Adenosine, caffeine, and sleep-wake regulation: state of the science and perspectives

Abstract

For hundreds of years, mankind has been influencing its sleep and waking state through the adenosinergic system. For ~100 years now, systematic research has been performed, first started by testing the effects of different dosages of caffeine on sleep and waking behaviour. About 70 years ago, adenosine itself entered the picture as a possible ligand of the receptors where caffeine hooks on as an antagonist to reduce sleepiness. Since the scientific demonstration that this is indeed the case, progress has been fast. Today, adenosine is widely accepted as an endogenous sleep-regulatory substance. In this review, we discuss the current state of the science in model organisms and humans on the working mechanisms of adenosine and caffeine on sleep. We critically investigate the evidence for a direct involvement in sleep homeostatic mechanisms and whether the effects of caffeine on sleep differ between acute intake and chronic consumption. In addition, we review the more recent evidence that adenosine levels may also influence the functioning of the circadian clock and address the question of whether sleep homeostasis and the circadian clock may interact through adenosinergic signalling. In the final section, we discuss the perspectives of possible clinical applications of the accumulated knowledge over the last century that may improve sleep-related disorders. We conclude our review by highlighting some open questions that need to be answered, to better understand how adenosine and caffeine exactly regulate and influence sleep.

Keywords: chronic caffeine; circadian; genetics; sleep deprivation; sleep homeostasis; sleep-wake disorder.

FIGURE 1

Timeline of sleep and circadian research discoveries demonstrating a role for adenosine in sleep–wake regulation (see text). ATP, adenosine triphosphate; EEG, electroencephalography; (N)REM, (non‐) rapid eye movement

FIGURE 2

Simplified schematic representation of adenosine formation, transport and metabolism in a hypothetical tripartite synapse consisting of a presynaptic terminal, a postsynaptic spine, and an astrocyte. Only selected processes and pathways mentioned in the text are shown (please see text for more detailed information). Neurones, astrocytes, and microglia can release adenosine and adenosine triphosphate (ATP). The unique co‐localisation and functional interactions among the G‐protein coupled adenosine (red), dopamine (green) and metabotropic glutamate receptors (blue) on striato‐pallidal neurones and circuits suggest a hypothesised integration of adenosine‐dopamine‐glutamate signalling and synaptic plasticity. 5′‐ENs, 5′‐ecto‐nucleotidases; 5′‐N, 5′‐nucleotidase; A₁, A_2A, adenosine A₁ and A_2A receptors; AC, adenylyl cyclase; ADA, adenosine deaminase; AdK, adenosine kinase; Ado, adenosine (red dots); ADP, adenosine diphosphate; AMP, adenosine monophosphate; CaMKII, Ca²⁺/calmodulin‐dependent protein kinase II; cAMP, cyclic adenosine monophosphate; CCPA, 2‐chloro‐N⁶‐cyclopentyladenosine; CPA, N⁶‐cyclopentyladenosine; CREB, cAMP responsive element binding protein; D₂, dopamine D₂ receptor; DAG, diacyl‐glycerol; EEG, electroencephalography; ENT, equilibrative nucleoside transporters; ER, endoplasmic reticulum; Glu, glutamate (blue dots); Ino, inosine; IP₃, inositol‐tri‐phosphate; mGluR5, metabotropic glutamate receptor of subtype‐5; PKC, PKA, protein kinase C and A; SAH, S‐adenosyl‐homocysteine; SAHH, S‐adenosyl‐homocysteine hydrolase

FIGURE 3

Simplified illustration of the impact of caffeine intake in the brain. (a) Approximately 30 min after oral intake, caffeine reaches the central nervous system and blocks adenosine A₁ and A_2A receptors. There is evidence in the animal domain that caffeine's main metabolite paraxanthine has similar affinity as caffeine (Snyder et al., 1981) to both receptors (Chou & Vickroy, 2003) and disturbs NREM sleep (Okuro et al., 2010). Beside caffeine itself, paraxanthine may therefore contribute to the wake‐promoting potential. (b) Typical reduction of SWA and increased sigma frequency activity in NREM sleep after acute caffeine intake (data from Landolt, Dijk, et al., 1995). Black triangles denote frequency bins in which power density after caffeine intake significantly differed from placebo (p < 0.05, paired t tests). (c) during daily repeated caffeine intake, the adenosine system may adapt to the daily presence of the stimulant. Animal studies suggest that plasma adenosine levels rise during daily intake (Conlay et al., 1997). Additionally, some studies suggest an upregulation in A₁ receptors (Boulenger & Marangos, ; Ramkumar et al., ; Shi et al., ; but also see Espinosa et al., ; Johansson et al., ; Johansson et al., ; Nabbi‐Schroeter et al., 2018). To our knowledge, an upregulation of A_2A receptors has not been observed (Espinosa et al., ; Johansson et al., ; Shi et al., 1993). The effects of regular caffeine consumption on its own metabolism are controversial and need to be further investigated. The available studies reported either no influence on, stimulation or inhibition of caffeine pharmacokinetic measures by chronic caffeine intake (Nehlig, 2018). We hypothesise that both pharmacodynamic and pharmacokinetic changes could underlie the different effects of caffeine on the sleep EEG during daily (versus acute) intake of the stimulant. (d) NREM sleep EEG SWA in human volunteers was not significantly reduced during daily caffeine intake, whereas sigma activity was lower compared to placebo intake (data from Weibel et al., ; statistics adapted regarding conditions). Black triangles indicate frequency bins in which paired t tests revealed a significant difference between caffeine and placebo (p < 0.05, paired t tests). EEG, electroencephalography; (N)REM, (non‐) rapid eye movement; SWA, slow‐wave activity

FIGURE 4

Effects of sleep deprivation (SD) and caffeine (Caff) treatment on input pathways, the suprachiasmatic nuclei (SCN) and behavioural functions. The SD does not change the electroretinogram (ERG, left panel) (Schoonderwoerd et al., 2022). In the SCN (middle panel, van Diepen et al., 2014), SD reduces the amplitude of the circadian modulation of SCN neuronal activity (Deboer et al., 2007) and the light‐induced increase in firing rate in SCN neurones (van Diepen et al., 2014). The latter can be reversed by Caff treatment (van Diepen et al., 2014). In humans, higher slow‐wave activity (SWA) in the beginning of the night predicts a lower functional magnetic resonance imaging (fMRI) blood‐oxygen‐level‐dependent (BOLD) response in an SCN encompassing region during task performance in the evening (Schmidt et al., 2009). On the output side, when analysing rest‐activity behaviour (right, here of a night‐active animal), SD in most cases, reduces light induced behavioural phase shifts (Burgess, ; Challet et al., ; Mistlberger et al., ; van Diepen et al., 2014). An exception to this was suggested to indicate a difference between diurnal and nocturnal animals (Jha et al., 2017). Caff treatment increases the phase‐shift response to light particularly at the end of the active phase (Jha et al., ; Ruby et al., 2018). In addition, Caff seems to slow down the circadian clock (Burke et al., ; Oike et al., ; Ruby et al., ; van Diepen et al., 2014) in both diurnal and nocturnal animals. This is also the case in vitro (Burke et al., ; Oike et al., 2011) and mirrored in humans after acute Caff intake in the evening by a phase‐delay of the dim‐light melatonin onset (Burke et al., 2015) and during daily caffeine intake by a later bedtime when compared to placebo (Weibel et al., 2021)