Adenosine, caffeine, and sleep–wake regulation: state of the science and perspectives (2024)

4.1. Effects of acute caffeine administration on sleep

Caffeine is a potent adenosine receptor antagonist with roughly equally high affinity for both A₁ and A_2A receptors. Work in mice provided strong evidence that caffeine promotes wakefulness primarily by blocking the A_2A subtype of adenosine receptors (Huang et al.,²⁰⁰⁵). While caffeine (at a dose of 15 mg/kg) failed to disrupt sleep in mice with genetically‐abolished A_2A receptor function, the stimulant promoted wakefulness in wild‐type mice as well as in transgenic mice without functional A₁ receptors. Subsequent experiments revealed that specifically the genetic deletion of A_2A receptors in the shell of the nucleus accumbens blocked caffeine‐induced wakefulness (Lazarus et al.,²⁰¹¹).

Research in humans typically relied on the study of caffeine, to investigate the role of adenosine on sleep homeostasis. Polysomnographic measures of sleep latency were consistently prolonged (Brezinova,¹⁹⁷⁴; Drapeau et al.,²⁰⁰⁶; Karacan et al.,¹⁹⁷⁶; Landolt, Dijk, et al.,¹⁹⁹⁵; Okuma et al.,¹⁹⁸²; Paterson et al.,²⁰⁰⁹; Robillard et al.,²⁰¹⁵; Youngstedt et al.,²⁰⁰⁰) and sleep efficiency was reduced (Bonnet & Arand,²⁰⁰³; Drapeau et al.,²⁰⁰⁶; Karacan et al.,¹⁹⁷⁶; Landolt, Dijk, et al.,¹⁹⁹⁵; Okuma et al.,¹⁹⁸²; Paterson et al.,²⁰⁰⁹; Robillard et al.,²⁰¹⁵) when caffeine was administered in the evening close to bedtime. Several studies also showed reduced SWA and increased activity in the frequency range of sleep spindles (~12–15 Hz; sigma range) (Drapeau et al.,²⁰⁰⁶; Landolt, Dijk, et al.,¹⁹⁹⁵; Robillard et al.,²⁰¹⁵) even after long periods of wakefulness (Carrier et al.,²⁰⁰⁹; Landolt et al.,²⁰⁰⁴; Landolt, Werth, et al.,¹⁹⁹⁵). Significant reductions in the SWA range were, however, in some cases restricted to a single bin (Landolt, Werth, et al.,¹⁹⁹⁵; Robillard et al.,²⁰¹⁵), only detectable in the first NREM sleep episode (Carrier et al.,²⁰⁰⁹), or even absent (Paterson et al.,²⁰⁰⁹). Additionally, it has not been elucidated whether adenosine receptor antagonism with caffeine affects the time course of the SWA decline during night‐time sleep. To our knowledge, there exists at present no evidence to suggest a compensatory mechanism in the EEG within one sleep episode after caffeine ingestion (such as a SWA rebound in the second or third sleep cycle compensating for a caffeine‐induced SWA reduction in the first sleep cycle or data suggesting caffeine‐induced SWA differences at the end of night‐time sleep). It remains to be tested if we can assume that baseline levels of sleep pressure at the start of the next waking episode are independent of prior evening caffeine intake. In this case, a homeostatic decrease of sleep pressure or sleep need could take place, probably independent of caffeine‐induced adenosine antagonism and even if caffeine hampers the expression of SWA at the beginning of night‐time sleep.

