title: Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice.
abstract: Sudden unexpected death in epilepsy (SUDEP) is a fatal epileptic event. DBA/1 mice are a relevant animal model for the study of SUDEP, as these mice exhibit seizure-induced respiratory arrest (S-IRA) leading to death, which has been observed in patients with witnessed SUDEP. Fluoxetine, a selective serotonin (5-hydroxytryptamine or 5-HT) reuptake inhibitor (SSRI), reduces S-IRA in DBA/1 mice. Given that DBA/1 mice with S-IRA can be resuscitated using a ventilator, we hypothesized that breathing stimulants can prevent S-IRA and that fluoxetine prevents S-IRA by enhancing ventilation in these mice. Spontaneous respiratory function in anesthetized or awake DBA/1 mice was examined using noninvasive plethysmography before and after administering fluoxetine or breathing stimulants, doxapram, and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP). The effects of these drugs on S-IRA in DBA/1 mice were tested. As reported previously, systemic administration of fluoxetine reduced S-IRA in awake DBA/1 mice, but fluoxetine in anesthetized and awake DBA/1 mice did not increase basal ventilation or the ventilatory response to 7% CO2. Both doxapram and PK-THPP increased ventilation in room air and in air+7% CO2 in anesthetized DBA/1 mice. However, neither of the breathing stimulants reduced the incidence of S-IRA. Our studies confirm that fluoxetine reduces S-IRA in DBA/1 mice without enhancing basal ventilation in the absence of seizures. Although breathing stimulants increased ventilation in the absence of seizures, they were ineffective in reducing S-IRA, indicating that drug-induced increases in ventilation are insufficient to compensate for S-IRA in DBA/1 mice.
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: 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.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cotten
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Forman
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Solt
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors.forename: Carl L
authors.initials: CL
authors.lastname: Faingold
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 / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000150:complications*; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008811:Mice, Inbred DBA; D012123:Pulmonary Ventilation / Q000187:drug effects*; D012131:Respiratory Insufficiency / Q000209:etiology / Q000517:prevention & control*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Breathing stimulants; SSRI; SUDEP; Seizure-induced respiratory arrest; Ventilation