The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

Abstract

Sudden unexpected death in epilepsy (SUDEP) is a significant public health burden. The mechanisms of SUDEP are elusive, although cardiorespiratory dysfunction is a likely contributor. Clinical and animal studies indicate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death in many SUDEP cases. Our prior studies demonstrated that intraperitoneal (IP) injection of atomoxetine, a norepinephrine reuptake inhibitor (NRI) widely used to treat attention deficit hyperactivity disorder, suppresses S-IRA in DBA/1 mice. In the current study, we injected atomoxetine intracerebroventricularly (ICV) and measured its effect on S-IRA in DBA/1 mice to determine its central effects. Additionally, to test our hypothesis that atomoxetine reduces S-IRA via altering cardiorespiratory function, we examined the effect of atomoxetine on respiratory and cardiac function using non-invasive plethysmography and ECG in anesthetized DBA/1 mice, and on blood pressure and heart rate using a tail-cuff system in conscious DBA/1 mice. ICV administration of atomoxetine at 200–250 nmol significantly reduced S-IRA evoked by acoustic stimulation in DBA/1 mice, consistent with a central atomoxetine effect on S-IRA. Peripheral atomoxetine administration at a dosage that reduces S-IRA (15 mg/kg, IP) slightly increased basal ventilation and the ventilatory response to 7% CO2, but exerted no effect on heart rate in anesthetized DBA/1 mice. IP injection of atomoxetine produced no effect on the heart rate and blood pressures in conscious mice. These data suggest that atomoxetine suppresses S-IRA through direct effects on the CNS and potentially through enhanced lung ventilation in DBA/1 mice.

Effect of monoamine reuptake inhibition and α1 blockade on respiratory arrest and death following electroshock‐induced seizures in mice

“…39,40 Recent data have implicated NE in S-IRA. 21,22 Here we demonstrate that 5-HT and NE may act as part of a circuit that regulates breathing following a seizure. Both NE and 5-HT are modulated by seizures, [41][42][43] are involved in breathing regulation, 18,44 and have antiepileptic properties.…”

“…Both NE and 5-HT are modulated by seizures, [41][42][43] are involved in breathing regulation, 18,44 and have antiepileptic properties. 21,22 Here we found that atomoxetine, as well as another NRI, reboxetine, reduced S-IRA and death following seizures induced in a different seizure model, MES. 46 Despite the antiepileptic properties of NE and 5-HT, drugs employed in this study that modulate these neurotransmitter systems did not significantly alter MES seizure severity.…”

“…n = 6-8 per group, as indicated in Recently, the NRI atomoxetine was shown to reduce S-IRA and death in the DBA/1 audiogenic seizure mouse model. 21,22 Here we found that atomoxetine, as well as another NRI, reboxetine, reduced S-IRA and death following seizures induced in a different seizure model, MES. In this study we further showed that the protective effect of NE is mediated through an α 1 receptor mechanism.…”

“…6 Although there is ample evidence to support a role for 5-HT in S-IRA, other neurotransmitters modulate breathing, arousal, and seizures, and could play a role in postictal respiratory control and SUDEP. 21,22 Because NE can modulate seizures 23 and breathing 18 is released by NE-producing locus coeruleus (LC) neurons following a seizure, 24 and is modulated in the LC by 5-HT, 25,26 we hypothesized that the NE and 5-HT systems interact in mediating S-IRA. 18 In 2 studies using DBA/1 mice, it was demonstrated that both the SSRIs fluvoxamine 19 and fluoxetine, 20 which have considerable activity at α 1 noradrenergic receptors, and the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine were more effective than the more 5-HT selective SSRI, paroxetine, in preventing S-IRA and subsequent death.…”

“…15 Recent evidence demonstrates that the norepinephrine reuptake inhibitor (NRI), atomoxetine, can also reduce susceptibility to S-IRA and death in DBA/ 1 mice. 21,22 Because NE can modulate seizures 23 and breathing 18 is released by NE-producing locus coeruleus (LC) neurons following a seizure, 24 and is modulated in the LC by 5-HT, 25,26 we hypothesized that the NE and 5-HT systems interact in mediating S-IRA. In this study we tested this hypothesis by pharmacologically manipulating the NE and 5-HT systems in Lmx1b f/f/p mice, their phenotypically WT littermates (Lmx1b f/f ), and C57BL/6 mice with or without toxin-mediated destruction of NE neurons in the LC, while monitoring seizure severity, respiratory activity, and survival following MES-induced seizures.…”