Effects of GF-015535-00, a novel α1 GABA A receptor ligand, on the sleep-wake cycle in mice, with reference to zolpidem

Abstract

Study objectives: Novel, safe, and efficient hypnotic compounds capable of enhancing physiological sleep are still in great demand in the therapy of insomnia. This study compares the sleep-wake effects of a new α1 GABA(A) receptor subunit ligand, GF-015535-00, with those of zolpidem, the widely utilized hypnotic compound.

Methods: Nine C57Bl6/J male mice were chronically implanted with electrodes for EEG and sleep-wake monitoring. Each mouse received 3 doses of GF-015535-00 and zolpidem. Time spent in sleep-wake states and cortical EEG power spectra were analyzed.

Results: Both zolpidem and GF-015535-00 prominently enhanced slow wave sleep and paradoxical sleep in the mouse. However, as compared with zolpidem, GF-015535-00 showed several important differences: (1) a comparable sleep-enhancing effect was obtained with a 10 fold smaller dose; (2) the induced sleep was less fragmented; (3) the risk of subsequent wake rebound was less prominent; and (4) the cortical EEG power ratio between slow wave sleep and wake was similar to that of natural sleep and thus compatible with physiological sleep.

Conclusion: The characteristics of the sleep-wake effects of GF-015535-00 in mice could be potentially beneficial for its use as a therapeutic compound in the treatment of insomnia. Further investigations are required to assess whether the same characteristics are conserved in other animal models and humans.

Keywords: Zolpidem; insomnia; mouse; sleep fragmentation; α1 GABAA receptor.

Figure 1

Effects of orally administered doses of GF-015535-00 and zolpidem on the cumulative amount of the sleep-wake states in mice. The compounds were administrated just before lights-off at 7:00 p.m. Results are expressed as the mean cumulative time (mean ± SEM) spent in each behavioral state. Note that both GF-015535-00 and zolpidem significantly enhanced slow wave sleep (SWS) and paradoxical sleep (PS), and that at a dose of 1.2 mg/kg, the sleep promoting effect of GF-015535-00 is comparable to that of zolpidem at a dose of 12 mg/kg. (*P < 0.05; **P < 0.01, Mann-Whitney nonparametric test, n = 9).

Figure 2

Effects of oral administration of GF-015535-00 and zolpidem on the sleep-wake states during 6-h post-dosing in mice. Results are expressed as average duration in min (± SEM) spent in each behavioral state during a recording period of 6 h in the same animals (n = 9). Note that the highest dose of zolpidem and GF-015535-00 gave rise to an increase in slow wave sleep (SWS) and paradoxical sleep (PS) and a decrease in waking (W) (*P < 0.05; **P < 0.01, Mann-Whitney nonparametric test).

Figure 3

Examples of a 6-h polygraphic recording (electroencephalogram EEG and electromyogram EMG), cortical EEG power spectral density (μV²) in slow frequency band (0.5-5 Hz) and corresponding hypnograms illustrating the effects of oral administration (just before lights-off at 7:00 p.m.) of zolpidem. Note (1) compared with the use of vehicle, the compound enhances markedly cortical slow activity (0.5-5 Hz), accompanied with an increase in slow wave sleep (SWS); and (2) slow activity after zolpidem treatment had a lower amplitude than that of vehicle. Other abbreviations: PS, paradoxical sleep; W, wake.

Figure 4

Examples of a 6-h polygraphic recording (electroencephalogram EEG and electromyogram EMG), cortical EEG power spectral density (μV²) in slow frequency band and corresponding hypnograms illustrating the effects of oral administration (just before lights-off at 7:00 p.m.) of GF-015535-00. Note (1) compared with the use of placebo, the compound enhances markedly cortical slow activity (0.5-5 Hz), accompanied with an increase in slow wave sleep (SWS); and (2) slow activity after the GF-015535-00 treatment displayed an amplitude similar to that of vehicle. Other abbreviations: PS, paradoxical sleep; W, wake.

Figure 5

Cortical EEG power ratio (0.5-60 Hz) between slow wave sleep and wakefulness after vehicle, zolpidem (12 mg/kg), or GF-015535-00 (1.2 mg/kg) treatment in the mouse. Data of EEG power were collected immediately after vehicle or drug administration between 7:00-11:00 p.m. They were made up of 478 episodes of 4-sec EEG samples of slow wave sleep (SWS) and wakefulness (W) from each analyzed animal. Note that zolpidem (12 mg/kg), but not GF-015535-00 (1.2 mg/kg), decreased significantly the cortical EEG SWS/W power ratio as compared with vehicle (***P < 0.001; 2-tailed Student's t test).