The Role of Adenosine in the Regulation of Sleep

Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
Current topics in medicinal chemistry (Impact Factor: 3.4). 03/2011; 11(8):1047-57. DOI: 10.2174/156802611795347654
Source: PubMed


This paper presents an overview of the current knowledge about the role of adenosine in the sleep-wake regulation with a focus on adenosine in the central nervous system, regulation of adenosine levels, adenosine receptors, and manipulations of the adenosine system by the use of pharmacological and molecular biological tools. The endogenous somnogen prostaglandin (PG) D(2) increases the extracellular level of adenosine under the subarachnoid space of the basal forebrain and promotes physiological sleep. Adenosine is neither stored nor released as a classical neurotransmitter and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The extracellular concentration of adenosine increases in the cortex and basal forebrain during prolonged wakefulness and decreases during the sleep recovery period. Therefore, adenosine is proposed to act as a homeostatic regulator of sleep and to be a link between the humoral and neural mechanisms of sleep-wake regulation. Both the adenosine A(1) receptor (A(1)R) and A(2A)R are involved in sleep induction. The A(2A)R plays a predominant role in the somnogenic effects of PGD(2). By use of gene-manipulated mice, the arousal effect of caffeine was shown to be dependent on the A(2A)R. On the other hand, inhibition of wake-promoting neurons via the A(1)R also mediates the sleep-inducing effects of adenosine, whereas activation of A(1)R in the lateral preoptic area induces wakefulness, suggesting that A(1)R regulates the sleep-wake cycle in a site-dependent manner. The potential therapeutic applications of agonists and antagonists of these receptors in sleep disorders are briefly discussed.

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Available from: Zhi-Li Huang, Apr 02, 2015
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    • "Caffeine binds with very similar affinity to adenosine A 1 (A 1 Rs) and A 2A (A 2A Rs) receptors, and, at doses commonly consumed by humans, adenosine actions at both receptors are antagonized . Adenosine is an inhibitory neuromodulator involved in sleep–wake regulation (Porkka-Heiskanen et al., 1997; Huang et al., 2011). Using global genetic knock-outs of A 1 Rs and A 2A Rs, in which the receptor is deleted from the entire animal, we demonstrated previously that the A 2A R, but not the A 1 R, mediates the arousal effect of caffeine (Huang et al., 2005). "
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    • "evidence shows that extracellular concentrations of AD are enhanced in association with natural or prolonged alertness in multiple brain areas (Porkka-Heiskanen et al., 2000, 2002; Blanco- Centurión et al., 2006; Huang et al., 2011). Since CBD promotes waking and AD is increased during alertness, we tested the hypothesis that this cannabinoid increases extracellular levels of AD in rats. "
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    ABSTRACT: Cannabidiol (CBD) is a constituent of Cannabis sativa that promotes wakefulness as well as enhances endogenous levels of wake-related neurotransmitters, including dopamine. However, at this date, the effects of CBD on the sleep-inducing molecules, such as adenosine (AD), are unknown. Here, we report that intrahypothalamic injection of CBD (10μg/1μL) increases the extracellular levels of AD collected from nucleus accumbens. Furthermore, the pharmacodynamic of this drug shows that effects on the contents of AD last 2h post-injection. These preliminary findings suggest that CBD promotes the endogenous accumulation of AD.
    Neuroscience Research 05/2014; 84. DOI:10.1016/j.neures.2014.04.006 · 1.94 Impact Factor
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    • "Sleep duration, wake episodes, and latency were recorded for 5 nights pre-and post-intervention via actigraphy (MicroMini-Motionlogger™, Ambulatory Monitoring Inc. Ardsley, N.Y.), which has good properties in detecting sleep in children (Meltzer et al., 2012). To provide sufficient measurement reliability, the following variables are reported as average times/scores over 5 nights (Huang et al., 2011): "
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    ABSTRACT: Sleep problems in children are associated with poor health, behavioural and cognitive problems, as are deficiencies of long-chain omega-3 fatty acids such as docosahexaenoic acid. Theory and some evidence support a role for these fatty acids in sleep regulation, but this issue has received little formal investigation. We examined associations between blood fatty acid concentrations (from fingerstick blood samples) and subjective sleep (using an age-standardized parent questionnaire) in a large epidemiological sample of healthy children aged 7–9 years (n = 395) from mainstream UK schools. In a randomized controlled trial, we then explored whether 16-week supplementation (600 mg day−1) with algal docosahexaenoic acid versus placebo might improve sleep in a subset of those children (n = 362) who were underperforming in reading. In a randomly selected subsample (n = 43), sleep was also assessed objectively via actigraphy. In 40% of the epidemiological sample, Child Sleep Habits Questionnaire scores indicated clinical-level sleep problems. Furthermore, poorer total sleep disturbance scores were associated weakly but significantly with lower blood docosahexaenoic acid (std coeff. −0.105*) and a lower docosahexaenoic acid : arachidonic acid ratio (std coeff. −0.119**). The treatment trial showed no significant effects on subjective sleep measures. However, in the small actigraphy subsample, docosahexaenoic acid supplementation led on average to seven fewer wake episodes and 58 min more sleep per night. Cautiously, we conclude that higher blood levels of docosahexaenoic acid may relate to better child sleep, as rated by parents. Exploratory pilot objective evidence from actigraphy suggests that docosahexaenoic acid supplementation may improve children's sleep, but further investigations are needed.
    Journal of Sleep Research 03/2014; 23(4). DOI:10.1111/jsr.12135 · 3.35 Impact Factor
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