Abstract
Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state.
Highlights
In this study we extend this approach to the basal forebrain (BFB), which is causally linked to the homeostatic control of sleep
To demonstrate the generality of our results we have examined the relationship between adenosine release and sleep status in three species: rats, mice, and Djungarian hamsters
Adenosine release was not significantly different in presence or absence of Ca2+ in either the BFB (Ca2+-free: 2.2160.74 mM; 2 mM Ca2+: 2.8261.33 mM; figure 2b) or cortex (Ca2+-free: 7.6062.08 mM; 2 mM Ca2+: 6.4061.92 mM; figure 2c) according to the Wilcoxon signed-rank test, n = 7. These results indicate that the mechanism of AMPA-evoked adenosine release in this in vitro preparation is independent of both intra- and extracellular Ca2+, indicating that it may not be mediated by vesicular exocytosis
Summary
The endogenous somnogen adenosine is a key mediator of sleep homeostasis. Adenosine or adenosine receptor agonists enhance sleep [1,2,3,4,5]. Adenosine receptor antagonists such as theophylline and caffeine are known stimulants that prevent sleep (for a review see [6]).The levels of adenosine increase throughout the brain during wakefulness and decrease during sleep, and this is notable in the basal forebrain (BFB), part of the ascending arousal system [7,8,9]. Identifying the mechanisms of adenosine production, release and activity are vital to understanding its role in sleep homeostasis
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