4.2. Effects of chronic caffeine administration on sleep

During daily intake of caffeine the situation changes. As summarised in Figure3, the continuous presence of caffeine and its main metabolite paraxanthine most likely trigger changes in the adenosine system, which may in turn affect sleep. Investigating the effects of regular daily intake in humans is challenging, because it is still unclear for how long an individual must abstain from caffeine to reach a state that is no longer confounded by the prior intake (James,²⁰¹⁴). On the other hand, comparing habitual consumers with non‐consumers may be biased by group differences such as differences in caffeine sensitivity and associated genetic variants in the adenosine system (Retey et al.,²⁰⁰⁷). The currently available evidence indicates that sleep latency and efficiency during night‐time sleep adapt to daily caffeine intake in humans (Bonnet & Arand,¹⁹⁹²; Weibel et al.,²⁰²¹). Sleep in cats under chronic caffeine was shown to normalise in the course of several days after an initial acute increase in waking, but the amount of the deepest stage of sleep remained lower than during baseline (Sinton & Petitjean,¹⁹⁸⁹). In humans, EEG activity in the SWA range during night‐time sleep did not differ after 9 days of caffeine intake (3 × 150 mg/day) when compared to placebo intake for the same duration (Weibel et al.,²⁰²¹). Similarly, chronic caffeine intake in adult mice, but not in pubertal rats (Olini et al.,²⁰¹³), did not elicit clear‐cut differences in NREM sleep SWA compared to a control condition (Panagiotou et al.,²⁰¹⁹). Surprisingly, chronic caffeine ingestion even induced a higher percentage of NREM sleep during the rest phase of the animals (Panagiotou et al.,²⁰¹⁹). Together, the findings indicate that sleep SWA, the classical marker of sleep homeostasis, is not chronically altered during daily caffeine intake. Sleep homeostasis most likely preserves its functions over longer periods of adenosine antagonism. Still, the daily presence of caffeine and metabolites alters sleep EEG power density in other frequency ranges (Panagiotou et al.,²⁰¹⁹; Weibel et al.,²⁰²¹), suggesting that the continuous presence of an adenosine antagonist affects sleep apart from a clear‐cut sleep‐homeostatic effect. Given the observation that an adaptation to daily caffeine was not observed when sleep was scheduled at the wrong circadian phase, such as after an eastward transmeridian travel (Beaumont et al.,²⁰⁰⁴), further indicates that caffeine affects sleep not only by acting on the homeostatic facet of sleep–wake regulation.

The normalisation in the course of the chronic consumption could be caused by changes in sensitivity or tolerance to caffeine (Bhorkar et al.,²⁰¹⁴; Bonnet & Arand,¹⁹⁹²; Dall'Igna et al.,²⁰⁰³; Dubroqua et al.,²⁰¹⁴; Sinton & Petitjean,¹⁹⁸⁹). As illustrated in Figure3, changes in adenosine levels or adenosine receptors could contribute to the observed adaptive effects. It has been shown in rats that adenosine levels were increased under chronic caffeine conditions (Conlay et al.,¹⁹⁹⁷). Furthermore, chronic caffeine administration increased the number of adenosine receptors in rats and mice (Boulenger et al.,¹⁹⁸³; reviewed by Nehlig et al.,¹⁹⁹²). In a recent mouse study, the mice stopped drinking at the start of the rest phase (Panagiotou et al.,²⁰¹⁹). When subsequently the absorbed caffeine is cleared from the system relatively fast, this would markedly decrease the caffeine availability. If adenosine and/or its receptors are increased under the influence of chronic caffeine in mice, this reduction in caffeine would enable the physiological expression of the available adenosine. This then may explain the increased sleep and EEG SWA after the start of the light period.

Similar to the state of research in animals, the extent of tolerance development is still controversial and not clearly established also in humans (Roehrs & Roth,²⁰⁰⁸). A complicating factor in humans is that, in contrast to the experimental protocols used in animals, humans have the possibility to switch to an alternative beverage and to avoid being exposed to caffeine, when adverse effects of caffeine on behaviour or sleep are experienced. Therefore, physiological information on the effects of chronic caffeine on sleep likely stems from individuals who tolerate caffeine relatively well. Nevertheless, epidemiological studies support the idea that increased caffeine use is associated with less sleep or more disturbed sleep, also when caffeine is used chronically (Clark & Landolt,²⁰¹⁷; Roehrs & Roth,²⁰⁰⁸).

4.3. Effects of caffeine on subjective sleepiness

Differences between acute and chronic caffeine intake have also been observed on self‐reported sleepiness. Depending on the duration of prior abstinence and the actual sleep pressure level, caffeine can reduce subjective estimates of sleepiness. These effects are particularly prominent when caffeine administration occurs after >24 h of abstinence and when sleep pressure is high (i.e., during sleep deprivation or after sleep restriction) (Aggarwal et al.,²⁰¹¹; Beaumont et al.,²⁰⁰¹; Dagan & Doljansky,²⁰⁰⁶; Hansen et al.,²⁰¹⁹; Killgore et al.,²⁰⁰⁶; Killgore et al.,²⁰¹²; Killgore & Kamimori,²⁰²⁰; Kohler et al.,²⁰⁰⁶; Landolt et al.,²⁰⁰⁴; Lieberman et al.,²⁰⁰²; Paech et al.,²⁰¹⁶; Patat et al.,²⁰⁰⁰; Penetar et al.,¹⁹⁹³; Wright, Badia, Myers, & Plenzler,¹⁹⁹⁷). When abstinence is <24 h, caffeine has still the potential to elicit feelings of improved alertness, but mainly under conditions of unusually high sleep pressure (Biggs et al.,²⁰⁰⁷; De Valck et al.,²⁰⁰³; De Valck & Cluydts,²⁰⁰¹; Reyner & Horne,²⁰⁰⁰; but see Lohi et al.,²⁰⁰⁷) and not under normal sleep–wake conditions (Bragg et al.,²⁰¹⁷; Kim et al.,²⁰¹³; Lane,¹⁹⁹⁴; but see Hammami et al.,²⁰¹⁰). Consistent therewith, self‐reported caffeine consumption during “typical days” (Chaudhary et al.,²⁰¹⁶) was not associated with daytime sleepiness in a representative sample (Chaudhary et al.,²⁰¹⁶). However, it is important to note that an extra dose of caffeine during regular intake and normal sleep–wake conditions can still induce an acute reduction of subjective sleepiness (Adan et al.,²⁰⁰⁸; Hayashi et al.,²⁰⁰³; Mets et al.,²⁰¹²; Rogers et al.,²⁰¹³). Taken together, the current evidence suggests that caffeine can reduce subjective sleepiness particularly under conditions, which do not regularly occur and where the adenosine system is not accustomed to. Otherwise, the system most likely adapts to regular intake, such that the psychostimulant cannot elicit strong net effects in subjective sleepiness after a certain phase of daily consumption.

