title: Serotonergic agents act on 5-HT3receptors in the brain to block seizure-induced respiratory arrest in the DBA/1 mouse model of SUDEP.
abstract: Drugs that enhance the action of serotonin (5-hydroxytrypamine, 5-HT), including several selective serotonin reuptake inhibitors (SSRIs), reduce susceptibility to seizure-induced respiratory arrest (S-IRA) that leads to death in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). However, it is not clear if specific 5-HT receptors are important in the action of these drugs and whether the brain is the major site of action of these agents in this SUDEP model. The current study examined the actions of agents that affect the 5-HT3receptor subtype on S-IRA and whether intracerebroventricular (ICV) microinjection of an SSRI would reduce S-IRA susceptibility in DBA/1 mice. The data indicate that systemic administration of SR 57227, a 5-HT3agonist, was effective in blocking S-IRA in doses that did not block seizures, and the S-IRA blocking effect of the SSRI, fluoxetine, was abolished by coadministration of a 5-HT3antagonist, ondansetron. Intracerebroventricular administration of fluoxetine in the present study was also able to block S-IRA without blocking seizures. These findings suggest that 5-HT3receptors play an important role in the block of S-IRA by serotonergic agents, such as SSRIs, which is consistent with the abnormal expression of 5-HT3receptors in the brainstem of DBA mice observed previously. Taken together, these data indicate that systemically administered serotonergic agents act, at least, in part, in the brain, to reduce S-IRA susceptibility in DBA/1 mice and that 5-HT3receptors may be important to this effect.
authors.affiliation: Department of Pharmacology and Neurology, Southern Illinois University, School of Medicine, Springfield, IL, USA. Electronic address: cfaingold@siumed.edu.
authors.forename: Carl L
authors.initials: CL
authors.lastname: Faingold
authors.affiliation: Department of Pharmacology and Neurology, Southern Illinois University, School of Medicine, Springfield, IL, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Randall
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Health Management Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Health Management Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Shifang
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Long
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: feng.huajun@mgh.harvard.edu.
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Feng
mesh_terms: D000818:Animals; D003645:Death, Sudden / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D012640:Seizures / Q000150:complications*; D058827:Serotonin 5-HT3 Receptor Agonists / Q000494:pharmacology*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology*; D018490:Serotonin Agents / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D005473:Fluoxetine; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 5-HT; Antagonist; Audiogenic seizures; Intracerebroventricular; SSRIs