Adenosine and sleep homeostasis in the basal forebrain: commentary on Blanco-Centurion et al. (2006).

1381 THE VERY IMPORTANT AND WELL-DESIGNED STUDY BY BLANCO-CENTURION ET AL.1 HAS ESTABLISHED THAT NEITHER THE ACTIVITY OF THE BASAL FOREBRAIN (BF) cholinergic neurons, which release adenosine (AD), nor the accumulation of AD in the BF during wake is necessary for sleep drive. These findings run against the hypothesis that AD released from the BF during waking is responsible for sleep homeostasis1-2 and also against the notion that localized buildup of AD during waking shuts off the activity of the cholinergic BF neurons—a necessary step for sleep drive.3 So, what do we now believe is the mechanism of AD hypnotic action? If accumulation of AD, which stimulates both A1 and A2 receptors, is not the cause for sleep drive, the question still remains as to why sleep is increased by administration of AD into the preoptic area (PO). Why is sleep increased by peripheral administration of deoxycoformycin—an inhibitor of adenosine deaminase that elevates the levels of AD in the central nervous system (CNS)? Why is sleep increased by in vivo microdialysis perfusion of AD into the brain? 4-6 Why does peripheral or central administration of adenosine A1 receptor agonists induce sleep in rats?1,7-9 While these and other studies have suggested a role for A1 receptors in sleep drive, only a couple of studies have found that A2a receptors also play a role in adenosine’s hypnotic action.10 This is of interest since A1 receptors are widely distributed throughout the brain including the brainstem,11 whereas A2 receptors have high densities in only several brain regions and are absent from the hypothalamus.12 Another way to evaluate the roles of A1 and A2 receptors in sleep homeostasis is to use caffeine, which blocks both subsets of AD receptors and produces wakefulness, and to compare caffeine’s sleep suppressant action with two other xanthines that antagonize either A1 or A2 receptors. Thus, when 8-cyclopenForum on Critical Topics – Sleep, Adenosine, and the Basal Forebrain