Accordingly, when caffeine intake was allowed before sleep deprivation (Erblang et al.,²⁰²¹; Hartley et al.,²⁰¹³; Walsh et al.,¹⁹⁹⁰) or given over several days (Ataka et al.,²⁰⁰⁸; Beaumont et al.,²⁰⁰⁴; James,¹⁹⁹⁸; Weibel et al.,²⁰²⁰), caffeine did not significantly change subjective sleepiness compared to placebo. Similarly, caffeine intake over several days of sleep restriction did not clearly mitigate increased feelings of sleepiness or reduced vigour (Baur et al.,²⁰²⁰; Doty et al.,²⁰¹⁷; James & Gregg,²⁰⁰⁴) nor continuously reduced sleepiness across consecutive simulated night shifts (Schweitzer et al.,²⁰⁰⁶). There exists even empirical evidence for higher sleepiness during daily caffeine intake (Bonnet & Arand,¹⁹⁹²; James & Gregg,²⁰⁰⁴; Wyatt et al.,²⁰⁰⁴), a phenomenon which echoes early clinical case reports of pathological sleepiness during excessive caffeine use (Regestein,¹⁹⁸⁹). As outlined above, we cannot readily explain these apparently paradoxical effects with caffeine‐induced sleep disturbances, because sleep appears to adapt to regular intake over time. As unintentional sleep onsets during long periods of scheduled wakefulness were reduced during chronic caffeine intake (Wyatt et al.,²⁰⁰⁴), a higher sleepiness in these participants may be related to the reduced probability to decrease sleep pressure during short periods of unintentional sleep. Alternatively, the higher sleepiness during chronic intake may mirror a state of withdrawal, which regularly comes to light within the 24‐h cycle, most likely dependent on the pattern of consumption and the individual speed of metabolism. It may reflect a compensatory mechanism of adaptation within the adenosine neuromodulatory system to the sustained presence of an adenosine receptor antagonist.

7.1. Adenosine receptors

Adenosine is generally thought to contribute to sleep–wake regulation by binding to high‐affinity A₁ and A_2A receptors, which are differently expressed in different brain areas and may play distinct roles in the regulation and the control of sleep. Surprisingly and apparently challenging the notion that A₁ binding sites contribute to sleep homeostasis, mice exhibiting constitutive and central nervous system specific, conditional ablation of A₁ receptors showed virtually unaltered sleep–wake behaviour and cognitive functions when studied under baseline sleep–wake conditions (Bjorness et al.,²⁰⁰⁹; Stenberg et al.,²⁰⁰³). Nevertheless, when the conditional knock‐out animals were subjected to prolonged wakefulness, their working memory was impaired and they did not extend their sleep nor showed a normal rebound in EEG SWA in recovery sleep after the sleep deprivation (Bjorness et al.,²⁰⁰⁹). Similarly, early studies suggested that a constitutive knock‐out of A_2A receptors may eliminate the homeostatic regulation of NREM sleep (Hayaishi et al.,²⁰⁰⁴). The findings of more recent work in genetically engineered mice, however, suggest a partly refined interpretation. More specifically, the chemogenetic or optogenetic activation of A_2A receptor expressing cells of the nucleus accumbens strongly induced slow‐wave sleep, yet this intervention did not affect the sleep rebound after sleep deprivation (Oishi et al.,²⁰¹⁷). There is a need for additional studies to clarify whether A₁ receptors contribute to the sleep homeostatic feedback signal and A_2A receptors provide sleep gating and modulate behavioural sleepiness without controlling sleep homeostasis as suggested on the basis of these insights from genetically modified mice (Lazarus et al.,²⁰¹⁹).

