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 40mg/kg was ineffective in blocking seizure-induced RA, and 60mg/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.
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, PO Box 19629, Springfield, IL 62794-9629, USA. cfaingold@siumed.edu
authors.forename: Carl L
authors.initials: CL
authors.lastname: Faingold
authors.forename: Marcus
authors.initials: M
authors.lastname: Randall
authors.forename: Yashanad
authors.initials: Y
authors.lastname: Mhaskar
authors.forename: Victor V
authors.initials: VV
authors.lastname: Uteshev
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D003645:Death, Sudden / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA / Q000145:classification; D010879:Piperazines / Q000627:therapeutic use*; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000150:complications / Q000209:etiology; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D013045:Species Specificity
chemical_list: D005473:Fluoxetine; D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C015068:1-(3-chlorophenyl)piperazine