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

Abstract

Summary 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.

Effects of Chronic Caffeine Consumption on Synaptic Function, Metabolism and Adenosine Modulation in Different Brain Areas

“…These observations further support the previous conclusion that the regular consumption of caffeine does not trigger behavior or neurophysiological modifications but instead prevents modifications caused by deleterious factors such as sleep, fatigue or triggers of brain damage (reviewed in [29]). Importantly, the present study focused on behavior and neurophysiological alterations related to locomotion, mood and memory, and it still remains to be tested if the chronic consumption of caffeine might impact on other important behavioral outputs known to be controlled by caffeine such as circadian rhythm [65], sleep/arousal [66], addition [67], food intake [68], vascular control [69] or changes in the properties of the blood brain barrier [70].…”

Sepsis-induced changes in spectral segregation and kinetics of brain oscillatory states

“…Although the molecular drivers of sleep homeostasis are not yet fully known, in ammation has been shown to affect expression molecules linked to sleep regulation, like BDNF and adenosine 2A receptors. [33][34][35][36][37][38] Additionally, cytokine signaling plays an important role in regulating sleep pressure under normal circumstances. 10 To investigate possible causes of oscillatory state switching within the hippocampal network we used a power spectrum-based state-space approach.…”

Precision caffeine therapy for apnea of prematurity and circadian rhythms: New possibilities open up

“…Nonetheless, it can be summarized that caffeine affects the sleep patterns in preterm infants, especially the AS and wakefulness, and the effects might persist into the childhood and even the adulthood. If this hypothesis holds true, then the inhibition of adenosine receptors by caffeine would exactly explain the altered sleep-wake states in preterm infants, as the association between caffeine, adenosine, and sleep has been well documented in adults ( Huang et al, 2011 ; Porkka-Heiskanen and Kalinchuk, 2011 ; Huang et al, 2014a ; Urry and Landolt, 2015 ; Reichert et al, 2022 ). In addition, the alteration of sleep-wake patterns might be partially responsible for the caffeine-induced increase in cerebral cortical activity ( Supcun et al, 2010 ; Hassanein et al, 2015 ) and decrease in apneic episodes ( Dietrich et al, 1978 ; Montandon et al, 2009 ; Seppä-Moilanen et al, 2019 ; Seppä-Moilanen et al, 2021 ).…”

“…The increased cytosolic cAMP/Ca 2+ activates the protein kinase A (PKA) and Ca 2+ /calmodulin-dependent protein kinase Ⅱ (CaMKⅡ), thereby leading to the phospho-dependent activation of cAMP response element binding protein (CREB), which in concert with its coactivators to activate the cAMP response element (CRE) ( Narishige et al, 2014 ; Harvey et al, 2020 ; Reichert et al, 2022 ). Besides, the increased intracellular Ca 2+ levels also result in the phosphorylation of extracellular regulated protein kinases (ERK), which drives to form the activator protein 1 (AP-1) transcription factor ( Jagannath et al, 2021 ).…”