In humans, no study has investigated the impact of functional variants of the A₁ receptor gene on the sleep EEG. With respect to the A_2A receptor gene (ADORA2A), the common variant rs5751876 was reported to modulate the EEG in both NREM and REM sleep. In a small case–control sample, EEG alpha activity (~7–10 Hz range) was invariably higher in C/C compared to T/T genotype carriers (Retey et al.,²⁰⁰⁵). More recent, larger studies confirmed this association (Tiechelmann et al., in preparation) and suggested that C‐allele hom*ozygotes exhibit increased time awake (as estimated from wrist actigraphy) and more frequent sleep complaints when compared to T‐allele carriers (Erblang et al.,²⁰²¹; Nova et al.,²⁰¹²). In addition, when an array of eight genetic variants of ADORA2A was simultaneously considered, the rebound in EEG SWA in NREM sleep after sleep deprivation differed between two distinct haplotype groups, suggesting that in humans the functional state of A_2A receptors modulates the dynamics of sleep homeostasis (Landolt,²⁰¹²).

This conclusion was further corroborated by controlled pharmacogenetic studies, which specifically investigated adenosine‐receptor‐mediated processes. Among >4,300 respondents to a brief internet questionnaire about self‐rated caffeine sensitivity and sleep, the level of habitual caffeine consumption was inversely associated with subjectively reduced sleep quality in caffeine‐sensitive respondents, but not in caffeine‐insensitive respondents (Retey et al.,²⁰⁰⁷). Intriguingly, the effects of double‐blind administration of 2 × 200 mg of the stimulant on EEG markers of disturbed sleep confirmed the classification of self‐rated caffeine sensitivity. Although the caffeine concentration in saliva did not differ, the stimulant induced sleep EEG characteristics of insomnia and attenuated the repercussions of prolonged wakefulness on psychom*otor vigilance and the SWA rebound in recovery NREM sleep exclusively in C‐allele carriers of the ADORA2A polymorphism rs5751876 (Bodenmann et al.,²⁰¹²; Retey et al.,²⁰⁰⁷). Together, the convergent results of this series of experiments suggest that genetic variants of ADORA2A alter the accumulation of homeostatically‐regulated sleep propensity during prolonged wakefulness. Thus, in humans, the A_2A receptor may be part of the molecular machinery regulating sleep homeostasis.

7.2. Adenosine formation and breakdown

Given that astrocytes are an important source of extracellular adenosine, astrocytes may also be a crucial component of sleep homeostatic signalling mechanisms. Indeed, mice carrying a conditional, dominant‐negative form of the SNARE (dnSNARE) protein that controls adenosine release from activated astrocytes, demonstrated a sleep–wake phenotype that was remarkably reminiscent of conditional A₁ receptor knock‐out animals (Bjorness et al.,²⁰⁰⁹; Halassa et al.,²⁰⁰⁹). The genetic construct eliminated the responses to A₁ receptor antagonists in vitro and in vivo, but conserved the actions of A₁ receptor agonists, which supports the notion that the genetic intervention eliminated the release of ATP by the astrocytes. Also the dnSNARE mice showed normal sleep at baseline but they lacked the SWA response to sleep deprivation (Halassa et al.,²⁰⁰⁹). In contrast to the A₁ receptor knock‐outs, however, the dnSNARE mice did not show cognitive deficits associated with sleep loss. This study suggests that the sleep homeostatic feedback signal includes astrocyte‐derived adenosine. The effects on sleep–wake regulation in mice with engineered mutations to reduce or enhance the expression of AdK, which is primarily expressed in astrocytes, are consistent with this hypothesis. They indicate that AdK could orchestrate signalling pathways involved in generating EEG oscillations that mark sleep–wake regulation (Palchykova et al.,²⁰¹⁰).

