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- Title
Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons.
- Authors
Uygun, David S.; Zhiwen Ye; Zecharia, Anna Y.; Harding, Edward C.; Xiao Yu; Yustos, Raquel; Vyssotski, Alexei L.; Brickley, Stephen G.; Franks, Nicholas P.; Wisden, William
- Abstract
Zolpidem, a GABAA receptor-positive modulator, is the gold-standard drug for treating insomnia. Zolpidem prolongs IPSCs to decrease sleep latency and increase sleep time, effects that depend on a α2 and/or α3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on a α1 subunit-containing receptors, and which may make zolpideminduced sleep less optimal. In this paper, we investigate whether zolpidem needs to potentiate only particular GABAergic pathways to induce sleep without reducing EEG power. Mice with a knock-in F771 mutation in the GABAa receptor γ2 subunit gene are zolpideminsensitive. Using these mice, GABAA receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of γ2I77 mice were made selectively sensitive to zolpidem by genetically swapping the -γ2I77 subunits with -γ2F77 subunits. When histamine neurons were made selectively zolpidem-sensitive, systemic administration of zolpidem shortened sleep latency and increased sleep time. But in contrast to the effect of zolpidem on wild-type mice, the power in the EEG spectra of NREM sleep was not decreased, suggesting that these EEG power-reducing effects of zolpidem do not depend on reduced histamine release. Selective potentiation of GABAA receptors in the frontal cortex by systemic zolpidem administration also reduced sleep latency, but less so than for histamine neurons. These results could help with the design of new sedatives that induce a more natural sleep.
- Subjects
ZOLPIDEM; INSOMNIA treatment; HISTAMINERGIC mechanisms; NEOCORTEX; NEURONS
- Publication
Journal of Neuroscience, 2016, Vol 36, Issue 44, p11171
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3714-15.2016