A 5HT2A Inverse Agonist Reverses Nicotine Withdrawal Effects on Sleep Stages



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Sleep disturbances are common in nicotine withdrawal, increasing risk for relapse to smoking. This study determined if the selective 5-HT2A serotonin receptor inverse agonist MDL 100907 (volinanserin) can increase time spent in restorative NREM sleep and reduce sleep fragmentation. All surgery was conducted under isoflurane anesthesia. Male Sprague-Dawley rats (N = 34) were implanted with EEG and EMG electrodes and with osmotic minipumps continuously infusing either 9 mg/kg/day s.c. nicotine bitartrate in saline or saline alone. After 7 days, pumps were removed to induce spontaneous nicotine withdrawal syndrome. Seventeen hours post-pump removal the rats were injected i.p. with 1 mg/kg MDL 100907 (volinanserin) in a vehicle of saline/DMSO/Tween80 or with a vehicle alone, 17 hours post-pump removal. The three treatment groups were: Saline infusion-Vehicle injection (n = 14), Nicotine infusion-Vehicle injection (n = 11) and Nicotine infusion-MDL injection 100907 (n = 9). Rats were monitored during peak withdrawal (18 to 22 hours post-pump removal) within the sleep-intensive, lights-on cycle. The EEG and EMG waves were scored by SleepSign software for the time spent in and number of separate bouts of Wake, NREM and REM. For accuracy, the resulting tracings were also scored manually under blind conditions. A one-way ANOVA revealed that nicotine withdrawal in the absence of volinanserin or (MDL100907) increased the average number of sleep bouts, decreased the percent time spent in NREM sleep, and increased EEG spectral band power across the spectrum. These findings are consistent with existing research on the effects of nicotine withdrawal on sleep. The nicotine withdrawal effect on average number of bouts, percent time spent in NREM sleep, and EEG spectral band power, was reduced by the injection of MDL100907. Inactivating 5HT2A receptors may favor NREM sleep and reduce sleep fragmentation, reversing the disruptive effects of nicotine withdrawal.



Nicotine withdrawal, sleep, EEG, MDL100907