Selective Enhancement of REM Sleep in Male Rats through Activation of Melatonin MT1 Receptors Located in the Locus Ceruleus Norepinephrine Neurons

J Neurosci. 2024 Jul 17;44(29):e0914232024. doi: 10.1523/JNEUROSCI.0914-23.2024.

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.

Keywords: EEG/EMG; REM sleep; locus ceruleus; melatonin MT1 receptors; norepinephrine; rats.

MeSH terms

  • Adrenergic Neurons / drug effects
  • Adrenergic Neurons / metabolism
  • Adrenergic Neurons / physiology
  • Animals
  • Locus Coeruleus* / drug effects
  • Locus Coeruleus* / metabolism
  • Locus Coeruleus* / physiology
  • Male
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / physiology
  • Norepinephrine / metabolism
  • Rats
  • Rats, Sprague-Dawley*
  • Receptor, Melatonin, MT1* / agonists
  • Receptor, Melatonin, MT1* / metabolism
  • Sleep, REM* / drug effects
  • Sleep, REM* / physiology

Substances

  • Receptor, Melatonin, MT1
  • Norepinephrine