Adenosine: A Mediator of the Sleep-Inducing Effects of Prolonged Wakefulness

Abstract

Both subjective and electroencephalographic arousal diminish as a function of the duration of prior wakefulness. Data reported here suggest that the major criteria for a neural sleep factor mediating the somnogenic effects of prolonged wakefulness are satisfied by adenosine, a neuromodulator whose extracellular concentration increases with brain metabolism and which, in vitro, inhibits basal forebrain cholinergic neurons. In vivo microdialysis measurements in freely behaving cats showed that adenosine extracellular concentrations in the basal forebrain cholinergic region increased during spontaneous wakefulness as contrasted with slow wave sleep; exhibited progressive increases during sustained, prolonged wakefulness; and declined slowly during recovery sleep. Furthermore, the sleep-wakefulness profile occurring after prolonged wakefulness was mimicked by increased extracellular adenosine induced by microdialysis perfusion of an adenosine transport inhibitor in the cholinergic basal forebrain but not by perfusion in a control noncholinergic region.Abundant experimental evidence supports the commonsense notion that prolonged wakefulness decreases the degree of arousal, which is usually measured as electroencephalographic activation (EEG arousal to the duration of prior wakefulness (1). What might be the neural mediator of this effect of prior wakefulness? Our laboratory has provided evidence that the basal forebrain and mesopontine cholinergic neurons whose discharge activity plays an integral role in EEG arousal (2) are under the tonic inhibitory control of endogenous adenosine, an inhibition that is mediated postsynaptically by an inwardly rectifying potassium conductance and by an inhibition of the hyperpolarization-activated current (3). Adenosine is of particular interest as a putative sleep-wakefulness neuromodulator (4) because (i) the production and concentration of adenosine in the extracellular space have been linked to neuronal metabolic activity (5); (ii) neural metabolism is much greater during wakefulness (W) than during delta slow wave sleep (SWS) (6); and (iii) caffeine and theophylline are powerful blockers of electrophysiologically relevant adenosine receptors, promoting both subjectively and EEGdefined arousal while suppressing recovery sleep after deprivation (7). Our laboratory has recently demonstrated that microdialysis perfusion of adenosine in the cholinergic basal forebrain and the mesopontine cholinergic nuclei reduces wakefulness and EEG arousal (8).Although the preceding evidence is consistent with adenosine as a neural sleep factor mediating the somnogenic effects of prolonged EEG arousal and wakefulness, key questions relevant to a demonstration of this role have remained unaddressed. (i) Are brain extracellular adenosine concentrations higher in spontaneous W than in SWS? (ii) Do adenosine concentrations increase with increasing duration of W and then decline slowly as recovery sleep occurs after W? (iii) Do pharmacological manipulations increasing brain adenosine concentra...

Effects of Caffeine are more Marked on Daytime Recovery Sleep than on Nocturnal Sleep

“…The stimulant effects of caffeine on the central nervous system at doses obtained through normal human consumption are due to caffeine's ability to antagonize adenosine receptors (Fredholm et al, 1999). Numerous reports have corroborated that adenosine is a neuromodulator that is involved in sleep regulation Benington et al, 1995;Porkka-Heiskanen et al, 1997;Radulovacki et al, 1982Radulovacki et al, , 1985Satoh et al, 1996Satoh et al, , 1999Scammell et al, 2001;Schwierin et al, 1996;Strecker et al, 2000;Ticho and Radulovacki, 1991;Urade et al, 2003). It has recently been proposed that in humans, caffeine mimics the effects of a reduction in sleep homeostasis during prolonged wakefulness (Landolt et al, 2004).…”

Normal Sleep and Circadian Rhythms: Neurobiologic Mechanisms Underlying Sleep and Wakefulness

“…Adenosine accumulates in certain areas of the brain when neurons consume energy in the form of ATP during prolonged wakefulness. In animal studies, adenosine levels in the brain increased during sleep deprivation and returned to baseline during sleep [14], [25], [26] . Other substances hypothesized to be involved in promoting sleep and contributing to the homeostatic factor include proinflammatory cytokines (interleukin-1) [18], [27] prostaglandin D 2 , and growth hormone-releasing hormone [27] .…”

“…Humans cannot remain awake voluntarily for longer than 2 to 3 days, and rodents cannot survive without sleep for longer than few weeks [10], [14] . The homeostatic factor represents an increase in the need for sleep (sleep pressure) with increasing duration of prior wakefulness.…”

Differential Effects of Caffeine on Dopamine and Acetylcholine Transmission in Brain Areas of Drug-naive and Caffeine-pretreated Rats

“…Thus, cholinergic nuclei of the mesopontine tegmentum (Ch 5 -Ch 6 nuclei, according to the nomenclature of Mesulam et al (1983)) are tonically inhibited by adenosine through an action onto A 1 receptors (Rainnie et al 1994). Prolonged wakefulness is associated to enhanced adenosine concentrations in the basal forebrain (Porkka-Heiskanen et al 1997) as a result of local brain metabolism; moreover, induction of SW sleep is associated to increased levels of adenosine in brain (Strecker et al 2000). On this basis it has been suggested that adenosine is an endogenous sleep factor (Strecker et al 2000) and modulates EEGarousal through ACh projections to the cortex (Portas et al 1997;Rainnie et al 1994;Strecker et al 2000).…”