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Science 23 May 1997: Vol. 276. no. 5316, pp. 1265 - 1268 Adenosine: A Mediator of the Sleep-Inducing Effects of Prolonged WakefulnessTarja Porkka-Heiskanen, Robert E. Strecker, Mahesh Thakkar, Alvhild A. Bjørkum, Robert W. Greene, Robert W. McCarley 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. T. Porkka-Heiskanen, Department of Psychiatry, Harvard Medical School, Brockton Veterans Administration Medical Center (VAMC), 116 A, 940 Belmont Street, Brockton, MA 02401, USA, and Institute of Biomedicine, University of Helsinki, Helsinki, Finland. R. E. Strecker, M. Thakkar, A. A. Bjørkum, R. W. Greene, R. W. McCarley, Department of Psychiatry, Harvard Medical School, Brockton VAMC, 116 A, 940 Belmont Street, Brockton, MA 02401, USA.
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