As mentioned above, deamination of adenosine to inosine by ADA occurs primarily under conditions with elevated adenosine levels (Borea et al.,²⁰¹⁸). In rodents, ADA is expressed in sleep–wake regulatory brain regions and exhibits region‐specific diurnal variation of enzymatic activity (Chagoya de Sanchez et al.,¹⁹⁹³; Okada et al.,²⁰⁰³). Pharmacological inhibition of ADA, elevated extracellular adenosine levels and prolonged the duration of slow‐wave sleep (Radulovacki,¹⁹⁸⁵). In humans, the gene encoding ADA is naturally polymorphic. Functional experiments revealed that heterozygous carriers of a non‐synonymous rs73598374 polymorphism of the ADA gene (referred to as G/A genotype) showed reduced breakdown of adenosine to inosine when compared to hom*ozygous carriers of the major allele (G/G genotype). Independent data from different studies and laboratories confirmed that G/A allele carriers exhibited elevated EEG delta power in NREM sleep and enhanced activity in theta/alpha frequencies (~6–12 Hz range) in all behavioural states when compared to G/G allele carriers (Bachmann et al.,²⁰¹²; Mazzotti et al.,²⁰¹²; Retey et al.,²⁰⁰⁵). Interestingly, the difference in the NREM sleep EEG was most pronounced in the 0.75–1.5 Hz range and persisted in baseline and recovery nights after sleep deprivation (Bachmann et al.,²⁰¹²). Similarly, waking EEG alpha (8–12 Hz) activity was invariably higher in G/A allele carriers than in G/G genotype individuals throughout 40 h of prolonged wakefulness (Bachmann et al.,²⁰¹²). The genotype‐related differences were not the consequence of different habitual sleep duration nor reflected an altered homeostatic response to sleep–wake history.

In contrast to the neurophysiological signals, self‐rated sleepiness did not differ between the ADA genotypes when sleep pressure was low. However, after sleep deprivation the G/A allele carriers were sleepier than the G/G allele carriers (Bachmann et al.,²⁰¹²; Reichert et al.,²⁰¹⁴). These observations may be consistent with a primary role of ADA to clear elevated adenosine levels and suggest that functional genetic variation of ADA in humans contributes to individual variation in sleep‐associated variables that reflect adaptive sleep homeostatic processes.

8.1. Hypersomnia disorders and excessive daytime sleepiness

In the doses commonly consumed from coffee and tea (~150–500 mg/day), acute caffeine intake promotes vigilance, attention and mood by blocking A₁ and A_2A receptors, particularly in conditions of insufficient sleep and increased sleepiness (Baur et al.,²⁰²⁰; Jarvis,¹⁹⁹³; Landolt et al.,²⁰⁰⁴; Lieberman et al.,²⁰⁰²; Penetar et al.,¹⁹⁹³; Wyatt et al.,²⁰⁰⁴). Coffee and caffeine were among the earliest treatment recommendations for excessive daytime sleepiness in narcolepsy (Redlich,¹⁹²⁵). Although there are more potent medications available today, as long as the diagnosis is lacking, many patients with narcolepsy “self‐medicate” with high amounts of caffeine to improve their alertness (Thorpy & Dauvilliers,²⁰¹⁵). Evidence from transgenic mice suggests that the alerting effects of caffeine are specifically mediated by antagonising A_2A receptors (Huang et al.,²⁰⁰⁵). Moreover, studies in rats revealed that the preferential A_2A (but also A₁) receptor antagonist, JNJ‐40255293, dose‐dependently enhanced wakefulness without affecting dopamine and noradrenaline release in prefrontal cortex and striatum (Atack et al.,²⁰¹⁴). Adenosine A_2A and dopamine D₂ receptors are co‐localised on medium spiny neurones of the indirect pathway in the striatum (Lazarus et al.,²⁰¹⁹). Activation of the excitatory A_2A binding sites of this pathway strongly induces sleep (Oishi et al.,²⁰¹⁷), whereas a blockade of A_2A receptors on these cells enhances dopaminergic neurotransmission by functional A_2A‐D₂ receptor antagonism (Figure2). The A_2A receptor was thus proposed to provide a promising target as add‐on treatment to ameliorate motor and non‐motor symptoms such as fatigue in Parkinson's disease (Schwarzschild et al.,²⁰⁰⁶). In an attempt to test this hypothesis, caffeine (up to 400 mg/day) failed to reduce daytime sleepiness in a randomised controlled trial (RCT) in patients with Parkinson's disease (Postuma et al.,²⁰¹²). However, the study did not control for caffeine consumption, sleep–wake history, nor common genetic variations in the A_2A receptor gene (ADORA2A). This is important, because the effects of caffeine depend on chronic caffeine intake, sleep pressure, as well as on polymorphisms of ADORA2A (see above). The prospective selection of study participants with predefined ADORA2A genotype is a powerful new paradigm to obtain reliable outcomes in clinical trials testing the responses to coffee, caffeine, and other adenosine receptor antagonists (Baur et al.,²⁰²⁰; Bodenmann et al.,²⁰¹²; Chen & Cunha,²⁰²⁰). Such studies may show that antagonists with more selective affinity for the A_2A receptor (e.g., istradefylline) have a more favourable safety profile to promote wakefulness when compared to high doses of caffeine or psychostimulants that can disturb sleep and cause anxiety and dependence.

