Effect of monoamine reuptake inhibition and α1 blockade on respiratory arrest and death following electroshock-induced seizures in mice
Stephen W. Kruse
Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa
The Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa
Search for more papers by this authorKyle G. Dayton
The Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa
The Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa
Search for more papers by this authorBenton S. Purnell
The Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa
The Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa
Search for more papers by this authorJared I. Rosner
The Secondary Student Training Program, University of Iowa, Iowa City, Iowa
Search for more papers by this authorCorresponding Author
Gordon F. Buchanan
The Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa
The Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa
Department of Neurology, University of Iowa, Iowa City, Iowa
The Carver College of Medicine, University of Iowa, Iowa City, Iowa
Correspondence
Gordon F. Buchanan, Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA.
Email: [email protected]
Search for more papers by this authorStephen W. Kruse
Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa
The Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa
Search for more papers by this authorKyle G. Dayton
The Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa
The Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa
Search for more papers by this authorBenton S. Purnell
The Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa
The Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa
Search for more papers by this authorJared I. Rosner
The Secondary Student Training Program, University of Iowa, Iowa City, Iowa
Search for more papers by this authorCorresponding Author
Gordon F. Buchanan
The Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa
The Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa
Department of Neurology, University of Iowa, Iowa City, Iowa
The Carver College of Medicine, University of Iowa, Iowa City, Iowa
Correspondence
Gordon F. Buchanan, Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA.
Email: [email protected]
Search for more papers by this authorSummary
Objective
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Although the mechanisms for SUDEP are incompletely understood, seizure-induced respiratory arrest (S-IRA) has been strongly and consistently implicated. A body of evidence indicates that serotonin (5-HT), a modulator of breathing, plays a critical role in SUDEP. Because the 5-HT and norepinephrine (NE) systems interact in many biologic processes and NE is known to modulate breathing and seizures, we hypothesized that NE may play a role in S-IRA and SUDEP.
Methods
We examined the effects of pharmacologic manipulation of 5-HT and NE on S-IRA and death following maximal electroshock (MES)–induced seizures in adult wild-type (WT) mice, genetically 5-HT neuron–deficient (Lmx1bf/f/p) mice, and chemically NE neuron–deficient mice. Mice were treated with pharmacologic agents targeting the serotonergic and noradrenergic systems and subjected to seizure induction via MES while breathing was measured via whole-body plethysmography.
Results
S-IRA and death was reduced in WT mice with NE reuptake inhibitors (NRIs), reboxetine and atomoxetine, selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the dual 5-HT/NE reuptake inhibitor (SNRI), duloxetine. S-IRA and death was also reduced in Lmx1bf/f/p mice with reboxetine and fluoxetine. The protective effects of the reuptake inhibitors were prevented by the α1 antagonist, prazosin. Citalopram did not reduce S-IRA and death in NE neuron–deficient mice.
Significance
These data suggest that 5-HT and NE critically interact in the modulation of breathing following a seizure and potentially inform preventive strategies for SUDEP.
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