Sleep disorders adversely affect daily activities and lead to physiological and psychiatric problems. The shortcomings of benzodiazepine hypnotics have led to the development of ramelteon, one of melatonin MT1 and MT2 agonists. Although sleep-promoting effects of ramelteon have been documented, few studies have precisely investigated structure of sleep, neural oscillatory activities and peripheral effects.
In this study, we recorded electrocorticograms in the primary motor cortex, the primary somatosensory cortex and the olfactory bulb, electrocardiograms, and electromyograms of unrestrained rats treated with either ramelteon or vehicle. Neural-oscillation-based algorithm classified behavior of rats into three vigilance states (e.g., awake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep). We demonstrated that ramelteon treatment promoted NREM sleep and enhanced fast gamma power in the primary motor cortex during NREM sleep, while REM sleep was unaffected. As neocortical gamma oscillations locally coordinate neuronal firing, ramelteon may contribute to precise information processing during sleep.
We further analyzed heartrate and its variability to evaluate effects of ramelteon on cardiac function. We found ramelteon treatment significantly decreased the standard deviation of R-R intervals during NREM sleep, but not during REM sleep. As severe arrhythmia is related to sudden death, ramelteon would not only promote sleep but also prevent cardiac irregularity.
Collectively, these results suggest that ramelteon ameliorates the quality of sleep by modulating central neural activity and regularizing cardiac rhythms.