Arousal effect of orexin A depends on activation of the histaminergic system.
Orexin neurons are exclusively localized in the lateral hypothalamic area and project their fibers to the entire central nervous system, including the histaminergic tuberomammillary nucleus (TMN). Dysfunction of the orexin system results in the sleep disorder narcolepsy, but the role of orexin in physiological sleep-wake regulation and the mechanisms involved remain to be elucidated. Here we provide several lines of evidence that orexin A induces wakefulness by means of the TMN and histamine H(1) receptor (H1R). Perfusion of orexin A (5 and 25 pmol/min) for 1 hr into the TMN of rats through a microdialysis probe promptly increased wakefulness for 2 hr after starting the perfusion by 2.5- and 4-fold, respectively, concomitant with a reduction in rapid eye movement (REM) and non-REM sleep. Microdialysis studies showed that application of orexin A to the TMN increased histamine release from both the medial preoptic area and the frontal cortex by approximately 2-fold over the baseline for 80 to 160 min in a dose-dependent manner. Furthermore, infusion of orexin A (1.5 pmol/min) for 6 hr into the lateral ventricle of mice produced a significant increase in wakefulness during the 8 hr after starting infusion to the same level as the wakefulness observed during the active period in wild-type mice, but not at all in H1R gene knockout mice. These findings strongly indicate that the arousal effect of orexin A depends on the activation of histaminergic neurotransmission mediated by H1R.
Huang
Z L
ZL
Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Japan.
Qu
W M
WM
Li
W D
WD
Mochizuki
T
T
Eguchi
N
N
Watanabe
T
T
Urade
Y
Y
Hayaishi
O
O
D000818:Animals; D001143:Arousal / Q000187:drug effects*; D002352:Carrier Proteins / Q000494:pharmacology*; D004569:Electroencephalography; D004576:Electromyography; D005625:Frontal Lobe / Q000502:physiology; D006632:Histamine / Q000502:physiology*; D007026:Hypothalamic Area, Lateral / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D009479:Neuropeptides / Q000494:pharmacology*; D064446:Orexin Receptors; D000068797:Orexins; D011301:Preoptic Area / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled; D011969:Receptors, Histamine H1 / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018013:Receptors, Neuropeptide; D012890:Sleep / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D011969:Receptors, Histamine H1; D018013:Receptors, Neuropeptide; D006632:Histamine