8.2. Insomnia and anxiety‐related disorders

Disturbed sleep and increased anxiety are typically seen when large amounts of caffeine (>500 mg/day) are chronically ingested (Bonnet & Arand,¹⁹⁹²). Furthermore, it has long been noted that in sensitive people (e.g., patients with anxiety disorders) caffeine consumption (of 10 mg/kg) can cause symptoms of anxiety and panic attacks, which are related to the plasma caffeine levels (Charney et al.,¹⁹⁸⁵). Moreover, healthy people with polymorphisms in the ADORA2A gene exhibit elevated risk of anxiety symptoms when consuming normal amounts of caffeine‐containing products (Alsene et al.,²⁰⁰³). Given that ADORA2A polymorphisms also modulate subjective and objective effects of caffeine on sleep quality, sleep architecture and the sleep EEG, it may be that the adenosine system could contribute to the neurobiological mechanism linking disturbed sleep and anxiety/anxiety‐related disorders (van Calker et al.,²⁰¹⁹).

Indeed, independent of caffeine, insomnia often co‐occurs with anxiety/anxiety‐related disorders (Jansen et al.,²⁰¹⁹) and functional genetic variants in adenosine receptors can predispose people to elevated trait anxiety and anxiety disorders (Geiger et al.,²⁰¹⁶; Hohoff et al.,²⁰¹⁰; Hohoff et al.,²⁰¹⁴). Some of these polymorphisms may affect the functional connectivity in core brain networks that process and regulate emotions and sleep, including the cingulate cortex, insula, and amygdala. The functional connectivity within these networks is altered in certain patients with anxiety disorders and insomnia (Chellappa & Aeschbach,²⁰²²). Notwithstanding, large genome‐wide association studies failed to provide evidence for enriched variant adenosinergic genes in patients with insomnia (Jansen et al.,²⁰¹⁹; Van Someren,²⁰²¹). Research is needed to elucidate whether such associations would emerge when hom*ogenous disease subtypes or states are considered. In addition, similar to chronic caffeine consumption and constitutive genetic knock‐out animal models, compensatory mechanisms may obscure the possible impact of functional gene variants on disease phenotypes.

Even though the accumulated evidence suggests that pharmacological activation of adenosine receptors may promote physiological sleep mechanisms, the use of adenosine receptor agonists for clinical applications in insomnia and other sleep–wake disorders faces important challenges. On one hand, available adenosine analogues hardly penetrate the blood–brain barrier. On the other hand, adenosine receptors are widely expressed in most tissues and organs and conventional adenosine analogues are likely to cause a variety of unwanted responses (e.g., adverse cardiovascular effects). Previous attempts to develop agonists that target adenosine receptors in tissue/organ specific manner have had limited success. Thus, the pharmacological enhancement of endogenous adenosine signalling, or the reduction of adenosine degradation may be more promising (Chen et al.,²⁰¹³). One such possibility is the development of allosteric enhancers. These compounds lack agonistic activity per se but may amplify the action of endogenous ligands at their receptors by stabilising the ligand–receptor complex (Ferre et al.,²⁰¹⁴). For example, benzodiazepines and Z‐drugs are positive allosteric modulators of GABA_A receptors. With respect to adenosine, a small, blood–brain‐barrier‐permeable positive allosteric modulator of A_2A receptors referred to as A_2AR PAM‐1 was recently shown to promote slow‐wave sleep in mice (Korkutata et al.,²⁰¹⁹). This compound specifically enhanced A_2A receptor signalling in the brain, without causing the typical unwanted cardiovascular complications of conventional A_2A receptor agonists. Clinical studies are needed to determine whether allosteric enhancers of adenosinergic neurotransmission have the potential to ameliorate sleep quality and sleep efficiency in patients with insomnia and neuropsychiatric disorders.

8.3. Restless legs syndrome

Restless legs syndrome (RLS) is frequently associated with insufficient iron availability in the brain (Manconi et al.,²⁰²¹). Preclinical studies suggest that brain iron deficiency can cause a hypo‐adenosinergic state and a disruption of the fine‐tuned balance of adenosine‐dopamine‐glutamate neurotransmission in the striatum (Ferre et al.,²⁰¹⁸). This evidence led to the recent hypothesis that pharmacologically increased extracellular adenosine concentrations may improve sensorimotor and sleep symptoms in RLS (Garcia‐Borreguero et al.,²⁰¹⁸). Consistent with this idea, blockade of adenosine reuptake by dipyridamole, a non‐selective ENT1/ENT2 inhibitor clinically used as vasodilator and inhibitor of blood platelet aggregation, proved therapeutic efficacy in RLS by reducing periodic limb movements during sleep, shortening sleep latency, increasing sleep efficiency, and enhancing the duration and proportion of slow‐wave sleep (Garcia‐Borreguero et al.,²⁰²¹).

