, B, C) Systemic injection of the 5-HT_1A receptor agonist 8-OH-DPAT at 1–10 mg/kg, 5-HT₆ receptor agonist WAY-208466 at 5–30 mg/kg and 5-HT₇ receptor agonist LP-211 at 0.25–1 mg/kg did not significantly alter the incidence of S-IRA compared with the corresponding vehicle control (dose zero) in DBA/1 mice, respectively. (Fisher’s exact test).