0337 The Effect of a 5-HT2A/2C Receptor Antagonist on Breathing During Sleep in Mice

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Abstract Introduction Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep due to the loss of pharyngeal muscle tone. Serotonergic pathways, particularly 5-HT2A/2C receptors, play a role in modulating respiratory and upper airway motor control. We aimed to evaluate the effects of the 5-HT2A/2C antagonist pimavanserin on breathing parameters during sleep and upper airway muscle activity in mice. Methods We conducted a randomized cross-over study of a single dose of Pimavanserin (3 mg/kg, subcutaneously) versus vehicle in adult C57BL6 male mice for respiratory recordings (n=8) and genioglossus (GG EMG ) activity ( n=12,14) from 10AM to 4PM. Mice were headmounted with EEG and EMG electrodes and recorded in whole- body plethysmography chambers. Respiratory recordings were analyzed using a respiratory analysis algorithm in MATLAB. GG EMG during sleep was normalized to quiet wakefulness. Results During NREM sleep, pimavanserin augmented minute ventilation compared to vehicle from 0.89 ± 0.20 mL/min to 1.18 ± 0.23 mL/min (n=8, p=0.06) due to an increase in respiratory rate from 153 ± 21 to 176 ± 12.8 breaths per minute (n=8, p=0.02). In NREM sleep, there was a trend to increase inspiratory flow limitation after pimavanserin from 0.74% ± 2.47% to 6.28% ± 7.44% of breaths (n=8, p=0.08). Pimavanserin greatly decreased the number of apneas from 12.3 ± 40.9 to 0.00 ± 0.38 events per hour (n=8, p=0.02). Pimavanserin showed no effect on respiratory parameters during REM sleep, however the data was inconclusive due to REM sleep suppression. Pimavanserin did not significantly affect GG EMG activity during NREM sleep, with 0.75 ± 0.14 normalized units after vehicle and 0.78 ± 0.22 after pimavanserin (n=14, p=0.52). Finally, pimavanserin showed a trend to increase GG EMG activity in REM sleep from 0.31 ± 0.15 to 0.40 ± 0.17 normalized units (n=12, p= 0.08). Conclusion Pimavanserin stimulated breathing during NREM sleep and abolished apneas while GG EMG was not significantly affected. Taken together, our data suggest that 5-HT2A/C blockers may contribute to pharmacotherapy of sleep disordered breathing. Support (if any)

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