Abstract
Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM) sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2)-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation.
Highlights
As the primary inhibitory neurotransmitter in the central nervous system, glycine is widely distributed throughout the brainstem and spinal cord [1,2,3]
There were marked differences between the salineand glycine-administered groups in the amount of both wakefulness and non-rapid eye movement (NREM) sleep, duration of wakefulness state, and stage count of both wakefulness and NREM sleep in the dark period (Fig. 1C,E,G)
These observations suggest that glycine decreased wakefulness time and increased NREM sleep time in mice when administered at the start of the dark period
Summary
As the primary inhibitory neurotransmitter in the central nervous system, glycine is widely distributed throughout the brainstem and spinal cord [1,2,3]. It acts as an allosteric modulator of the N-methyl-D-aspartate (NMDA) receptor [4,5]. Glycine is thought to play important roles in sleep regulation. It was reported that orally administered glycine increased subjective sleep quality without any adverse effect [10]. The mechanisms and sites of action of these effects of glycine administration on sleep have remained largely unclear
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