A Genetic Variation in the Adenosine A2A Receptor Gene (ADORA2A) Contributes to Individual Sensitivity to Caffeine Effects on Sleep

Rétey, Julia V.; Adam, Martin; Khatami, Ramin; Luhmann, Ulrich F O; Jung, Hans H.; Berger, Wolfgang; Landolt, Hans‐Peter

doi:10.1038/sj.clpt.6100102

Cited by 235 publications

(184 citation statements)

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“…From cognitive performance under sleepdeprivation conditions, it is known that the degree of impairment varies highly among individuals (34). Differences in caffeine effects have been linked to sleep-loss-induced performance impairments (35) and to genetic variants of the adenosinergic system (36,37). Along these lines, we defined two subgroups based on the A 1 AR availability decrease, of which one group showed a strong decline in receptor availability, whereas the other revealed only a minor decline.…”

Section: Discussionmentioning

confidence: 99%

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Elmenhorst

Hennecke

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Adenosine and functional A 1 adenosine receptor (A 1 AR) availability are supposed to mediate sleep-wake regulation and cognitive performance. We hypothesized that cerebral A 1 AR availability after an extended wake period decreases to a well-rested state after recovery sleep. [ 18 F]CPFPX positron emission tomography was used to quantify A 1 AR availability in 15 healthy male adults after 52 h of sleep deprivation and following 14 h of recovery sleep. Data were additionally compared with A 1 AR values after 8 h of baseline sleep from an earlier dataset. Polysomnography, cognitive performance, and sleepiness were monitored. Recovery from sleep deprivation was associated with a decrease in A 1 AR availability in several brain regions, ranging from 11% (insula) to 14% (striatum). A 1 AR availabilities after recovery did not differ from baseline sleep in the control group. The degree of performance impairment, sleepiness, and homeostatic sleep-pressure response to sleep deprivation correlated negatively with the decrease in A 1 AR availability. Sleep deprivation resulted in a higher A 1 AR availability in the human brain. The increase that was observed after 52 h of wakefulness was restored to control levels during a 14-h recovery sleep episode. Individuals with a large increase in A 1 AR availability were more resilient to sleep-loss effects than those with a subtle increase. This pattern implies that differences in endogenous adenosine and A 1 AR availability might be causal for individual responses to sleep loss.S leep loss is known to impair almost every aspect of cognition, such as learning (1), long-term memory consolidation (2), attention and psychomotor vigilance (PVT) (3), and executive functions (4), including decision making (5) and emotional control (6). Sleep deprivation further typically alters the frequency distribution of the waking electroencephalogram (EEG) as an indicator of alertness corresponding to cognitive performance (7). However, large interindividual differences exist in the degree of cognitive performance decline during sleep deprivation (3). In a trait-like process, some individuals keep high-level performance during sustained wakefulness, whereas others suffer from severe performance loss (3). The neuro-molecular mechanisms in the brain responsible for these different vulnerabilities are still largely unknown. Caffeine, commonly consumed for fighting fatigue, promotes wakefulness via adenosine receptor antagonism. It seems likely that the adenosinergic system is a neurochemical link between performance and sleep (8). Adenosine is contributing to the homeostatic process of sleep-wake regulation (for review, see refs. 9-12). As has been shown in cats and rats, extracellular adenosine concentration fluctuates rhythmically in many brain regions, such as the basal forebrain, increasing during wakefulness and decreasing during sleep: it thereby induces sleep after wake extension and is in turn restored to baseline levels after recovery sleep (13). For additional information on adenosine, see...

