Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jun;26(3):377-385.
doi: 10.1111/jsr.12523. Epub 2017 Apr 11.

Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats

Markus Dworak  1   2 , Tae Kim  1   3 , Robert W Mccarley  1 , Radhika Basheer  1
Affiliations

Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats

Markus Dworak et al. J Sleep Res. 2017 Jun.

Abstract

Sleep has been postulated to promote brain energy restoration. It is as yet unknown if increasing the energy availability within the brain reduces sleep need. The guanidine amino acid creatine (Cr) is a well-known energy booster in cellular energy homeostasis. Oral Cr-monohydrate supplementation (CS) increases exercise performance and has been shown to have substantial effects on cognitive performance, neuroprotection and circadian rhythms. The effect of CS on cellular high-energy molecules and sleep-wake behaviour is unclear. Here, we examined the sleep-wake behaviour and brain energy metabolism before and after 4-week-long oral administration of CS in the rat. CS decreased total sleep time and non-rapid eye movement (NREM) sleep significantly during the light (inactive) but not during the dark (active) period. NREM sleep and NREM delta activity were decreased significantly in CS rats after 6 h of sleep deprivation. Biochemical analysis of brain energy metabolites showed a tendency to increase in phosphocreatine after CS, while cellular adenosine triphosphate (ATP) level decreased. Microdialysis analysis showed that the sleep deprivation-induced increase in extracellular adenosine was attenuated after CS. These results suggest that CS reduces sleep need and homeostatic sleep pressure in rats, thereby indicating its potential in the treatment of sleep-related disorders.

Keywords: creatine; energy metabolism; sleep deprivation; sleep homeostasis.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest: MD is currently an employee of Novartis Pharma, Germany.

Figures

Figure 1
Figure 1. Creatine-supplementation increases waking time in the light not in the dark period
Increased spontaneous waking time after creatine supplementation (CS): Four weeks of oral CS increased wake time during the light period (+ 19.10 %; P=0.014) but not during the dark (P=0.158) period. NREM SWS decreased significantly by −15.14% in the same diurnal pattern (Cr: 31.1± 4.8 %; pre-diet control: 46.3±7.8 %TST; P=0.04), while REM sleep did not change significantly before and after CS (Cr: 6.1±2.8 %; pre-diet control: 8.7±2.7 %; P=0.445). 24h EEG recordings were performed before (BL, black line) and after 4 weeks of oral Cr-supplementation (Cr, red line) in the same animals (n=6). D) Wake time was increased in the initial hours during the light period. Significant higher levels (* P<0.05) were observed under CS conditions at 9AM E) SWS was reduced during the beginning of the light period. Significant lower levels (* P<0.05) were observed at 9AM and 10 AM when compared to BL. F) REM-sleep before and after Cr-supplementation remained unchanged. Only at 1PM, REM-sleep was significantly increased after Cr-supplementation when compared to BL (* P<0.05). G) No changes in NREM Delta during spontaneous sleep-wake behavior before and after Cr-supplementation were observed.
Figure 2
Figure 2. Cr supplementation diminishes sleep pressure after 6h of sleep deprivation
Changes in wake, NREM and REM sleep were observed during 6h of sleep deprivation followed by 6h of recovery sleep before and after 4 weeks of Cr-supplementation. Wake time was significantly higher after Cr-supplementation in the last hour of SD and the first 2h of recovery sleep (RS) (A). NREM sleep was significantly reduced in the last hour of SD and the initial hours of RS (B), when REM sleep was reduced (C). NREM delta activity (0.5–4.5 Hz) was also reduced at the end of SD (6h) and the first hour of RS (D), indicating a reduced homeostatic sleep pressure.
Figure 3
Figure 3. Effects of 4 weeks oral creatine supplementation on brain tissue creatine (Cr) and phosphocreatine (PCr) levels
A) Coronal sections of the brain showing bregma coordinates of dissected brain regions: frontal cortex, basal forebrain, cingulate cortex and hippocampus. B) PCr/Cr-levels measured before and after 4 weeks of oral creatine supplementation. Cr levels did not differ significantly before and after creatine supplementation in all examined brain regions. No significant change in PCr levels was observed in the examined brain regions before and after the diet. There was just a tendency for increased PCr levels after the supplementation period.
Figure 4
Figure 4
A) Cellular ATP concentrations measured via a luciferin-luciferase based assay. ATP-levels decreased significantly in frontal cortex, basal forebrain and hippocampus after 2 weeks of CS when compared to BL. B) Effects of Cr-supplementation on [AD]ex during 6h SD and RS. After Cr-supplementation, [AD]ex was significantly reduced after 6h SD when compared to BL (P=0.03). No changes were observed during the RS period. C) Correlation between [AD]ex und NREM delta activity: A significant positive correlation between [AD]ex and average NREM delta activity was observed.
Figure 5
Figure 5. Model for the effects of CS on brain energy metabolism and sleep need during sleep deprivation
This model summarizes our hypothesis about the effect of CS on [AD]ex during sleep deprivation and sleep-wake regulation. a) Under normal conditions, [AD]ex concentrations depend on AD release from intracellular sources and to a major extend on the extracellular production out of ATP via ecto-nucleotidase (ecto-NT). High [AD]ex concentrations modulate neuronal activity and increase NREM delta activity via A1 receptor binding. b) Creatine supplementation tend to increase brain PCr levels via a concomitant decrease in brain ATP through the CK reaction. Lower cellular ATP levels will result in less ATP release and reduced [AD]ex by reducing the substrate for the ecto-NT reaction. A reduced AD tone may be associated with a reduced sleep drive during sleep deprivation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Alle H, Roth A, Geiger JR. Energy-efficient action potentials in hippocampal mossy fibers. Science. 2009;325:1405–8. - PubMed
    1. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR. Functions and effects of creatine in the central nervous system. Brain Res Bull. 2008;76:329–43. - PubMed
    1. Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab. 2001;21:1133–45. - PubMed
    1. Basheer R, Porkka-Heiskanen T, Stenberg D, McCarley RW. Adenosine and behavioral state control: adenosine increases c-Fos protein and AP1 binding in basal forebrain of rats. Br Res Mol Br Res. 1999;73:1–10. - PubMed
    1. Basheer R, Strecker RE, Thakkar MM, Mccarley RW. Adenosine and sleep-wake regulation. Prog Neurobiol. 2004;73:379–96. - PubMed

MeSH terms