Effects of ramelteon (TAK-375) on nocturnal sleep in freely moving monkeys.
We investigated the effects of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4]furan-8-yl)ethyl]propionamide (ramelteon, TAK-375), a novel MT1/MT2 receptor agonist, on nocturnal sleep in freely moving monkeys and compared these results with those of melatonin and zolpidem. Treatment with ramelteon (0.03 and 0.3 mg/kg, p.o.) significantly shortened latency to sleep onset and significantly increased total duration of sleep. Treatment with melatonin (0.3, 1, and 3 mg/kg, p.o.) also decreased sleep latency, but the effect was weak; the only significant reduction was seen with the 0.3 mg/kg dose on latency to light sleep. Melatonin had no significant effects on the duration of sleep. Zolpidem had no significant effects on latency to sleep onset in this study at any dose (1, 3, 10, and 30 mg/kg, p.o.). The highest dose (30 mg/kg) of zolpidem had a tendency to increase slow wave sleep; however, it also induced apparent sedation and myorelaxation. Treatment with ramelteon and melatonin had no evident effect on the general behavior of the monkeys. Spectral analysis (fast Fourier transform, FFT) of both ramelteon and melatonin revealed sleep patterns that were indistinguishable from those of naturally occurring sleep. The EEG power spectra of zolpidem were qualitatively different from that of naturally occurring physiological sleep. Results of the present study support the investigation of ramelteon as a sleep-promoting agent in humans.
Yukuhiro
Nobuhito
N
Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Osaka 532-8686, Japan.
Kimura
Hiroyuki
H
Nishikawa
Hisao
H
Ohkawa
Shigenori
S
Yoshikubo
Shin-ichi
S
Miyamoto
Masaomi
M
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007192:Indenes / Q000494:pharmacology; D008252:Macaca fascicularis; D008550:Melatonin / Q000494:pharmacology; D017286:Polysomnography / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D044094:Receptors, Melatonin / Q000819:agonists*; D012890:Sleep / Q000187:drug effects*; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects*; D000077334:Zolpidem
D000577:Amides; D006993:Hypnotics and Sedatives; D007192:Indenes; D011725:Pyridines; D044094:Receptors, Melatonin; D000077334:Zolpidem; C495910:ramelteon; D008550:Melatonin; C034666:propionamide