title: Induction of prolonged, continuous slow-wave sleep by blocking cerebral H₁ histamine receptors in rats.
abstract: OBJECTIVE
  Classic H(1) histamine receptor (H(1)R) antagonists are non-selective for H(1)R and known to produce drowsiness. Modern antihistamines are more selective for H(1)R, and are 'non-drowsy' presumably due to reduced permeability through the blood-brain barrier. To characterize both histaminergic sleep regulation and the central actions of antihistamines, in the present study we analysed the effect of classic and modern antihistamines on rats' sleep using continuous i.c.v. infusions.
  
  
  METHODS
  Effects of classic (d-chlorpheniramine; d-CPA) and second-generation (cetirizine) antihistamines on sleep were compared after i.p. injections or continuous i.c.v. infusions into rats. Fluorescent cetirizine/DBD-pz was synthesized to trace the approximate distribution of cerebral cetirizine. Furthermore, the effects of H(1) R antagonists on cultured preoptic neurons were examined using calcium imaging.
  
  
  RESULTS
  d-CPA 4 mg·kg(-1) i.p. increased non-rapid eye movement (REM) sleep whereas 10-40 mg·kg(-1) d-CPA decreased non-REM sleep at dark onset time. Nocturnal i.c.v. infusions of d-CPA (10 µmol·100 µL(-1)·10 h(-1)) increased drowsiness but not non-REM sleep, whereas the same i.c.v. infusions of cetirizine significantly increased non-REM sleep, abolished REM sleep, and decreased wakefulness for more than 10 h. The medial preoptic area contained the greatest fluorescent labelling after i.c.v. cetirizine/DBD-pz infusions. Histamine-induced Ca(2+) increases in medial preoptic neurons were blocked by d-CPA or cetirizine, whereas d-CPA, but not cetirizine, increased Ca(2+) irrespective of antihistaminergic activity at ≥ 100 µM.
  
  
  CONCLUSIONS
  The excitatory action of d-CPA may explain the seemingly inconsistent actions of d-CPA on sleep. Cerebral H(1)R inhibition by cetirizine induces synchronization of cerebral activity and prolonged, continuous slow-wave sleep.
authors.affiliation: Graduate School of Innovative Life Science, University of Toyama, Toyama, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ikeda-Sagara
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ozaki
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahid
authors.forename: Eri
authors.initials: E
authors.lastname: Morioka
authors.forename: Kazuma
authors.initials: K
authors.lastname: Wada
authors.forename: Kazuki
authors.initials: K
authors.lastname: Honda
authors.forename: Ayana
authors.initials: A
authors.lastname: Hori
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuya
authors.forename: Naoki
authors.initials: N
authors.lastname: Toyooka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D017332:Cetirizine / Q000494:pharmacology*; D002744:Chlorpheniramine / Q000494:pharmacology*; D005456:Fluorescent Dyes; D006367:HeLa Cells; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects*; D013194:Staining and Labeling
chemical_list: D005456:Fluorescent Dyes; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D002744:Chlorpheniramine; D002118:Calcium; D017332:Cetirizine