Unveiling the role of Melatonin MT2 receptor in sleep and anxiety

January 11, 2013
2:30 p.m.

Insomnia and anxiety are a common public health problem. Melatonin (MLT) is a pleiotropic and multitasking neurohormone controlling many physiological processes including circadian rhythms, mood regulation, anxiety, sleep, and appetite. The neurohormone is synthesized in the brain by the pineal gland during the night and acts through two G-protein coupled receptors, MT1 and MT2. Although a bulk of research has examined the physiopathological effects of MLT, limited studies have investigated the selective role played by MT1 and MT2 receptors. Using pharmacological (a selective MT2 receptors partial agonist UCM765) and genetic (knockout mice for MLT receptors) approaches, the role of MT2 receptors on sleep and anxiety regulation was examined. The recording of the electroencephalographic (EEG) and electromyographic (EMG) sleep-wake patterns across the 24-h light-dark cycle showed that the novel MT2 receptor partial agonist UCM765 (40 mg/kg) selectively promoted non rapid eye movement sleep (NREMS) in rats and mice. No significant effects of UCM765 were reported on the number of episodes of NREMS and wakefulness as well as on REMS variables. The enhancement of NREMS by UCM765 was nullified by the pharmacological blockade or genetic deletion of MT2 receptors. MT2, but not MT1, knockout mice displayed a decrease in NREMS compared to the wild strain. Anxiety related behaviours were assessed in the elevated plus maze test (EPMT), novelty suppressed feeding test (NSFT) and open field test (OFT). UCM765 at a lower dose (10 mg/kg) than that having hypnotic effects showed anxiolytic-like properties by increasing the time spent in the open arm of the EPMT, and by reducing the latency to eat in a novel environment in the NSFT. Moreover, it did not affect the total time and the number of entries into the central area of the OFT as well as total locomotion. The anxiolytic effects of UCM765 were blocked using a pre-treatment with the MT1/MT2 antagonist luzindole (10 mg/kg) or the MT2 antagonist 4P-PDOT (10 mg/kg). UCM765 has therefore anxiolytic and hypnotic effects depending on the dosage and it does not produce sedation. These findings demonstrate the proof of concept that MT2 receptor might represent a novel target for the treatment of sleep and anxiety-related disorders.