Recent reports from our laboratory have shown that extracellular adenosine levels selectively increase in basal forebrain during prolonged wakefulness in cats and rats. Furthermore, microdialysis perfusion of adenosine into the basal forebrain (BF) increased sleepiness and decreased wakefulness in both the species, whereas perfusion of the A1-receptor-selective antagonist, cyclopentyl-1,3-dimethylxanthine resulted in increased wakefulness, an observation similar to that found with caffeine or theophylline administration. The selective participation of the A1 subtype of the adenosine receptor in mediating the effects of adenosine in the BF was further examined by the technique of single unit recording performed in conjunction with microdialysis perfusion of selective agonists and antagonists. Perfusion of the A1 agonist cyclohexyladenosine, inhibited the activity of wake-active neurons in the basal forebrain. The effect of prolonged wakefulness-induced increases in adenosine levels were further investigated by determining the changes in the BF in the levels of A1 receptor binding and the levels of its mRNA. We observed that A1 receptor mRNA levels increase after 6 h of sleep deprivation. One of the transcription factors that showed increased DNA-binding activity was nuclear factor κB (NF-κB) and may regulate the expression of A1 mRNA. We observed, using a gel shift assay, that the DNA-binding activity of NF-κB increased following 3 h of sleep deprivation. This was further supported by the increased appearance of NF-κB protein in the nuclear extracts and the consequent disappearance of cytoplasmic protein inhibitor κB (I-κB). Together our results reviewed in this report suggest that the somnogenic effects of adenosine in the BF area may be mediated by the A1 subtype of adenosine receptor, and its expression might be regulated by induction in the NF-κB protein as its transcription factor. This positive feedback might mediate some of long-duration effects of sleep deprivation, including ‘sleep debt’.