Sleep-wake characterization of double MT₁/MT₂ receptor knockout mice and comparison with MT₁ and MT₂ receptor knockout mice.

The neurohormone melatonin activates two G-protein coupled receptors, MT1 and MT2. Melatonin is implicated in circadian rhythms and sleep regulation, but the role of its receptors remains to be defined. We have therefore characterized the spontaneous vigilance states in wild-type (WT) mice and in three different types of transgenic mice: mice with genetic inactivation of MT1 (MT1(-/-)), MT2 (MT2(-/-)) and both MT1/MT2 (MT1(-/-)/MT2(-/-)) receptors. Electroencephalographic (EEG) and electromyographic sleep-wake patterns were recorded across the 24-h light-dark cycle. MT1(-/-)mice displayed a decrease (-37.3%) of the 24-h rapid eye movement sleep (REMS) time whereas MT2(-/-)mice showed a decrease (-17.3%) of the 24-h non rapid eye movement sleep (NREMS) time and an increase in wakefulness time (14.8%). These differences were the result of changes occurring in particular during the light/inactive phase. Surprisingly, MT1(-/-)/MT2(-/-) mice showed only an increase (8.9%) of the time spent awake during the 24-h. These changes were correlated to a decrease of the REMS EEG theta power in MT1(-/-)mice, of the NREMS EEG delta power in MT2(-/-)mice, and an increase of the REMS and wakefulness EEG theta power in MT1(-/-)/MT2(-/-) mice. Our results show that the genetic inactivation of both MT1 and MT2 receptors produces an increase of wakefulness, likely as a result of reduced NREMS due to the lack of MT2 receptors, and reduced REMS induced by the lack of MT1 receptors. Therefore, each melatonin receptor subtype differently regulates the vigilance states: MT2 receptors mainly NREMS, whereas MT1 receptors REMS.