Also other blockers of adenosine reuptake may ameliorate RLS. Based on anecdotal evidence from patients and case reports, the consumption of recreational marijuana products can improve sensorimotor symptoms and the quality of sleep in RLS (Sullivan & Winkelman,²⁰²⁰). The underlying mechanisms for these observations may be complex and have not been elucidated, and RCTs such as with dipyridamole are lacking. Nevertheless, it is interesting to note that one of the most abundant components in the native cannabis plant, cannabidiol, inhibits the ENT1 (Carrier et al.,²⁰⁰⁶). Together with the evidence outlined above, the data provide convergent support of a role for adenosine in RLS. Strategies that increase endogenous adenosine levels or specifically target adenosine receptors or nucleoside transporters may provide therapeutic benefits for patients with this neurological disorder. Future studies that elucidate whether the beneficial effects of dipyridamole and cannabidiol on RLS symptoms indeed reflect enhanced adenosinergic neurotransmission or another action of these non‐selective compounds (e.g., (Friedman & Devinsky,²⁰¹⁵) are warranted.

8.4. Depressive disorders

Depending on the severity of symptoms, 60%–90% of patients with a major depressive episode present with disturbed sleep (Argyropoulos et al.,²⁰⁰⁵). Notwithstanding, acute sleep deprivation ‐ or “wake therapy” ‐ improves depressive symptoms in ~60% of all patients (Wirz‐Justice & Van den Hoofdakker,¹⁹⁹⁹). The antidepressant response of sleep deprivation is quantitatively similar to what can be achieved after several weeks of available standard treatments, including pharmaco‐, psycho‐ and electroconvulsive therapies (Wu & Bunney,¹⁹⁹⁰). Unfortunately, the wakefulness‐induced mood improvement is typically short‐lived and followed by a relapse into the depressive state upon recovery sleep (Boland et al.,²⁰¹⁷). This characteristic of sleep‐deprivation therapy prohibits persistent remission. Nevertheless, the unique psychopathological switch‐phenomenon of rapid onset and offset of depressive symptoms in relation to wakefulness and sleep represents a powerful paradigm to study the pathophysiology of depressed mood. Insights gained from such research may lead to more rapidly acting antidepressant treatments that are urgently needed.

Several models were proposed to explain the antidepressant response to sleep deprivation; a comprehensive review of the different theories is beyond the scope of this article. Within the conceptual framework of the “Two‐Process” model, Borbély and Wirz‐Justice hypothesised that depression is associated with a deficient build‐up of homeostatic sleep propensity during wakefulness (Borbély & Wirz‐Justice,¹⁹⁸²). Accordingly, after a normal duration of wakefulness sleep propensity would not reach the level attained by non‐depressed individuals, resulting in “depression‐like” sleep structure and reduced EEG SWA in NREM sleep. The model proposed that the deficient S‐process in depressive patients is normalised by sleep deprivation. Although the underlying biochemical/molecular mechanisms are still elusive, the available findings confirm that increased process S is a core mechanism underlying the antidepressant efficacy of wake therapy (Dallaspezia & Benedetti,²⁰¹⁵).

Convergent lines of evidence indicate that adenosine could contribute to the neurobiological link between sleep and mood regulation and that depression and antidepressant interventions may alter adenosinergic signalling and purine metabolism in the brain. For example, polymorphisms in adenosine related genes, including the genes encoding ADA (rs6031682 and rs452159) and ENT3 (rs12256138), were associated with a lower risk of depression and disturbed sleep (Gass et al.,²⁰¹⁰). While sex differences in adenosinergic mechanisms may be important (Gass et al.,²⁰¹⁰; Pierling et al.,²⁰²¹), female depressed patients who responded to the serotonin‐reuptake inhibitor fluoxetine, also exhibited 30% lower brain ATP levels as quantified with magnetic resonance spectroscopy than treatment non‐responders (Renshaw et al.,²⁰⁰¹). Reduced adenosinergic signalling may thus predispose to depression, whereas increased adenosinergic signalling may elicit antidepressant efficacy.

