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


CONCLUSIONS
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.
Integrative Physiology of Brain Arousal Systems, Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR 5292, Faculty of Medicine, Claude Bernard University, 8 Avenue Rockefeller, Lyon Cedex 08, France.
Christelle
C
Anaclet
Mei
M
Zhang
Chunmei
C
Zhao
Colette
C
Buda
Laurent
L
Seugnet
Jian-Sheng
JS
Lin
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D012890:Sleep / Q000187:drug effects* / Q000502:physiology; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology; D000077334:Zolpidem
C546241:Gabra1 protein, mouse; D006993:Hypnotics and Sedatives; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem