A recent report published by the Institute of Medicine of the National Academy of Sciences concluded that sleep disorders represent a substantial unmet public health problem in the US [1]. Ramelteon ((S)-N-[2-(1,6,7,8 tetrahydro-2H-indeno-[5,4]furan-8-yl)ethyl]propIonamide), the first of a new class of insomnia drugs which are melatonin receptor agonists, recently gained FDA approval for the treatment of insomnia characterised by difficulty with sleep onset [2]. Ramelteon was demonstrated to be effective at promoting sleep in cats [3] and monkeys [4]. This study compared the effects of ramelteon with melatonin and zolpidem, a GABA(A) receptor agonist and the dominant prescription hypnotic, on the sleep-wake cycle in the rat using the EEG telemetry model which is routinely used in drug development as a predictor of clinical hypnotic activity. In radioligand binding assays on recombinant human MT₁ and MT₂ receptors, both ramelteon and melatonin showed high affinity, but little subtype selectivity (ramelteon; pK_i MT₁ 10.05±0.04; MT₂ 9.70±0.07, melatonin; pK_i MT₁ 9.29±0.02; MT₂ 9.34±0.04). In a functional model, the pigment aggregation response of Xenopus melanophores [5], ramelteon, like melatonin, was a potent full agonist (EC₅₀ 11.48±0.02; melatonin EC₅₀ 10.45±0.02). Adult male Sprague-Dawley rats (~350g, n=6) housed under a 12:12 L:D cycle were implanted (i.p.) with telemetric probes (F40-EET; DSI) under general anaesthesia (75mg/kg i.p. ketamine, 0.5mg/kg i.p. medetomidine) to record cortical EEG and neck muscle EMG. Semi-automated scoring using SleepSign™ (Kissei-Comtec) was used to discriminate 10 s epochs into non-REM (NREM) sleep, rapid eye movement (REM) sleep, or wake (W). Ramelteon, melatonin and zolpidem (all at 10 mg/kg, i.p.) were administered in a randomised protocol at mid-dark. Time to NREM and REM onset, and NREM, REM and W durations were then determined. Data were analysed using one-way ANOVA followed by Bonferroni’s multiple comparison test. Ramelteon, melatonin and zolpidem significantly decreased the latency to NREM sleep onset (vehicle 46.6±5.9 min, ramelteon 26.8±1.4 min, melatonin 25.1±4.4 min; zolipidem 9.7±1.5 min, p<0.05). Ramelteon and zolpidem increased NREM duration up to 1 h post-injection compared to vehicle (p2 h after injection. Power spectra during NREM episodes in the first hour demonstrated no change with melatonin or ramelteon, but an increase in delta power (0-3 Hz) and a decrease in theta power (4-8 Hz) with zolpidem. All three agents were effective at promoting NREM sleep, but ramelteon and melatonin appear to produce a natural sleep and are relatively short-acting, while zolpidem has a longer duration of action and altered sleep architecture.