Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice

• Published in: Epilepsy & behavior 2015-04, Vol.45, p.1-7
• Main Authors: Zeng, Chang, Long, Xiaoyan, Cotten, Joseph F, Forman, Stuart A, Solt, Ken, Faingold, Carl L, Feng, Hua-Jun
• Format: Article
• Language: English
• Subjects: Animals; Breathing stimulants; Death, Sudden - etiology; Death, Sudden - prevention & control; Disease Models, Animal; Epilepsy - complications; Fluoxetine - pharmacology; Fluoxetine - therapeutic use; Mice; Mice, Inbred DBA; Neurology; Pulmonary Ventilation - drug effects; Respiratory Insufficiency - etiology; Respiratory Insufficiency - prevention & control; Seizure-induced respiratory arrest; Serotonin Uptake Inhibitors - pharmacology; Serotonin Uptake Inhibitors - therapeutic use; SSRI; SUDEP; Ventilation
• ISSN: 1525-5050; 1525-5069
• DOI: 10.1016/j.yebeh.2015.02.013

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.