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Section: Discussionmentioning

confidence: 99%

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Elmenhorst

Hennecke

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…An internet survey about self-rated caffeine sensitivity and sleep was recently conducted among 20'343 University students [16]. A total number of 2'308 men and 2'021 women responded (response rate: 21 %).…”

Section: Sleep Durationmentioning

confidence: 99%

Genotype-Dependent Differences in Sleep, Vigilance, and Response to Stimulants

Landolt

2008

CPD

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Abstract:To better understand the neurobiology of sleep disorders, detailed understanding of circadian and homeostatic sleep-wake regulation in healthy volunteers is mandatory. Sleep physiology and the repercussions of experimentallyinduced sleep deprivation on sleep and waking electroencephalogram (EEG), vigilance and subjective state are highly variable, even in healthy individuals. Accumulating evidence suggests that many aspects of normal sleep-wake regulation are at least in part genetically controlled. Current heritability estimates of sleep phenotypes vary between approximately 20-40 % for habitual sleep duration, to over 90 % for the spectral characteristics of the EEG in nonREM sleep. The molecular mechanisms underlying the trait-like, inter-individual variation are virtually unknown, and the human genetics of normal sleep is only at the beginning of being explored. The first studies identified distinct polymorphisms in genes contributing to the endogenous circadian clock and neurochemical systems previously implicated in sleep-wake regulation, to modulate sleep architecture and sleep EEG, vulnerability to sleep loss, and subjective and objective effects of caffeine on sleep. These insights are reviewed here. They disclose molecular mechanisms contributing to normal sleep-wake regulation in humans, and have potentially important implications for the neurobiology of sleep-wake disorders and their pharmacological treatment.

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“…Genetic background is therefore a crucial variable when evaluating novel drugs. Examples of specific gene polymorphism or transgenic models associated with altered efficacy of stimulants are, for amphetamine, the dopamine transporter (Lott et al, 2005;Wisor et al, 2001), homer1a (Tappe and Kuner, 2006), casein kinase I-e (Palmer et al, 2005), and brain-derived neurotrophic factor (BDNF) (Flanagin et al, 2006); for modafinil, catechol-O-methyltransferase (Dauvilliers et al, 2002) and the dopamine transporter (Wisor et al, 2001); and for caffeine, the adenosine A2a receptor (Alsene et al, 2003;Retey et al, 2007). The finding that casein kinase I-e is involved in the response to amphetamine in mice (Palmer et al, 2005) was recently confirmed in humans (Veenstra-VanderWeele et al, 2006), demonstrating that the mouse model can be of direct relevance for predicting genetic-background effects in humans.…”

Section: Introductionmentioning

confidence: 99%

How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion

Hasan

Pradervand

Ahnaou³

et al. 2009

Neuropsychopharmacol

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Wake-promoting drugs are widely used to treat excessive daytime sleepiness. The neuronal pathways involved in wake promotion are multiple and often not well characterized. We tested d-amphetamine, modafinil, and YKP10A, a novel wake-promoting compound, in three inbred strains of mice. The wake duration induced by YKP10A and d-amphetamine depended similarly on genotype, whereas opposite strain differences were observed after modafinil. Electroencephalogram (EEG) analysis during drug-induced wakefulness revealed a transient B2 Hz slowing of theta oscillations and an increase in beta-2 (20-35 Hz) activity only after YKP10A. Gamma activity (35-60 Hz) was induced by all drugs in a drug-and genotype-dependent manner. Brain transcriptome and clustering analyses indicated that the three drugs have both common and specific molecular signatures. The correlation between specific EEG and gene-expression signatures suggests that the neuronal pathways activated to stay awake vary among drugs and genetic background.

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A Genetic Variation in the Adenosine A2A Receptor Gene (ADORA2A) Contributes to Individual Sensitivity to Caffeine Effects on Sleep

Cited by 235 publications

References 40 publications

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Genotype-Dependent Differences in Sleep, Vigilance, and Response to Stimulants

How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion

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A Genetic Variation in the Adenosine A2A Receptor Gene (ADORA2A) Contributes to Individual Sensitivity to Caffeine Effects on Sleep

Cited by 235 publications

References 40 publications

Recovery sleep after extended wakefulness restores elevated A 1 adenosine receptor availability in the human brain

Recovery sleep after extended wakefulness restores elevated A 1 adenosine receptor availability in the human brain

Genotype-Dependent Differences in Sleep, Vigilance, and Response to Stimulants

How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion

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Product

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Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain