期刊
NEUROPSYCHOPHARMACOLOGY
卷 41, 期 4, 页码 1144-1155出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2015.256
关键词
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资金
- USAMRAA [DR080789P1]
- DFG fellowship [DI 1718/1-1]
- NIH [R01 NS077408]
The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH- or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos(+) cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH- and ALM-treated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL- but not in VEH-or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.
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