0318 The Effect of a 5-HT 2A/2C Receptor Antagonist Pimavanserin on Sleep Architecture in Mice

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Abstract Introduction Serotonergic (5-hydroxytryptophan, 5-HT) neurons in the dorsal raphe nucleus have been implicated in mechanisms of sleep-wake regulation. The 5-HT2A/2C receptor blocker pimavanserin has shown beneficial effects on sleep in patients with Parkinson’s disease. However, the effect of pimavanserin on macro- and microstructure of sleep still requires further investigation. We aimed to examine the effect of pimavanserin on sleep architecture in C57BL/6J male mice. Methods We performed a randomized cross-over trial of a single dose of pimavanserin (3.0 mg/kg, subcutaneously) versus vehicle 1 week apart in adult C57BL6 male mice (n = 17). Mice were instrumented with EEG/EMG headmounts. Polysomnography was performed from 10 am to 4 pm (light-phase) inside of a whole-body plethysmography chamber. Results Pimavanserin did not significantly affect NREM sleep time, but increased NREM bout duration from 0.60 ± 0.12 min to 1.24 ± 0.51 min (p = 0.0003) and decreased the number of NREM sleep bouts from 133.6 ± 32.33 to 58.76 ± 40.13 (p = 0.0004). Pimavanserin increased the delta power in NREM sleep compared to vehicle (p< 0.0001). Sleep latency, total sleep time, wake after sleep onset (WASO), sleep efficiency, and the total arousal index remained unchanged with pimavanserin. Pimavanserin significantly suppressed REM sleep time from 11.03 ± 7.57 min to 2.57 ± 3.31 min (p=0.0010). Pimavanserin also decreased the number of respiratory arousals from 4.62 ± 4.10 to 0.37 ± 1.06 events per hour (n=8, p=0.01). Conclusion Pimavanserin improved the quality of NREM sleep by consolidating sleep bouts, increasing the sleep depth, and suppressing respiratory arousals. Our data suggests that pimavanserin may help in alleviating conditions associated with sleep fragmentation, e.g. sleep-disordered breathing. Support (if any) Shionogi-Apnimed Sleep Science

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