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 243 publications

(190 citation statements)

References 40 publications

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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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“…This polymorphism is linked to a expression (Alsene et al, 2003). Rétey and co-workers observed that the 1976T>C polymorphism not only contributes to individual sensitivity to the effects of caffeine on sleep (Rétey et al, 2007), but also affects EEG activity in all sleep/vigilance states. In a case-control study, spectral power in the ~ 7-10 Hz range was shown to be invariably higher in subjects with the C/C genotype than in subjects with the T/T genotype (Rétey et al, 2005).…”

Section: T>c Polymorphism Of Adenosine a 2a Receptor (Adora2a) Genementioning

confidence: 99%

Genetic determination of sleep EEG profiles in healthy humans

Landolt

2011

Progress in Brain Research

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The contribution of slow brain oscillations including delta, theta, alpha, and sigma frequencies to the sleep electroencephalography (EEG) is finely regulated by circadian and homeostatic influences, and reflects functional aspects of wakefulness and sleep. Accumulating evidence demonstrates that individual sleep EEG patterns in non-rapid-eye-movement (NREM) sleep and rapid-eye-movement (REM) sleep are heritable traits. More specifically, multiple recordings in the same individuals, as well as studies in monozygotic and dizygotic twins suggest that a very high percentage of the robust interindividual variation and the high intraindividual stability of sleep EEG profiles can be explained by genetic factors (> 90% in distinct frequency bands). Still little is known about which genes contribute to different sleep EEG phenotypes in healthy humans. The genetic variations that have been identified to date include functional polymorphisms of the clock gene PER3 and of genes contributing to signal transduction pathways involving adenosine (ADA, ADORA2A), brain-derived neurotrophic factor (BDNF), dopamine (COMT), and prion protein (PRNP). Some of these polymorphisms profoundly modulate sleep EEG profiles; their effects are reviewed here. It is concluded that the search for genetic contributions to slow sleep EEG oscillations constitutes a promising avenue to identify molecular mechanisms underlying sleep-wake regulation in humans.

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

Cited by 243 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

Genetic determination of sleep EEG profiles in healthy humans

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

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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 243 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

Genetic determination of sleep EEG profiles in healthy humans

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

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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