The sleep-promoting action of ramelteon (TAK-375) in freely moving cats.
BACKGROUND
Ramelteon (TAK-375) is an MT1/MT2 receptor agonist being studied for the treatment of insomnia and circadian rhythm sleep disorders. We compared the behavioral effects of ramelteon and exogenous melatonin in freely moving cats.


METHODS
Ramelteon and melatonin were each suspended in a 0.5% (weight per volume) methylcellulose solution and administered orally to freely moving cats. In the control trial, each cat was given vehicle. Each dose of ramelteon or melatonin was compared with the vehicle control in a crossover design. Electroencephalogram, electromyogram, and electrooculogram recordings were assessed.


RESULTS
Ramelteon significantly decreased wakefulness at doses of 0.001,0.01, and 0.1 mg/kg, increased slow-wave sleep at doses of 0.001, 0.01, and 0.1 mg/kg, and increased rapid eye movement sleep at a dose of 0.1 mg/kg, compared with the vehicle controls, as assessed by analysis of variance. The effects of ramelteon lasted for up to 6 hours when evaluated by reduction of wakefulness. Exogenous melatonin (0.01-1 mg/kg) significantly increased slow-wave sleep, but the effect was weaker than that of ramelteon and lasted for only 2 hours. The lowest doses of ramelteon (0.0001 mg/kg) and melatonin (0.001 mg/kg) had no significant effect on sleep-wakefulness stage.


CONCLUSIONS
Ramelteon was more effective than exogenous melatonin in promoting and maintaining sleep in freely moving cats. Based on its unique mechanism of action, ramelteon should be studied further to evaluate its potential for the treatment of sleep disorders.
Miyamoto
Masaomi
M
Pharmacology Research Laboratories I, Takeda Pharmaceutical Company Ltd, Osaka, Japan. Miyamoto_Masaomi@takeda.co.jp
Nishikawa
Hisao
H
Doken
Yayoi
Y
Hirai
Keisuke
K
Uchikawa
Osamu
O
Ohkawa
Shigenori
S
D000818:Animals; D001143:Arousal / Q000187:drug effects; D002415:Cats; D002940:Circadian Rhythm / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D007192:Indenes / Q000494:pharmacology*; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D017286:Polysomnography / Q000187:drug effects; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects; D013493:Suprachiasmatic Nucleus / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
D007192:Indenes; C495910:ramelteon; D008550:Melatonin