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.2012 Jan;165(1):167-82.
doi: 10.1111/j.1476-5381.2011.01547.x.

Induction of prolonged, continuous slow-wave sleep by blocking cerebral H₁ histamine receptors in rats

Affiliations

Induction of prolonged, continuous slow-wave sleep by blocking cerebral H₁ histamine receptors in rats

Masami Ikeda-Sagara et al. Br J Pharmacol.2012 Jan.

Abstract

Background and purpose: Classic H(1) histamine receptor (H(1)R) antagonists are non-selective for H(1)R and known to produce drowsiness. Modern antihistamines are more selective for H(1)R, 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 approach: Effects 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 H(1) R antagonists on cultured preoptic neurons were examined using calcium imaging.

Key results: d-CPA 4 mg·kg(-1) i.p. increased non-rapid eye movement (REM) sleep whereas 10-40 mg·kg(-1) d-CPA decreased non-REM sleep at dark onset time. Nocturnal i.c.v. infusions of d-CPA (10 µmol·100 µL(-1)·10 h(-1)) 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 ≥ 100 µM.

Conclusion and implications: The excitatory action of d-CPA may explain the seemingly inconsistent actions of d-CPA on sleep. Cerebral H(1)R inhibition by cetirizine induces synchronization of cerebral activity and prolonged, continuous slow-wave sleep.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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Figures