These hypotheses were tested in a behavioural model of chronic despair in genetically engineered mice (Serchov et al.,²⁰¹⁵). Although animal models of neuropsychiatric disorders have to be evaluated with caution, mice with conditionally enhanced A₁ receptor expression on forebrain neurones appeared to be protected against acute and chronic depressive‐like behaviour. Conversely, genetically‐induced A₁ receptor deficiency sensitised the animals to depressive‐like behaviour and precluded the antidepressant‐like response of sleep deprivation.

Recent findings in mice suggest that the immediate early gene Homer1a and metabotropic glutamate receptors of subtype 5 (mGluR5) may link sleep–wake related changes in A₁ receptor signalling to the antidepressant‐like effects of sleep deprivation and antidepressant medications in mice (Holz et al.,²⁰¹⁹; Serchov et al.,²⁰¹⁵). These molecules are required for sleep–wake related changes in synaptic plasticity in vitro and the weakening of synapses during sleep in mice (de Vivo et al.,²⁰¹⁷; Diering et al.,²⁰¹⁷; Hu et al.,²⁰¹⁰). More specifically, Homer1a is a core brain molecular correlate of sleep loss, responds to waking‐induced increased extracellular adenosine levels, enhances mGluR5 signalling, and uncouples mGluR5 from the downstream signalling cascades during sleep (Holz et al.,²⁰¹⁹; Maret et al.,²⁰⁰⁷; Martin et al.,²⁰¹⁹). Consistent with the notion that Homer1a induction contributes to the antidepressant effect of sleep deprivation, specific knock‐down of Homer1a in the medial prefrontal cortex (mPFC) enhanced depressive‐like behaviour and prevented the antidepressant effects of A₁ receptor up‐regulation, sleep deprivation, and different pharmacological interventions (Serchov et al.,²⁰¹⁵). Subsequent studies in transgenic mice revealed that the antidepressant effect of sleep deprivation and Homer1a induction are mediated by mGluR5 in forebrain excitatory neuronws and depend on the synaptic expression and activity of glutamatergic α‐amino‐3‐hydroxy‐5‐methyl‐4‐ isoxazolepropionic acid (AMPA) receptors (Holz et al.,²⁰¹⁹). Mice without functional mGluR5 exhibit severe dysregulation of sleep–wake homeostasis, including lack of recovery sleep, and impaired behavioural adjustment after sleep deprivation (Holst et al.,²⁰¹⁷).

Data in humans are consistent with these ideas derived from preclinical research. First, a combined genome‐wide association, replication and neuroimaging study provided convergent evidence that the human gene HOMER1 plays a role in the aetiology of major depression (Rietschel et al.,²⁰¹⁰). The authors suggested that the HOMER1 genetic variation affects depression by a dysregulation of cognitive and motivational processes. Furthermore, in healthy volunteers, the availability of mGluR5 correlates with changes in physiological and behavioural markers of sleep need after prolonged wakefulness and recovery sleep. Quantified with receptor‐specific positron emission tomography, prolonged wakefulness increased the density of A₁ receptors (Elmenhorst et al.,²⁰⁰⁷). Furthermore, mGluR5 availability in the cerebral cortex correlated with NREM sleep “high delta” (2–4 Hz) activity in baseline and after sleep deprivation, as well as increased high delta power, elevated sleepiness, and involuntary sleep intrusions during waking after a night without sleep (Hefti et al.,²⁰¹³; Holst et al.,²⁰¹⁷). Importantly, the elevated availability of A₁ receptors and mGluR5 after sleep loss returned to baseline levels after recovery sleep (Elmenhorst et al.,²⁰¹⁷; Weigend et al.,²⁰¹⁹). Finally, the density of mGluR5 was reported to be reduced in depressed patients (Deschwanden et al.,²⁰¹¹). Future research may establish whether therapeutic sleep deprivation normalises mGluR5 density and whether changes in receptor expression are related to the antidepressant efficacy.

Taken together, based on the convergent preclinical and clinical findings outlined above, we hypothesise that sleep loss‐induced changes in A₁ receptors (and mGluR5) could contribute to the neurochemical mechanisms underlying the rapid mood enhancing effect of sleep deprivation therapy. Interestingly, a recent meta‐analysis of observational studies including almost 370,000 adults from the general population demonstrated that coffee and caffeine consumption was dose‐dependently associated with decreased risk of depression (Wang et al.,²⁰¹⁶). This study does not permit conclusions regarding the presence of a causal relationship between coffee/caffeine intake and depression nor the underlying mechanisms for the observed association. Future research is warranted, to investigate the roles of adenosine‐modulated neurotransmission and its impact on homeostatic and circadian sleep–wake regulatory processes for the antidepressant efficacy of therapeutic sleep deprivation.

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