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Differential effects of acute and repeat dosing with the H 3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice
Author(s) -
Guo RX,
Anaclet C,
Roberts JC,
Parmentier R,
Zhang M,
Guidon G,
Buda C,
Sastre JP,
Feng JQ,
Franco P,
Brown SH,
Upton N,
Medhurst AD,
Lin JS
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00205.x
Subject(s) - narcolepsy , orexin , modafinil , dosing , histaminergic , antagonist , endocrinology , medicine , wakefulness , pharmacology , non rapid eye movement sleep , receptor antagonist , receptor , neuropeptide , electroencephalography , psychiatry
Background and purpose: Histamine H 3 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. Experimental approach: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H 3 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 H 3 and H 1 receptor expression in this model using radioligand binding and autoradiography. Key results: In Ox+/+ and Ox−/− mice, acute administration of GSK189254 (3 and 10 mg·kg −1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg −1 ), while it reduced narcoleptic episodes in Ox−/− mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·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 H 3 or H 1 receptor expression between Ox+/+ and Ox−/− mice. Conclusions and implications: These studies provide further evidence to support the potential use of H 3 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.