Pre-treatment with Ssris and 5-HT2 Agonists Have Distinct Temporal and Sleep State-dependent Effects on Post-ictal Breathing in Amygdala Kindled Mice
Abstract number :
3.045
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2022
Submission ID :
2204362
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Katelyn Joyal, BA – The University of Iowa; alexandra Petrucci, BS – Graduate Student, Neurology, University of Iowa; Mydirah Littlepage-Saunders, BS – University of Iowa; Nicole Boodhoo, NA – University of Iowa; Linder Wendt, MS – Biostatistics – University of Iowa; Gordon Buchanan, MD, PHD – Neurology – University of Iowa
This abstract has been invited to present during the Basic Science Poster Highlights poster session
Rationale: Seizures can cause profound dysregulation of breathing. Seizures arising from sleep may confer even greater breathing impairment than those emerging from wakefulness and are more likely to result in sudden unexpected death in epilepsy (SUDEP). The neurotransmitter serotonin (5-HT) plays a major in breathing and sleep-wake regulation and is heavily implicated in epilepsy and SUDEP. We hypothesized that pharmacologically increasing 5-HT neurotransmission prior to seizure induction would improve post-ictal breathing, especially when seizures are induced during sleep compared to wake.
Methods: Sixteen adult (8-12 wks, balanced male/female) C57BL/6J mice were instrumented for EEG/EMG recording and implanted with a bipolar stimulating/recording electrode into the right basolateral amygdala [AP: -1.3 mm; ML: -2.8 mm; DV: -4.7 mm]. After recovery, afterdischarge threshold determination and kindling (80-380 mA; 1 s train of 1 msec biphasic square waves; 60 Hz; 2x/day), seizures were induced via amygdala stimulation during wake and NREM sleep following treatment with vehicle; 5-HT2 agonists, TCB-2 and MK-212 (10 mg/kg each); and selective 5-HT reuptake inhibitors (SSRI) citalopram (20 mg/kg) and fluoxetine (10 mg/kg), alone, or 15 min after 5-HT2 receptor antagonists MDL-11393 or RS-102221 (10 mg/kg each). All drugs were given intraperitoneally 30-60 min prior to seizure. Breathing was assessed before, during, and after seizures using whole-body plethysmography. Breathing measures included frequency (fR), tidal volume (VT), minute ventilation (VE), inter-breath interval, and apnea. Breathing variability was assessed with Poincaré analysis. EEG/EMG analysis and video recording were used to assess sleep state and seizure progression. Statistical comparisons were computed using multivariate linear mixed effect models.
Results: SSRIs and 5-HT2 agonists increased postictal fR, VT, and VE on different timescales following seizures induced during wakefulness. These effects were lost when seizures were induced during NREM sleep. SSRIs but not 5-HT2 agonists suppressed ictal and post-ictal apnea regardless of sleep state. Citalopram, TCB-2, and MK-212 decreased breathing variability following seizures during wakefulness at different postictal timepoints. Only MK-212 decreased breathing variability when seizures were induced during NREM sleep. Administration of the 5-HT2A antagonist MDL-11939, but not the 5-HT2C antagonist RS-102221, prior to citalopram modulated its effects on fR, VT, VE, and breathing variability.
Conclusions: These results indicate that various 5-HT receptor mechanisms impact post-ictal breathing on different timescales during the recovery of eupnea. They also suggest that dysfunction of the 5-HT system in epilepsy in conjunction with decreased 5-HT tone during sleep reduces the efficacy of 5-HTergic treatments in improving post-ictal respiration.
Funding: NIH/NINDS F31NS125955 to K.G.J., AES and NIH/NINDS F31NS113479 to A.N.P., NIH/NINDS R01NS095842 to G.F.B.
Basic Mechanisms