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 language | English |
|---|---|
| Pages (from-to) | 104-110 |
| Number of pages | 7 |
| Journal | Brain Research |
| Volume | 1418 |
| DOIs | |
| State | Published - 18 Oct 2011 |
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Keywords
- 5-HT receptors
- DBA1 mice
- DBA2 mice
- Epilepsy
- Respiratory arrest
- Sudden death
- m-Chlorophenylpiperazine
Cite this
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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. / Faingold, Carl L.; Randall, Marcus; Mhaskar, Yashanad; Uteshev-Gaard, Victor V.
In: Brain Research, Vol. 1418, 18.10.2011, p. 104-110.Research output: Contribution to journal › Article
TY - JOUR
T1 - 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
AU - Faingold, Carl L.
AU - Randall, Marcus
AU - Mhaskar, Yashanad
AU - Uteshev-Gaard, Victor V.
PY - 2011/10/18
Y1 - 2011/10/18
N2 - 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.
AB - 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.
KW - 5-HT receptors
KW - DBA1 mice
KW - DBA2 mice
KW - Epilepsy
KW - Respiratory arrest
KW - Sudden death
KW - m-Chlorophenylpiperazine
UR - http://www.scopus.com/inward/record.url?scp=80053385551&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2011.08.043
DO - 10.1016/j.brainres.2011.08.043
M3 - Article
C2 - 21920504
AN - SCOPUS:80053385551
VL - 1418
SP - 104
EP - 110
JO - Brain Research
JF - Brain Research
SN - 0006-8993
ER -