The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems.
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.
SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, CA, USA.
Gregory S
GS
Parks
SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, CA, USA.
Deepti R
DR
Warrier
SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, CA, USA.
Lars
L
Dittrich
SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, CA, USA.
Michael D
MD
Schwartz
SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, CA, USA.
Jeremiah B
JB
Palmerston
Department of Psychiatry, SF VA Medical Center/NCIRE/University of California, San Francisco, CA, USA.
Thomas C
TC
Neylan
SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, CA, USA.
Stephen R
SR
Morairty
SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, CA, USA.
Thomas S
TS
Kilduff
D000081:Acetamides / Q000008:administration & dosage*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism; D004569:Electroencephalography; D004576:Electromyography; D006632:Histamine / Q000378:metabolism; D007546:Isoquinolines / Q000008:administration & dosage*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000068796:Orexin Receptor Antagonists / Q000008:administration & dosage*; D000068797:Orexins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism; D012894:Sleep Stages / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects*; D000077334:Zolpidem
D000081:Acetamides; C000596232:Hcrt protein, rat; D007546:Isoquinolines; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D000077334:Zolpidem; D006632:Histamine; C519150:almorexant