Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep-wake cycle and narcoleptic episodes in Ox-/- mice.
OBJECTIVE
Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously.


METHODS
EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep-wake cycle in wild-type (Ox+/+) and orexin knockout (Ox-/-) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography.


RESULTS
In Ox+/+ and Ox-/- mice, acute administration of GSK189254 (3 and 10 mg x kg(-1) p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg x kg(-1)), while it reduced narcoleptic episodes in Ox-/- mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg x kg(-1)) on W in both Ox+/+ and Ox-/- mice was significantly reduced, while the effect on narcoleptic episodes in Ox-/- mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox-/- mice.


CONCLUSIONS
These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies.
INSERM/UCBL-U628, Integrated Physiology of Brain Arousal Systems, Department of Experimental Medicine, Faculty of Medicine, Claude Bernard University, Lyon Cedex, France.
R X
RX
Guo
C
C
Anaclet
J C
JC
Roberts
R
R
Parmentier
M
M
Zhang
G
G
Guidon
C
C
Buda
J P
JP
Sastre
J Q
JQ
Feng
P
P
Franco
S H
SH
Brown
N
N
Upton
A D
AD
Medhurst
J S
JS
Lin
D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000077408:Modafinil; D009290:Narcolepsy / Q000188:drug therapy* / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068797:Orexins; D011869:Radioligand Assay; D018100:Receptors, Histamine H3 / Q000378:metabolism; D012890:Sleep / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects*
D001552:Benzazepines; D001559:Benzhydryl Compounds; D054828:Histamine H3 Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D018100:Receptors, Histamine H3; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide; D000077408:Modafinil