BOSTON—The novel MT2 selective partial agonist UCM765 induces and promotes non-REM (NREM) sleep without affecting REM sleep, which suggests that the MT2 receptor might serve as a target for the treatment of sleep-related disorders, researchers reported at the 26th Annual Meeting of the Associated Professional Sleep Societies.
Although drugs such as benzodiazepines also increase NREM, they disturb the deep and restorative delta sleep of NREM, said Gabriella Gobbi, MD, PhD, a researcher at McGill University in Montreal. “UCM765 instead increases this delta sleep,” Dr. Gobbi told Neurology Reviews. “The fact that [UCM765] does not change REM means that UCM765 does not disrupt the architecture of sleep.”
MT2 and NREM Sleep
Using the novel MT2 compound UCM765 in a rat model, Dr. Gobbi and her colleagues evaluated whether selective activation of MT2 receptors could alter NREM sleep.
Sleep-wake patterns of animals treated with UCM765 were measured with EEG and EMG across the 24-hour light-dark cycle. Every four hours, the rats received either 20-, 40-, or 60-mg/kg doses of UCM765.
“We found something very interesting,” said Dr. Gobbi. “The doses of 40 and 60 mg/kg decreased the latency of the first episode of NREM.” Latency decreased by 59% with the 40-mg/kg dose and by 49% with the 60-mg/kg dose.
The 40- and 60-mg/kg doses also increased the total amount of NREM sleep during the inactive/light phase by 48% and 33%, respectively. However, the 40- and 60-mg/kg doses decreased the total amount of wakefulness during the inactive/light phase by 37% and 26%, respectively.
A 40-mg/kg dose of UCM765 increased the number of spindles per minute during the inactive/light phase of sleep, but it did not affect the active phase. The compound increased the delta power of NREM sleep during both the light and dark phases, however.
A Novel Target
According to the researchers, UCM765 did not show significant effects on the number of episodes of NREM sleep and wakefulness or on REM. “We didn’t find any change in REM,” commented Dr. Gobbi.
Both MT1 and MT2 receptors allow melatonin to function in the brain, but the receptors have different, complementary roles in sleep. The MT1 receptor may have an opposite effect compared with MT2 and could impair REM, said Dr. Gobbi.
Dr. Gobbi and her colleagues confirmed the roles of MT1 and MT2 receptors by performing experiments in which the MT2 and MT1 receptors were knocked out in mice. In MT2 knockout mice, NREM sleep was decreased, while MT1 knockout mice showed an increase in NREM and impairment in REM. “These data confirmed that the MT2 receptor is involved in the regulation of NREM or slow wave sleep,” said Dr. Gobbi.
Further study showed that MT2 receptors are located in sleep-related regions of the brain, particularly the reticular thalamus. UCM765 functions by activating the firing and burst activity of reticular thalamus neurons, which triggers NREM.
“We think there is a certain balance between MT1 and MT2, but if you just want to increase the NREM without changing REM, the pharmacological activation of the MT2 receptor could be a good strategy. MT2 could represent a novel target for hypnotic drugs,” concluded Dr. Gobbi.
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