Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control.
The hypothesis that histaminergic neurons are involved in brain arousal is supported by many studies. However, the effects of the selective long-term abolition of histaminergic neurons on the sleep-wake cycle, indispensable in determining their functions, remain unknown. We have compared brain histamine(HA)-immunoreactivity and the cortical-EEG and sleep-wake cycle under baseline conditions or after behavioral or pharmacological stimuli in wild-type (WT) and knock-out mice lacking the histidine decarboxylase gene (HDC-/-). HDC-/-mice showed an increase in paradoxical sleep, a decrease in cortical EEG power in theta-rhythm during waking (W), and a decreased EEG slow wave sleep/W power ratio. Although no major difference was noted in the daily amount of spontaneous W, HDC-/-mice showed a deficit of W at lights-off and signs of somnolence, as demonstrated by a decreased sleep latencies after various behavioral stimuli, e.g., WT-mice placed in a new environment remained highly awake for 2-3 hr, whereas HDC-/-mice fell asleep after a few minutes. These effects are likely to be attributable to lack of HDC and thus of HA. In WT mice, indeed, intraperitoneal injection of alpha-fluoromethylhistidine (HDC-inhibitor) caused a decrease in W, whereas injection of ciproxifan (HA-H3 receptor antagonist) elicited W. Both injections had no effect in HDC-/-mice. Moreover, PCR and immunohistochemistry confirmed the absence of the HDC gene and brain HA-immunoreactive neurons in the HDC-/-mice. These data indicate that disruption of HA-synthesis causes permanent changes in the cortical-EEG and sleep-wake cycle and that, at moments when high vigilance is required (lights off, environmental change em leader ), mice lacking brain HA are unable to remain awake, a prerequisite condition for responding to behavioral and cognitive challenges. We suggest that histaminergic neurons also play a key role in maintaining the brain in an awake state faced with behavioral challenges.
Parmentier
Régis
R
Institut National de la Santé et de la Recherche Médicale U480, Department of Experimental Medicine, Faculty of Medicine, Claude Bernard University, 69373 Lyon, France.
Ohtsu
Hiroshi
H
Djebbara-Hannas
Zahia
Z
Valatx
Jean-Louis
JL
Watanabe
Takehiko
T
Lin
Jian-Sheng
JS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008762:Methylhistidines / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology; D013826:Theta Rhythm / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D008762:Methylhistidines; C115705:ciproxifan; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D006640:Histidine Decarboxylase