Differences in serotonin receptor expression in the brainstem may explain the differential ability of a serotonin agonist to block seizure-induced sudden death in DBA/2 vs. DBA/1 mice

DBA mice are models of sudden unexpected death in epilepsy (SUDEP) that exhibit audiogenic generalized convulsive seizures (GCS), ending in death due to respiratory arrest (RA). Serotonin (5-HT) normally enhances respiration in response to elevated CO2 levels, which occur during GCS in patients. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), blocks GCS-induced SUDEP in both DBA/2 and DBA/1 mice. This study examined the effects of a 5-HT2B/2C agonist (m-chlorophenylpiperazine, mCPP) to test the generality of serotonergic effects on DBA mice. In DBA/2 mice mCPP pre-treatment [5 or 10 (but not 2) mg/kg, i.p.] significantly reduced RA incidence without blocking seizure susceptibility. However, in DBA/1 mice mCPP in doses up to 40 mg/kg was ineffective in blocking seizure-induced RA, and 60 mg/kg was toxic. The cause of this strain difference was perplexing. Previous studies showed that brainstem 5-HT receptor protein expression was abnormal in DBA/2 mice. Therefore, expression of 5-HT receptor proteins in the medial–caudal brainstem of DBA/1 mice was evaluated using Western blots. In DBA1/mice 5-HT2C and 5-HT3B receptor expression levels were significantly reduced, as seen previously in DBA/2 mice. However, 5-HT2B receptor expression was also reduced in DBA/1 mice, contrasting with the 5-HT2B receptor elevation seen in DBA/2 mice. This difference may explain the differential effects of the 5-HT2B/2C agonist in these SUDEP models. mCPP blocked RA in DBA/2 mice and concomitantly reduced tonic seizures, which also occurs. Fluoxetine is the only agent tested that blocks RA selectively in these SUDEP models, which may be clinically relevant.

► A 5-HT2B/2C agonist (mCPP) blocks seizure-induced death in DBA/2 mice. ► mCPP is not effective in blocking seizure-induced death in DBA/1 mice. ► Decreased brainstem 5-HT2B receptor protein occurred in DBA/1 mice. ► 5-HT2B receptor expression in DBA/2 mice was elevated in previous studies. ► This difference in 5-HT2B expression may explain the difference in mCPP effects.