Figure 1
Figure 1
(A) Chemical structure of cetirizine (1), DBD-pz (2) and their conjugated forms (3). EDC,N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; DMPA,N,N-dimethylaminopyridine. (B) Dose–response curve of inhibition of histamine (30 µM, 1 min)-induced Ca2+ increase by cetirizine and cetirizine/DBD-pz in HeLa cells.
Figure 3
Figure 3
Dose–response curves for the effect ofd-CPA on non-REM sleep (A) and REM sleep (B). The 3 h cumulative amount of sleep after i.p. injections ofd-CPA were plotted. Non-REM sleep increased and REM sleep decreased in a dose-dependent manner with doses ofd-CPA between 0.04–4 mg·kg−1. Higher doses ofd-CPA (10 or 40 mg·kg−1) significantly inhibited non-REM and REM sleep. The less-active enantiomerl-CPA similarly reduced non-REM and REM sleep at 40 mg·kg−1. Cetirizine failed to modulate sleep at 4 mg·kg−1 but increased non-REM sleep and decreased REM sleep at 40 mg·kg−1. (n= 4–6 for each drug concentration;n= 24 for saline-injected control). *P < 0.05, **P < 0.01 compared with saline-injected controls.
Figure 2
Figure 2
Effects of i.p. injection ofd-CPA on daily sleep-wake activity in rats. Graphs show the amount of time spent in non-REM sleep, REM sleep, and wakefulness during 1 day afterd-CPA or saline control (n= 24 pooled) injections (arrows). Black and open bars on the bottom row indicate dark and light periods, respectively. Note that there was a transient increase in non-REM sleep and decreases in REM sleep and wakefulness after 4 mg·kg−1d-CPA injections (n= 6) whereas non-REM sleep and REM sleep were both significantly reduced after 40 mg·kg−1d-CPA injections (n= 6). *P < 0.05, **P < 0.01.
Figure 5
Figure 5
Effects of continuous i.c.v. infusion of 10 µmol·100 µL−1·10 h−1 cetirizine (as indicated by the shaded bar) on non-REM sleep and REM sleep in the rat. Black and open bars on the bottom indicate the dark and light periods respectively. The amount of sleep under control conditions before the cetirizine infusion was superimposed on the plots during the cetirizine infusion day and recovery day (open circles). *P < 0.05, **P < 0.01 (n= 5). Dashed lines denote the replacement of infusion tubing, which caused temporary reductions in sleep.
Figure 4
Figure 4
Effects of continuous i.c.v. infusion of 10 µmol·100 µL−1·10 h−1d-CPA (as indicated by the shaded bar) on non-REM sleep and REM sleep in rats. Continuous vehicle infusion (10 µL·h−1) was initiated 1 week befored-CPA infusion and continued through the end of the experiment. Black and open bars on the bottom indicate dark and light periods respectively. The amount of sleep under control conditions before thed-CPA infusion was superimposed on the plots during thed-CPA infusion day and recovery day (open circles). *P < 0.05, **P < 0.01 (n= 5). Dashed lines denote the replacement of infusion tubing, which caused temporary reductions in sleep.
Figure 6
Figure 6
The 12 h cumulative amounts of sleep and wakefulness during and after i.c.v. infusion ofd-CPA or cetirizine. Black and open bars denote mean amount of sleep during dark and light periods, respectively (n= 5 for each dose of drug;n= 20 for saline-infused controls). *P < 0.05, **P < 0.01 compared with the corresponding saline infusion group.
Figure 7
Figure 7
(A) An example of a sleep polygraph (combination of EEG and EMG) during the i.c.v. infusion of saline (upper) or 10 µmold-CPA (lower) in a rat. (B) An example sleep polygraph during the infusion of saline (upper) or 10 µmol cetirizine (lower two panels are polygraphs from one continuous non-REM sleep episode) in a rat. Based on the sleep polygraph, sleep stages were determined in 8 s bins. S, slow-wave sleep (i.e. non-REM sleep); W, wakefulness; D, drowsiness; R, REM sleep. Drowsiness was composed of slow-wave-like EEG patterns with incomplete EMG relaxation, which was not categorized as non-REM sleep. Drowsiness was frequent during thed-CPA infusions. On the other hand, steady high-amplitude slow-wave EEG coinciding with EMG relaxation was dominant during cetirizine infusions. (C) Fast-Fourier-Transform (FFT) analysis of non-REM sleep EEG waves (i.e. slow waves) during saline-infusion during the light and dark periods or cetirizine-infusion during the dark. For comparison, the FFT spectrum of drowsy EEG waves duringd-CPA infusion was plotted as grey squares. Means were calculated from 30 pre-averaged typical epochs in five animals. Frequencies less than 0.5 Hz were eliminated using a filter installed in the amplifiers. Note that the slow-wave spectrum at 1.5–1.75 Hz (black bar) was higher during cetirizine infusion (P < 0.01). The drowsy EEG spectrum duringd-CPA infusion was of significantly lower amplitude at 1.0–3.5 Hz (open bar) compared with the slow-wave EEG spectrum during saline or cetirizine infusions (P < 0.01).
Figure 8
Figure 8
Approximate cetirizine distribution in the rat brain was estimated using i.c.v. infusion of fluorescent-conjugated cetirizine (cetirizine/DBD-pz). (A) An example of a coronal brain section c.a. 100 µm anterior to the infusion plane, which was fixed after a 4 h third-ventricular infusion of cetirizine/DBD-pz (4 µmol·40 µL−1·4 h−1). TL, transmitted light image; FL, background-subtracted fluorescence image. Approximate location of the cannula is indicated as a blue dotted line. Cetirizine/DBD-pz fluorescence was observed both near the lateral ventricle (Lv) and third ventricle (3v). Squares marked as (a) and (b) were enlarged below (Aa,b). (a) The dorsolateral septal nucleus (LSD) is observed as fibrous staining with cetirizine/DBD-pz. (b) The most significant signal was found in the medial preoptic area (MPO) including the median preoptic nucleus (MnPO). (B) Cetirizine/DBD-pz diffused into the mesencephalic duct and permeated the ventrolateral periaqueductal grey matter (vlPAG), but the signal was not detected in the dorsal end of the laterodorsal tegmental nuclei (LDTg).
Figure 9
Figure 9
Calcium imaging of POAH slice cultures. A Ca2+ sensor (YC2.1) gene linked to a neuron-specific enolase promoter was transfected into slice cultures to visualize individual neuronal responses to histamine and H1R antagonists. (A) Typical histamine-induced cytosolic Ca2+ response in a medial POAH neuron. Arrows indicate a 30 µM histamine (HA) pulse. The perfusion ofd-CPA (10 µM) completely blocked the histamine response. The inset is a fluorescence image of the recorded neuron. (B) Approximate location of the recorded neurons in the preoptic slice. Black and white circles indicate location of histamine-responsive and non-responsive neuronal cell bodies respectively. Black and white triangles indicate the location of histamine-responsive and non-responsive cell bodies respectively, in the presence of the Na+ channel blocker, tetrodotoxin (0.5 µM). Medial POAH (MPO) but not ventrolateral preoptic (VLPO) neurons responded to histamine. (C)d-CPA at higher concentrations increased Ca2+ in medial POAH neurons. Four neurons (as different grey scale or dotted traces) were simultaneously monitored in this experiment and 100 µMd-CPA evoked mobilization of Ca2+ in one neuron. Most medial POAH neurons responded to >5 mMd-CPA. (D) In a different set of experiments, cetirizine (0.1–5 mM) was perfused prior tod-CPA (1 mM) perfusion. Cetirizine did not evoke any Ca2+ responses.
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