Elsevier

Sleep Medicine Reviews

Volume 15, Issue 2, April 2011, Pages 123-135
Sleep Medicine Reviews

Physiological review
Adenosine, energy metabolism and sleep homeostasis

https://doi.org/10.1016/j.smrv.2010.06.005Get rights and content

Summary

Adenosine is directly linked to the energy metabolism of cells. In the central nervous system (CNS) an increase in neuronal activity enhances energy consumption as well as extracellular adenosine concentrations. In most brain areas high extracellular adenosine concentrations, through A1 adenosine receptors, decrease neuronal activity and thus the need for energy. Adenosine may be a final common pathway for various sleep factors.

We have identified a relatively specific area, the basal forebrain (BF), which appears to be central in the regulation/execution of recovery sleep after sleep deprivation (SD), or prolonged wakefulness. Adenosine concentration increases in this area during SD, and this increase induces sleep while prevention of the increase during SD abolishes recovery sleep. The increase in adenosine is associated with local changes in energy metabolism as indicated by increases in levels of pyruvate and lactate and increased phosphorylation of AMP-activated protein kinase. The increases in adenosine and sleep are associated with intact cholinergic system since specific lesion of the BF cholinergic cells abolishes both. Whether adenosine during SD is produced by the cholinergic neurons or astrocytes associated with them remains to be explored.

An interesting, but so far unexplored question regards the relationship between the local, cortical regulation of sleep homeostasis and the global regulation of the state of sleep as executed by lower brain mechanisms, including the BF. The increase in adenosine concentration during SD also in cortical areas suggests that adenosine may have a role in the local regulation of sleep homeostasis. The core of sleep need is probably related to primitive functions of life, like energy metabolism. It can be noted that this assumption in no way excludes the possibility that later in evolution additional functions may have developed, e.g., related to complex neuronal network functions like memory and learning.

Section snippets

Adenosine levels during spontaneous sleep–wake cycles

The measurements of extracellular adenosine concentrations during spontaneous sleep–wake cycles during lights-on period were made in several brain areas of cats using in vivo microdialysis.*27, *56 Basal levels of adenosine measured in microdialysate samples from probes in the BF and thalamus (N = 10) were 32.8 ± 3.0 nmol/l (mean ± SEM); hence, from these data we estimated that extracellular adenosine concentrations are in the range of 165–300 nM, based on a in vitro microdialysis probe

Sleep in adenosine receptor knock-out (KO) mice

Sleep

The basal forebrain

In vitro studies have shown that in the BF adenosine decreases

Effects of prolonged wakefulness on adenosine metabolism and transport

We found no changes in the activity of AK, ecto-5′-nucleotidase or endo-5′-nucleotidase after 3 or 6 h of SD either in the BF area or in the cortex.23 Similar results have been reported by another group that measured the activities of both the cytosolic and extracellular forms of 5′-nucleotidase,104 as well as activity of ADA and AK. Enzymes were found to exhibit diurnal variation in many brain regions, while SD did not alter the activity of any of these enzymes.104 These studies suggest that

An adenosine-associated sleep factor: NO

Several molecules and groups of biologically active substances have the ability to influence vigilance states. Several cytokines (for review, see112), brain-derived neurotrophic factor (BDNF),14, 113 GnRH,114, 115 chaperone protein BiP/GRP78,116 PDG282 are among substances that clearly have sleep-promoting functions.

Recently a new candidate to this group was introduced: NO.*117, *118, 119 NO is a gaseous neurotransmitter that is involved in regulation of circulation and acts also in many

Acknowledgement

This work was supported by a grant from the Academy of Finland.

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