title: Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep.
abstract: Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep-wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep-wake regulatory network.
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International , Menlo Park, California 94025.
authors.forename: Michael D
authors.identifier: 0000-0002-3472-8900
authors.initials: MD
authors.lastname: Schwartz
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International , Menlo Park, California 94025.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Nguyen
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International , Menlo Park, California 94025.
authors.forename: Deepti R
authors.initials: DR
authors.lastname: Warrier
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International , Menlo Park, California 94025.
authors.forename: Jeremiah B
authors.initials: JB
authors.lastname: Palmerston
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International , Menlo Park, California 94025.
authors.forename: Alexia M
authors.initials: AM
authors.lastname: Thomas
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International , Menlo Park, California 94025.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Morairty
authors.affiliation: UCSF San Francisco VA Medical Center/NCIRE , San Francisco, California 94121.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Neylan
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International , Menlo Park, California 94025.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kilduff
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D000068797:Orexins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1 / Q000633:toxicity; D000076985:Saporins; D012895:Sleep, REM / Q000187:drug effects*; D013686:Telemetry; D014851:Wakefulness / Q000187:drug effects; D000077334:Zolpidem
chemical_list: D000081:Acetamides; D058785:GABA-A Receptor Agonists; D007546:Isoquinolines; D000068797:Orexins; D011725:Pyridines; D054789:Ribosome Inactivating Proteins, Type 1; D000077334:Zolpidem; D006632:Histamine; C519150:almorexant; D000076985:Saporins; D009638:Norepinephrine
keywords: arousal; hypnotics; insomnia; monoamine; orexin; paradoxical sleep