Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep-wake cycle architecture

The novel antidepressant, agomelatine, behaves as an agonist at melatonin MT1 and MT2 receptors and as an antagonist at serotonin (5-HT)(2C) receptors. In animal models and clinical trials, agomelatine displays antidepressant properties and re-synchronizes disrupted circadian rhythms. The objectives of this study were to compare the influence of agomelatine upon sleep-wake states to the selective melatonin agonists, melatonin and ramelteon, and to the selective 5-HT2C receptor antagonist, S32006. Rats were administered with vehicle, agomelatine, ramelteon, melatonin, or S32006, at the onset of either dark or light periods. Polygraphic recordings were performed and changes determined over 24 h, i.e., number and duration of sleep-wake episodes, latencies to rapid eye movement (REM) and slow-wave (SWS) sleep, power band spectra of the electroencephalogram (EEG), and circadian changes. Administered at light phase onset, no changes were induced by agomelatine. In contrast, administered shortly before dark phase, agomelatine (10 and 40 mg/kg, per os) enhanced duration of REM and SWS sleep and decreased wake state for 3 h. Melatonin (10 mg/kg, per os) induced a transient enhancement in REM sleep followed by a reduction in REM and SWS sleep and an increase in waking. Ramelteon (10 mg/kg, per os) provoked a transient increase in REM sleep. Finally, S32006 (10 mg/kg, intraperitoneally), administered at dark phase onset, mimicked the increased SWS provoked by agomelatine, yet diminished REM sleep. Agomelatine possesses a distinctive EEG profile compared with melatonin, ramelteon, and S32006, possibly reflecting co-joint agonist and antagonist properties at MT1/MT2 and 5-HT2C receptors, respectively.