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

Carl L. Faingold, Marcus Randall, Yashanad Mhaskar, Victor V. Uteshev-Gaard

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Abstract

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 CO 2 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-HT 2B/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-HT 2C and 5-HT 3B receptor expression levels were significantly reduced, as seen previously in DBA/2 mice. However, 5-HT 2B receptor expression was also reduced in DBA/1 mice, contrasting with the 5-HT 2B receptor elevation seen in DBA/2 mice. This difference may explain the differential effects of the 5-HT 2B/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.

Original languageEnglish
Pages (from-to)104-110
Number of pages7
JournalBrain Research
Volume1418
DOIs
StatePublished - 18 Oct 2011

Fingerprint

Serotonin Receptor Agonists
Inbred DBA Mouse
Serotonin Receptors
Sudden Death
Brain Stem
Seizures
Serotonin
Receptor, Serotonin, 5-HT2B
Epilepsy
Fluoxetine
Reflex Epilepsy
Receptor, Serotonin, 5-HT2C
Poisons
Serotonin Uptake Inhibitors
Carbon Monoxide
Respiration
Proteins
Western Blotting

Keywords

  • 5-HT receptors
  • DBA1 mice
  • DBA2 mice
  • Epilepsy
  • Respiratory arrest
  • Sudden death
  • m-Chlorophenylpiperazine

Cite this

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title = "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",
abstract = "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 CO 2 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-HT 2B/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-HT 2C and 5-HT 3B receptor expression levels were significantly reduced, as seen previously in DBA/2 mice. However, 5-HT 2B receptor expression was also reduced in DBA/1 mice, contrasting with the 5-HT 2B receptor elevation seen in DBA/2 mice. This difference may explain the differential effects of the 5-HT 2B/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.",
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AU - Mhaskar, Yashanad

AU - Uteshev-Gaard, Victor V.

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