Abstracts

This abstract has been invited to present during the Broadening Representation Inclusion and Diversity by Growing Equity (BRIDGE) poster session.

Rationale: Selective serotonin reuptake inhibitors (SSRIs) reduce the rate of serotonin reuptake at synapses, resulting in stronger serotonergic signaling. Observation of patients in clinics shows reduced serotonin levels in cases of SUDEP and impairments to serotonergic respiratory centers. Administering SSRIs reduced seizure activity and related respiratory distress in multiple genetic seizure models. Previous work showed acutely seizing rats subjected to mammalian diving reflex (MDR) challenges all suffered sudden deaths primarily due to lack of gasping/autoresuscitation respiratory drive. Sudden deaths in this model exhibited a physiological progression mirroring the progression seen in SUDEP. Further work implicated the carotid body signaling pathway as the primary driver of this response. SSRIs heavily impact carotid body signaling. We can learn more about the role of serotonin in regulating respiratory drive and preventing sudden death by exploring the short-term effects of SSRI administration on recovery from respiratory crisis challenges in this model.

Methods: We used urethane to anesthetize Long Evans rats and recorded blood pressure, ECG, and respiration. We triggered MDRs by spraying cold water into the nasal cavity through a cannula. After performing baseline MDR challenges, we administered kainic acid intraperitoneally to induce seizures. We allowed for seizure activity to develop for an hour before administering escitalopram oxalate, an SSRI, intraperitoneally. Thirty minutes after administering the SSRI, we performed up to twelve experimental MDR challenges at five-minute intervals.

Results: After receiving SSRI treatment, rats survived for 10/12 and 12/12 of the experimental MDR challenges. Previous experiments show seizing animals receiving no intervention survive 3.2 ± 3.8 MDR challenges (n = 10), while seizing animals with carotid body stimulation survive 10.5 ± 4.7 MDR challenges (n = 8), and control animals always survive all 12 MDR challenges (n = 4) (Data from “Carotid Body Stimulation as a Potential Intervention in Sudden Death in Epilepsy,” Epilepsy & Behavior, accepted with revisions). Physiological recordings show seizure activity continuing after SSRI administration, so the protective effect from the SSRI is not a result of seizure termination.

Conclusions: Our results support the hypothesis that an acute strengthening of serotonin signaling improves outcomes in respiratory crises linked to sudden death. While SSRIs might not work broadly as a clinical preventative for SUDEP due to a multiplicity of factors, these experiments support hypotheses on mechanisms of respiratory control which suggest serotonin-amplifying interventions could improve outcomes in populations at risk of SUDEP. More targeted experimentation with serotonergic compounds could identify specific targets for pharmacological interventions to prevent sudden death.

Funding: NIH OD023847