title: Alpha-fluoromethylhistidine, a histamine synthesis inhibitor, inhibits orexin-induced wakefulness in rats.
abstract: Orexins A and B are involved in the regulation of feeding and arousal state. Previously, we reported that third intracerebroventricular (icv) infusion of both orexins A and B induced a significant arousal effect in rats. We determined the effects of intraperitoneal (i.p.) injection of alpha-fluoromethylhistidine (alpha-FMH), a histamine synthesis inhibitor, on orexin-induced wakefulness in freely behaving rats. Male Sprague-Dawley rats were chronically implanted with cortical electroencephalogram (EEG) and neck electromyogram (EMG) electrodes, and a cannula for icv infusion. EEG and EMG were monitored for three consecutive days during continuous icv saline infusion at a rate of 10 microl/h. For a 5-h diurnal period, orexin-B (10 nmol/50 microl saline) replaced the icv infusion of saline. alpha-FMH (100mg/kg, i.p.) was administered 6h before icv infusion of orexin-B. Orexin-B at a dose of 10 nmol/h markedly increased the amount of wakefulness by 99.4% (p<0.05) over the baseline value, whereas alpha-FMH decreased orexin-B-induced wakefulness by 48.8%. Orexin-B-induced suppression of non-REM sleep was reversed by alpha-FMH treatment. Pretreatment with alpha-FMH, significantly inhibited orexin-B-induced wakefulness in rats. The findings of this study therefore suggest that arousal-state regulation by orexin neurons is possibly mediated via the histaminergic system in the tuberomammilary nucleus.
authors.affiliation: Department of Biosystem Regulation, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Seki
authors.initials: S
authors.lastname: Yasuko
authors.forename: Akanmu Moses
authors.initials: AM
authors.lastname: Atanda
authors.forename: Matsuura
authors.initials: M
authors.lastname: Masato
authors.forename: Yanai
authors.initials: Y
authors.lastname: Kazuhiko
authors.forename: Honda
authors.initials: H
authors.lastname: Kazuki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004576:Electromyography; D006632:Histamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; C054284:alpha-fluoromethylhistamine; D006632:Histamine; D006640:Histidine Decarboxylase