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Article Dans Une Revue Neuropsychopharmacology Année : 2013

Enhanced Histaminergic Neurotransmission and Sleep-Wake Alterations, a Study in Histamine H3-Receptor Knock-Out Mice

Elise Gondard
  • Fonction : Auteur
Christelle Anaclet
  • Fonction : Auteur
Rui-Xian Guo
  • Fonction : Auteur
Mei Zhang
  • Fonction : Auteur
Colette Buda
  • Fonction : Auteur
Patricia Franco
  • Fonction : Auteur
Hidehito Kotani
  • Fonction : Auteur
Jian-Sheng Lin

Résumé

Long-term abolition of a brain arousal system impairs wakefulness (W), but little is known about the consequences of long-term enhancement. The brain histaminergic arousal system is under the negative control of H3-autoreceptors whose deletion results in permanent enhancement of histamine (HA) turnover. In order to determine the consequences of enhancement of the histaminergic system, we compared the cortical EEG and sleep-wake states of H3-receptor knockout (H3R-/-) and wild-type mouse littermates. We found that H3R-/-mice had rich phenotypes. On the one hand, they showed clear signs of enhanced HA neurotransmission and vigilance, i.e., a higher EEG θ power during spontaneous W and a greater extent of W or sleep restriction during behavioral tasks, including environmental change, locomotion, and motivation tests. On the other hand, during the baseline dark period, they displayed deficient W and signs of sleep deterioration, such as pronounced sleep fragmentation and reduced cortical slow activity during slow wave sleep (SWS), most likely due to a desensitization of postsynaptic histaminergic receptors as a result of constant HA release. Ciproxifan (H3-receptor inverse agonist) enhanced W in wild-type mice, but not in H3R-/-mice, indicating a functional deletion of H3-receptors, whereas triprolidine (postsynaptic H1-receptor antagonist) or α-fluoromethylhistidine (HA-synthesis inhibitor) caused a greater SWS increase in H3R-/- than in wild-type mice, consistent with enhanced HA neurotransmission. These sleep-wake characteristics and the obesity phenotypes previously reported in this animal model suggest that chronic enhancement of histaminergic neurotransmission eventually compromises the arousal system, leading to sleep-wake, behavioral, and metabolic disorders similar to those caused by voluntary sleep restriction in humans.

Dates et versions

hal-03066544 , version 1 (15-12-2020)

Identifiants

Citer

Elise Gondard, Christelle Anaclet, Hidéo Akaoka, Rui-Xian Guo, Mei Zhang, et al.. Enhanced Histaminergic Neurotransmission and Sleep-Wake Alterations, a Study in Histamine H3-Receptor Knock-Out Mice. Neuropsychopharmacology, 2013, 38 (6), pp.1015-1031. ⟨10.1038/npp.2012.266⟩. ⟨hal-03066544⟩
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