BACKGROUND AND PURPOSEClassic H1 histamine receptor (H1R) antagonists are non-selective for H1R and known to produce drowsiness. Modern antihistamines are more selective for H1R, 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.
EXPERIMENTAL APPROACHEffects 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 H1R antagonists on cultured preoptic neurons were examined using calcium imaging. ) 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 Ն100 mM.
KEY RESULTS
d-CPA
CONCLUSION AND IMPLICATIONSThe excitatory action of d-CPA may explain the seemingly inconsistent actions of d-CPA on sleep. Cerebral H1R inhibition by cetirizine induces synchronization of cerebral activity and prolonged, continuous slow-wave sleep.
BackgroundThe sleep sequence: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, but the underlying mechanisms are unknown. It has been shown that this sequence is disrupted by sudden REM sleep onset during active wakefulness (i.e., narcolepsy) in orexin-deficient mutant animals. Phospholipase C (PLC) mediates the signaling of numerous metabotropic receptors, including orexin receptors. Among the several PLC subtypes, the β4 subtype is uniquely localized in the geniculate nucleus of thalamus which is hypothesized to have a critical role in the transition and maintenance of sleep stages. In fact, we have reported irregular theta wave frequency during REM sleep in PLC-β4-deficient mutant (PLC-β4−/−) mice. Daily behavioral phenotypes and metabotropic receptors involved have not been analyzed in detail in PLC-β4−/− mice, however.Methodology/Principal FindingsTherefore, we analyzed 24-h sleep electroencephalogram in PLC-β4−/− mice. PLC-β4−/− mice exhibited normal non-REM sleep both during the day and nighttime. PLC-β4−/− mice, however, exhibited increased REM sleep during the night, their active period. Also, their sleep was fragmented with unusual wake-to-REM sleep transitions, both during the day and nighttime. In addition, PLC-β4−/− mice reduced ultradian body temperature rhythms and elevated body temperatures during the daytime, but had normal homeothermal response to acute shifts in ambient temperatures (22°C–4°C). Within the most likely brain areas to produce these behavioral phenotypes, we found that, not orexin, but group-1 metabotropic glutamate receptor (mGluR)-mediated Ca2+ mobilization was significantly reduced in the dorsal lateral geniculate nucleus (LGNd) of PLC-β4−/− mice. Voltage clamp recordings revealed that group-1 mGluR-mediated currents in LGNd relay neurons (inward in wild-type mice) were outward in PLC-β4−/− mice.Conclusions/SignificanceThese lines of evidence indicate that impaired LGNd relay, possibly mediated via group-1 mGluR, may underlie irregular sleep sequences and ultradian body temperature rhythms in PLC-β4−/− mice.
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