Altered sleep-wake characteristics and lack of arousal response to H_3 receptor antagonist in histamine H_1 receptor knockout mice

摘要

Histaminergic neurons play an important role in the regulation of sleep-wake behavior through histamine H_1 receptors (H_1R). Blockade of the histamine H_3 receptor (H_3R) 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 H_1R knockout (KO) mice and their arousal responses to an H_3R antagonist. Under baseline conditions, H_1R 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 H_1R antagonist pyrilamine mimicked these effects in WT mice. When an H_3R antagonist, ciproxifan, was administered i.p., wakefulness increased in WT mice in a dose-dependent manner but did not increase at all in H_1R 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 H_1R is involved in the regulation of behavioral state transitions from NREM sleep to wakefulness and that the arousal effect of the H_3R antagonist completely depends on the activation of histamin-ergic systems through H_1R.