Cholecystokinin-B (CCK-B) receptor antagonists improve "aged" sleep: a new class of sleep modulators?
Sleep disorders are a major, although often minimized and underdiagnosed, medical problem. Current therapy is based on the use of hypnotics, mainly benzodiazepines, which disrupt the sleep pattern often suppressing rapid-eye-movement (REM) sleep. Here, new types of pharmacological tools such as cholecystokinin (CCK) receptor antagonists are examined. In particular, since the awake-sleep rhythm is mainly altered in old age in humans, the influence of these compounds over REM and non-REM sleep has been studied in aged rats (21 months) vs. young rats (5 months) prepared for electroencephalographic (EEG) recordings. Basal EEG data indicated that REM and non-REM sleep was reduced in aged rats vs. young rats. GV-150013, a selective CCK-B receptor antagonist, was found to increase REM sleep, as well as non-REM sleep, and therefore total sleep (non-REM + REM) mainly in aged rats. The dose-range of activity (0.5-60 micrograms/kg) together with the evidence that another CCK-B receptor antagonist, L-365,260 (5 micrograms/kg) increased, while devazepide (a CCK-A receptor antagonist; 20 micrograms/kg) decreased non-REM sleep and total sleep time, support the original hypothesis that the activity of GV-150013 on sleep progress through CCK-B receptors. Furthermore, no tolerance was detected after chronic treatments with GV-150013. In contrast, typical EEG modifications (decrease of REM) and the development of tolerance towards benzodiazepines were monitored following chronic treatment with triazolam (400 micrograms/kg). These results suggest that the CCKergic compounds studied are involved via a different mechanism of action than benzodiazepines in the modulation of the awake-sleep rhythm. A further observation is that the total sleep time recorded in aged rats after treatment with GV-150013 reached the value of the total sleep time of young untreated rats also prepared for EEG. Finally, this work suggests that CCK receptor antagonists, GV-150013 in particular, are more effective in aged resulting in an improvement of sleep quality towards that of young rats.
Crespi
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Department of Pharmacology, Glaxo Wellcome S.p.A., Verona, Italy. FC20377@ggr.co.uk
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000375:Aging / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D004569:Electroencephalography / Q000187:drug effects; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D010671:Phenylurea Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012890:Sleep / Q000187:drug effects*; D014229:Triazolam / Q000494:pharmacology
D018757:GABA Modulators; C111554:GV 150013X; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D014229:Triazolam; D000218:Adamantane