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.
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.
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.
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.
"Abuse liability with BZRA insomnia medications, particularly with long-term use, remains a significant concern among prescribing physicians. Ramelteon is a novel, selective MT 1 /MT 2 melatonin receptor agonist (Miyamoto et al., 2004; Yukuhiro et al., 2004) that has been recently approved for the treatment of insomnia. In adults with transient and chronic insomnia, ramelteon has been shown to reduce latency to persistent sleep and is well tolerated (Roth, Seiden, et al., 2005; Roth, Stubbs, & Walsh, 2005; Zammit et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: The acute and chronic effects of ramelteon, an MT1/MT2 receptor agonist, were evaluated in rhesus monkeys (Macaca mulatta) to assess discriminative stimulus effects in comparison with traditional benzodiazepine receptor agonists and to assess physical dependence potential. Discriminative effects of ramelteon were compared with midazolam in untreated monkeys and in diazepam-dependent monkeys that discriminated flumazenil. Dependence potential of ramelteon after daily 1-year administration (and intermittent discontinuation) was evaluated with standard operant procedures. Ramelteon did not produce benzodiazepine-like discriminative stimulus effects at doses up to 10 mg/kg. Long-term treatment or its discontinuation had no significant effect on spontaneous behavior, operant behavior, body weight, motor activity, or posture. These findings suggest that ramelteon is not likely to have benzodiazepine-like abuse or dependence liability.
[Show abstract][Hide abstract] ABSTRACT: A b s t r a c t A b s t r a c t A b s t r a c t A b s t r a c t A b s t r a c t The purpose of this updating manuscript is to briefly describe the profile, clinical use and indication of some of the most used sedative and hypnotic compounds. About 2/3 of all hypnotic prescriptions go to chronic use. Benzodiazepines are among the most prescribed drugs worldwide. Women, elderly, psychiatric and medical disease patients are among chronic users of hypnotics. Zolpidem is now the most prescribed hypnotic in most countries. It appears to be safer, compared to benzodazepines, and might be an option for long-term and controlled use ("as needed"). Sedative antidepressants are also among the most prescribed drug for sedation in insomnia patients in USA and UK. Sedative effect and use of trazodone, mirtazapine, doxepine, amitryptilin are described. The authors also discuss the use of melatonin and its sleep properties, and the rational use of sedative antipsychotics for chronic insomnia, particularly in psychiatric patients. Finally, some phytotherapeutic compounds are mentioned.
[Show abstract][Hide abstract] ABSTRACT: 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.
Brain Research 12/2004; 1027(1-2):59-66. DOI:10.1016/j.brainres.2004.08.035 · 2.84 Impact Factor
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