Orexin/hypocretin and histamine: Distinct roles in the control of wakefulness demonstrated using knock-out mouse models

Christelle Anaclet, Régis Parmentier, Koliane Ouk, Gérard Guidon, Colette Buda, Jean Pierre Sastre, Hidéo Akaoka, Olga A. Sergeeva, Masashi Yanagisawa, Hiroshi Ohtsu, Patricia Franco, Helmut L. Haas, Jian Sheng Lin

Research output: Contribution to journalArticlepeer-review

172 Scopus citations


To determine the respective role played by orexin/hypocretin and histamine (HA) neurons in maintaining wakefulness (W), we characterized the behavioral and sleep-wake phenotypes of orexin (Ox) knock-out (-/-) mice and compared them with those of histidine-decarboxylase (HDC, HA-synthesizing enzyme)-/- mice. While both mouse strains displayed sleep fragmentation and increased paradoxical sleep (PS), they presented a number of marked differences: (1) the PS increase in HDC-/- mice was seen during lightness, whereas that in Ox-/-mice occurred during darkness; (2) contrary to HDC-/-, Ox-/-mice had no W deficiency around lights-off, nor an abnormal EEG and responded to a new environment with increased W; (3) only Ox-/-, but not HDC-/-mice, displayed narcolepsy and deficient W when faced with motor challenge. Thus, when placed on a wheel, wild-type (WT), but not littermate Ox-/- mice, voluntarily spent their time in turning it and as a result, remained highly awake; this was accompanied by dense c-fos expression in many areas of their brains, including Ox neurons in the dorsolateral hypothalamus. The W and motor deficiency of Ox-/- mice was due to the absence of Ox because intraventricular dosing of orexin-A restored their W amount and motor performance whereas SB-334867 (Ox1-receptor antagonist, i.p.) impaired Wand locomotion of WT mice during the test. These data indicate that Ox, but not HA, promotes W through enhanced locomotion and suggest that HA and Ox neurons exert a distinct, but complementary and synergistic control of W: the neuropeptide being more involved in its behavioral aspects, whereas the amine is mainly responsible for its qualitative cognitive aspects and cortical EEG activation.

Original languageEnglish (US)
Pages (from-to)14423-14438
Number of pages16
JournalJournal of Neuroscience
Issue number46
StatePublished - Nov 18 2009

ASJC Scopus subject areas

  • General Neuroscience


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