title: Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep.
abstract: Orexin-A and orexin-B are hypothalamic neuropeptides that play critical roles in the maintenance of wakefulness. Intracerebroventricular (ICV) administration of orexin-A has been shown to promote wakefulness and suppress both rapid eye movement (REM) sleep and non-REM (NREM) sleep through the orexin receptor-1 (OX(1)R) and orexin receptor-2 (OX(2)R). Here, we elucidated the differential roles of orexin receptors in the regulation of sleep and wakefulness by comparing the effects of ICV orexin-A administration in wild-type, OX(1)R(-/-), and OX(2)R(-/-) mice. The effects of orexin-A on wakefulness and NREM sleep were significantly attenuated in both knock-out mice as compared with wild-type mice, with substantially larger attenuation in OX(2)R(-/-) mice than in OX(1)R(-/-) mice. These results suggest that although the OX(2)R-mediated pathway has a pivotal role in the promotion of wakefulness, OX(1)R also plays additional roles in promoting arousal. In contrast, suppression of REM sleep by orexin-A administration was slightly and similarly attenuated in both OX(1)R(-/-) and OX(2)R(-/-) mice, suggesting a comparable contribution of the two receptors to REM sleep suppression. Histological studies demonstrated differential distributions of each receptor subtype in distinct neuronal populations with specific neurotransmitter identities in brainstem cholinergic/monoaminergic neurons. In the laterodorsal tegmental and pedunculopontine tegmental nuclei especially, cholinergic neurons exclusively expressed OX(1)R mRNA, but OX(2)R mRNA was expressed mainly in GABAergic putative interneurons. Thus, each orexin receptor subtype plays differential roles in gating NREM and REM sleep through distinct neuronal pathways.
authors.affiliation: Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan. mieda@med.kanazawa-u.ac.jp
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mieda
authors.forename: Emi
authors.initials: E
authors.lastname: Hasegawa
authors.forename: Yaz Y
authors.initials: YY
authors.lastname: Kisanuki
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sinton
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D007276:Injections, Intraventricular / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D009479:Neuropeptides / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012894:Sleep Stages / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism; D014851:Wakefulness / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D000954:Antigens, Surface; C501103:Cd200r1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D020319:Oligodeoxyribonucleotides, Antisense; D064446:Orexin Receptors; D000068797:Orexins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C493453:Slc18a2 protein, mouse; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1