Selective Serotonin Reuptake Inhibitors and 5-HT 2 Receptor Agonists Have Distinct, Sleep-state Dependent Effects on Postictal Breathing in Amygdala Kindled Mice

• Published in: Neuroscience 2023-03, Vol.513, p.76
• Main Authors: Joyal, Katelyn G, Petrucci, Alexandra N, Littlepage-Saunders, Mydirah V, Boodhoo, Nicole A, Wendt, Linder H, Buchanan, Gordon F
• Format: Article
• Language: English
• Subjects: Animals; Citalopram; Death, Sudden - etiology; Mice; Respiration; Seizures - complications; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Receptor Agonists; Sleep
• ISSN: 1873-7544

Seizures can cause profound breathing disruptions. Seizures arising from sleep cause greater breathing impairment than those emerging from wakefulness and more often result in sudden unexpected death in epilepsy (SUDEP). The neurotransmitter serotonin (5-HT) plays a major role in respiration and sleep-wake regulation. 5-HT modulates seizure susceptibility and severity and is dysregulated by seizures. Thus, the impact of seizures on breathing dysregulation may be due to impaired 5-HT neurotransmission. We examined whether pharmacologically increasing 5-HT neurotransmission prior to seizures improves postictal breathing and how sleep-state during seizure induction contributes to these effects. We assessed breathing with whole-body plethysmography in 84 amygdala-kindled mice pre-treated with selective serotonin reuptake inhibitors (SSRI) or 5-HT receptor agonists. SSRIs and 5-HT agonists increased postictal breathing frequency (f ), tidal volume (V ), and minute ventilation (V ) at different timepoints following seizures induced during wakefulness. These effects were not observed following seizures induced during NREM sleep. SSRIs suppressed ictal and postictal apnea regardless of sleep state. The SSRI citalopram and the 5-HT agonists TCB-2 and MK-212 decreased breathing variability following wake-occurring seizures at different postictal timepoints. Only MK-212 decreased breathing variability when seizures were induced during NREM sleep. The 5-HT antagonist MDL-11939 reduced the effect of citalopram on f , V , and V , and enhanced its effect on breathing variability in the initial period following a seizure. These results suggest that 5-HT mechanisms that are dependent on or independent from the 5-HT family of receptors impact breathing on different timescales during the recovery of eupnea, and that certain serotonergic treatments may be less effective at facilitating postictal breathing following seizures emerging from sleep.