Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state

This review describes a series of animal experiments that investigate the r ole of endogenous adenosine (AD) in sleep. We propose that AD is a modulato r of the sleepiness associated with prolonged wakefulness. More specificall y, we suggest that, during prolonged wakefulness, extracellular AD accumula tes selectively in the basal forebrain (BF) and cortex and promotes the: tr ansition from wakefulness to slow wave sleep (SWS) by inhibiting cholinergi c and non-cholinergic wakefulness-promoting BF neurons at the AD A1 recepto r. New in vitro data are also compatible with the hypothesis that, via pres ynaptic inhibition of GABAergic inhibitory input, AD may disinhibit neurons in the preoptic/anterior hypothalamus (POAH) that have SWS-selective activ ity and Fos expression. Our in vitro recordings initially showed that endog enous AD suppressed the discharge activity of neurons in the BF cholinergic zone via the AD Al receptor. Moreover, in identified mesopontine cholinerg ic neurons, AD was shown to act post-synaptically by hyperpolarizng the mem brane via an inwardly rectifying potassium current and inhibition of the hy perpolarization-activated current, I-h(-). In vivo microdialysis in the cat has shown that AD in the BF cholinergic zone accumulates during prolonged wakefulness, and declines slowly during subsequent sleep, findings confirme d in the rat. Moreover, increasing BF AD concentrations to approximately th e level as during sleep deprivation by a nucleoside transport blocker mimic ked the effect of sleep deprivation on both the EEG power spectrum and beha vioral state distribution: wakefulness was decreased, and there were increa ses in SWS and REM sleep. As predicted, microdialyis application of the spe cific Al receptor antagonist cyclopentyltheophylline (CPT) in the BF produc ed the opposite effects on behavioral state, increasing wakefulness and dec reasing SWS and REM. Combined unit recording and microdialysis studies have shown neurons selectively active in wakefulness, compared with SWS, have d ischarge activity suppressed by both AD and the Al-specific agonist cyclohe xyladenosine (CHA), while discharge activity is increased by the Al recepto r antagonist, CPT. We next addressed the question of whether AD exerts its effects locally or globally. Adenosine accumulation during prolonged wakefu lness occurred in the BF and neocortex, although, unlike in the BF, cortica l AD levels declined in the 6th h of sleep deprivation and declined further during subsequent recovery sleep. Somewhat to our surprise, AD concentrati ons did not increase during prolonged wakefulness (6 h) even in regions imp ortant in behavioral state control, such as the POAH, dorsal raphe nucleus, and pedunculopontine tegmental nucleus, nor did it increase in the ventrol ateral/ventroanterior thalamic nucleii. These data suggest the presence of brain region-specific differences in AD transporters and/or degradation tha t become evident with prolonged wakefulness, even though AD concentrations are higher in all brain sites sampled during the naturally occurring (and s horter duration) episodes of wakefulness as compared to sleep episodes in t he freely moving and behaving cat. Might AD also produce modulation of acti vity of neurons that have sleep selective transcriptional (Fos) and dischar ge activity in the preoptic/anterior hypothalamus zone? Whole cell patch cl amp recordings in the in vitro horizontal slice showed fast and likely GABA ergic inhibitory post-synaptic potentials and currents that were greatly de creased by bath application of AD. Adenosine may thus disinhibit and promot e expression of sleep-related neuronal activity in the POAH. In summary, a growing body of evidence supports the role of AD as a mediato r of the sleepiness following prolonged wakefulness, a role in which its in hibitory actions on the BF wakefulness-promoting neurons may be especially important. (C) 2000 Elsevier Science B.V. All rights reserved.