Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 12, Pages 4687-4692Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0600451103
Keywords
brief awakening; ciproxifan; microdialysis; pyrilamine; wakefulness
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Histaminergic neurons play an important role in the regulation of sleep-wake behavior through histamine H-1 receptors (H1R). Blockade of the histamine H-3 receptor (H3R) is proposed to induce wakefulness by regulating the release of various wake-related transmitters, not only histamine. In the present study, we characterized sleep-wake cycles of H1R knockout (KO) mice and their arousal responses to an H3R antagonist. Under baseline conditions, H1R KO mice showed sleep-wake cycles essentially identical to those of WT mice but with fewer incidents of brief awakening (< 16-sec epoch), prolonged durations of non-rapid eye movement (NREM) sleep episodes, a decreased number of state transitions between NREM sleep and wakefulness, and a shorter latency for initiating NREM sleep after an i.p. injection of saline. The H1R antagonist pyrilamine mimicked these effects in WT mice. When an H3R antagonist, ciproxifan, was administered i.p., wakefulness increased in WT mice in a dose-dependent manner but did not increase at all in H1R KO mice. In vivo microdialysis revealed that the i.p. application of ciproxifan increased histamine release from the frontal cortex in both genotypes of mice. These results indicate that H1R is involved in the regulation of behavioral state transitions from NREM sleep to wakefulness and that the arousal effect of the H3R antagonist completely depends on the activation of histaminergic systems through H1R.
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