Selective Enhancement of REM Sleep in Male Rats through Activation of Melatonin MT1 Receptors Located in the Locus Ceruleus Norepinephrine Neurons
- Martha López-Canul1,
- Qianzi He1,
- Tania Sasson1,
- Mohamed Ettaoussi1,
- Danilo De Gregorio1,2,
- Rafael Ochoa-Sanchez1,
- Helene Catoire3,
- Luca Posa1,
- Guy Rouleau3,
- Jean Martin Beaulieu4,
- Stefano Comai1,2,5,6,*, and
- Gabriella Gobbi1,7,*
- 1Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec H3A 1A1, Canada
- 2IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- 3Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada
- 4Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5G 2C8, Canada
- 5Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua 35131, Italy
- 6Department of Biomedical Sciences, University of Padua, Padua 35131, Italy
- 7Research Institute, McGill University Health Center, McGill University, Montreal, Quebec H3A 1A1, Canada
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Author contributions: M.L-C., G.R., J.M.B., S.C., and G.G. designed research; M.L-C., Q.H., T.S., M.E., D.G., R.O-S., H.C., and L.P. performed research; G.R. and J.M.B. contributed unpublished reagents/analytic tools; M.L-C., Q.H., T.S., D.G., R.O-S., and S.C. analyzed data; M.L-C., S.C., and G.G. wrote the paper.
Abstract
Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.
- Received May 11, 2023.
- Revision received April 3, 2024.
- Accepted April 6, 2024.
- Copyright © 2024 López-Canul et al.
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