Abstract
The finding that orexin deficiency causes narcolepsy suggested that these hypothalamic neuropeptides play a critical role in regulating sleep/wakefulness states. The actions of orexins are mediated via two receptors named orexin 1 (OX1R) and orexin 2 (OX2R) receptors. Some reports have indicated that the effect of orexin on wakefulness is largely mediated by activation of the histaminergic system through OX2R. Consistently, OX2R knockout mice exhibit a narcoleptic phenotype, while OX1R knockout mice show almost normal sleep/wakefulness behavior. However, it is important not to disregard the importance of this receptor in the regulation of sleep/wakefulness states, because the phenotype of double receptor knockout mice is more severe than OX2R knockout mice, supporting an important but less significant contribution of OX1R. In this study, we analyzed phenotype of OX1R/histamin H1R -double deficient mice to further examine the importance of the histaminergic pathway as the downstream effecter of orexin. OX1R/HX1R -double deficient mice do not show cataplexy or direct transition from wakefulness to REM sleep. However, these mice showed severe fragmentation of wakefulness period, while both OX1R knockout mice and H1R knockout mice show almost normal sleep-waking behavior. These finding suggest that 1) the histaminergic pathway is important for stabilization of wakefulness states. 2) OX2R in regions other than TMN histaminergic cells are important for REM sleep regulation. 3) OX1R is also important for stabilization of wakefulness states. [J Physiol Sci. 2007;57 Suppl:S136]
