0336 Pimavanserin Alters Baseline Ventilation and Hypercapnic Chemoreflex in Mice

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Abstract Introduction Hypercapnic ventilatory response (HCVR) is a key driver of the respiratory control. Serotonin (5-hydroxytryptophan, 5-HT) plays an important role in central chemoreception. The depressed HCVR leads to hypoventilation, whereas overly robust HCVR increases loop gain and contributes to central and obstructive sleep apnea. CO2 is also a key stimulus inducing respiratory arousals from sleep, and mechanisms of respiratory arousals are also orchestrated by 5-HT signaling. We investigated whether pharmacological antagonism of serotonergic 5-HT2A/2C receptors with pimavanserin alters baseline ventilation and HCVR during wakefulness, and CO₂-induced arousal threshold during sleep Methods We conducted a randomized cross-over study of a single dose of Pimavanserin (3 mg/kg, subcutaneously) versus vehicle one week apart in adult male C57BL6 mice. Mice were instrumented with EEG/EMG head mounts and underwent assessments of HCVR (n = 18) and CO₂-induced arousal threshold (n = 11). Tidal volume (VT), respiratory rate (RR), and minute ventilation (VE) were measured, and HCVR was determined by the slope of VE versus inspired CO₂ (0 - 8%) using linear least-squares regression analysis. The arousal threshold was determined by arousal latency from stable NREM sleep to the hypercapnic challenge (8% CO2). Results Pimavanserin increased room air VE during quiet wakefulness compared to vehicle (1.1±0.06 vs 1.5±0.07 mL/min/g, p=0.0001) by elevating both VT (0.19±0.01 vs 0.2±0.01 mL, p=0.03) and RR (164.3±4.6 vs 187.7±4.9 bpm, p=0.001). In contrast, during hypercapnia, pimavanserin significantly decreased VT (0.39±0.01 vs 0.34±0.01 ml, p=0.005) and VE (4.8±0.17 vs 4.2±0.16 ml/min/g, p=0.01), which resulted in the HCVR suppression (0.46±0.02 vs 0.33±0.03 ∆ml/min/∆%CO2/g, p=0.003). In our set-up, arousal latency to hypercapnia was not altered (17.02±2.0 vs 13.9±1.3 sec, p=0.17). Conclusion Pimavanserin increases baseline ventilation and suppresses hypercapnic chemoreflex during wakefulness. Our findings suggest that pimavanserin may be helpful in patients with overly robust hypercapnic chemoreflex, which may support the role of 5-HT2A/2C receptors in loop gain regulation. Surprisingly, 5-HT2A/2C antagonism did not significantly affect arousal latency to hypercapnia as shown in previous studies. The role of 5-HT2A/2C receptors in the regulation of respiratory arousal threshold needs to be further investigated. Support (if any) Shionogi-Apnimed Sleep Sciences

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