It should be noted that there is not a prolonged action of GSK189254 as the data in Figure 3 (and also Figure 5) represent hourly cumulative values of sleepCwake amounts. administration of GSK189254 (3 and 10 mgkg?1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mgkg?1), while it reduced narcoleptic episodes in Ox?/? mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mgkg?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 and implications: These studies provide further evidence Alizarin 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. 1996). Conversely, blockade of H3 receptors with selective antagonists/inverse agonists can increase the release of histamine (Arrang (1999) and kept on C57BL/6J genomic background by five to nine more backcrosses during the present study. To obtain experimental animals, male Ox?/? mice were backcrossed with female wild-type (Ox+/+) mice, and the generated Ox+/? mice were crossed between them resulting in both heterozygotes and homozygotes. Only littermate homozygote Ox+/+ and Ox?/? mice (binding assays 1C2 h post dose (B. Crook, unpubl. obs.). The pharmacokinetic properties of GSK189254 in CD1 mice are comparable to rats, with the plasma half life following oral dosing being around 1.7 h and pharmacokinetics being linear with dose (M. Briggs, unpubl. obs.). Concentrations of GSK189254 determined in CD1 mice were around 1C3 molL?1 following oral dosing of 3 and 10 mgkg?1 and there was no evidence for drug accumulation. These brain concentrations are well above the Student’s and Oxlittermates during a 4 h recording in the lights-on period In OBSCN wild-type Ox+/+ mice during the lights-on phase (when the mice slept most of the time at baseline), acute oral administration of GSK189254 (3 and 10 mgkg?1) caused an increase in W and a corresponding decrease in SWS and PS compared with vehicle-treated mice. Representative examples of hypnograms from Ox+/+ mice are shown in Figure 1A. In EEG spectral analysis, these effects were manifest as a suppression of neocortical slow activity (including range 0.8C2.5 Hz) and spindles (8C15 Hz) and an increase in power spectral density of neocortical fast rhythms ( and bands, mainly 30C60 Hz), resulting in marked enhancement of cortical activation (i.e. low voltage and fast electrical activity). Very similar effects on the sleepCwake cycle and cortical EEG were observed in Ox?/? littermates following acute oral administration of GSK189254 Alizarin (3 and 10 mgkg?1 p.o.), and representative examples of hypnograms from Ox?/? mice are shown in Figure 1B. Open in a separate window Figure 1 Alizarin Representative examples of hypnograms showing the sleepCwake cycle in (A) wild-type (Ox+/+) and (B) Ox?/? mice over a 5 h period in the lights-on phase. Arrows show where vehicle (placebo) and GSK189254 (3 and 10 mgkg?1) were administered. GSK189254 increased wakefulness (W) and decreased slow wave sleep (SWS) and paradoxical sleep (PS) in both Ox+/+ and Ox?/? mice compared with vehicle-treated mice. As shown in the analysis of sleepCwake states over the 4 h post-dose period (Figure 2A), acute single administration of GSK189254 (3 and 10 mgkg?1) to wild-type Ox+/+ mice significantly increased ( 0.05, 0.05, 0.05, 0.05, 0.05, and Alizarin Oxlittermates during a 4 h recording in the lights-on period We were also interested in exploring the effects of repeat dosing with GSK189254 given that this would potentially be required for future therapeutic use in narcolepsy or other sleep disorders. Both Ox+/+ and Ox?/? mice were treated with GSK189254 (3 and 10 mgkg?1 p.o.) twice a day for 8 days respectively at 10 h 00 min and 19 h 00 min and effects on the sleepCwake cycle were studied on the ninth day when GSK189254 was also administered at 10 h 00 min and 19 h 00 min. During the lights-on phase when untreated mice were sleepy and inactive at baseline, GSK189254 (10 mgkg?1, p.o.) was still able to significantly increase W and decrease SWS and PS ( 0.05, 0.05, and Oxlittermates over 8 h during the lights-on period We also measured the cumulative effects of GSK189254 on the sleepCwake cycle over Alizarin an 8 h period to get an indication of whether any sleep rebound occurred after the waking effect. During the recovery periods between the fifth and eighth hours after dosing, total amount of W and SWS in both Ox+/+ and Ox?/? mice remained significantly increased and decreased respectively, indicating that no.
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