title: First and second generation H₁ histamine receptor antagonists produce different sleep-inducing profiles in rats.
abstract: First generation H₁ histamine receptor antagonists, such as d-chlorpheniramine (d-CPA) and diphenhydramine, produce drowsiness in humans. They are currently used as over-the-counter sleep aids. However, the mechanisms underlying drowsiness induced by these H₁ histamine receptor antagonists remain obscure because they produce heterogeneous receptor-independent actions. Ketotifen is a second generation H₁ histamine receptor antagonist which is more permeable to the brain than newer H₁ histamine receptor antagonists. Therefore, to access sleep-inducing profiles by H₁ histamine receptor blocking actions, the present study compared the dose-dependent effects of diphenhydramine and ketotifen (1-40 mg/kg, intraperitoneal injection at dark onset time) on daily sleep-wake patterns in rats. Ketotifen dose-dependently decreased rapid-eye-movement (REM) sleep and increased non-REM sleep by amplifying slow-wave electroencephalogram powers. Diphenhydramine at 4 mg/kg transiently increased non-REM sleep and reduced REM sleep similar to the effects of ketotifen. The larger injections of diphenhydramine (10-40 mg/kg), however, reduced non-REM sleep, abolished slow-wave enhancements and facilitated wakefulness. The bi-directional action of diphenhydramine on sleep is similar to our former results using d-CPA. Taken together, the arousal effects caused by over-dose administrations of the first generation H₁ histamine receptor antagonists may be mediated by H₁ histamine receptor-independent actions. To further examine the tolerance of ketotifen-induced sleep, 3 mg/kg ketotifen was injected daily for 5 days 3 h before light onset time. These experiments consistently enhanced non-REM-sleep at the end of the active phase of rats, suggesting that ketotifen may function as a desirable sleep aid although the coincidental REM sleep reduction requires attention.
authors.affiliation: Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Unno
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ozaki
authors.forename: Shahid
authors.initials: S
authors.lastname: Mohammad
authors.forename: Saki
authors.initials: S
authors.lastname: Tsuno
authors.forename: Masami
authors.initials: M
authors.lastname: Ikeda-Sagara
authors.forename: Kazuki
authors.initials: K
authors.lastname: Honda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D002940:Circadian Rhythm; D004155:Diphenhydramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004569:Electroencephalography / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007665:Ketotifen / Q000494:pharmacology; D008297:Male; D004366:Nonprescription Drugs / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects*; D012894:Sleep Stages / Q000187:drug effects; D012895:Sleep, REM / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D006634:Histamine H1 Antagonists; D006993:Hypnotics and Sedatives; D004366:Nonprescription Drugs; D004155:Diphenhydramine; D007665:Ketotifen