Adenosine, prolonged wakefulness, and A(1)-activated NF-kappa B DNA binding in the basal forebrain of the rat

There is considerable evidence to suggest that adenosine is a modulator of behavioral state. Our previous reports showed that perfusion of adenosine i nto the basal forebrain decreased wakefulness. Furthermore. prolonged wakef ulness resulted in increased levels of extracellular adenosine in the basal forebrain of cats and rats. However. the longer-term consequences of prolo nged wakefulness and increased adenosine are largely unknown. We report her e an increase in the DNA binding activity of the transcription factor, nucl ear factor-kappa B (NF-kappaB) following 3 h of sustained wakefulness in th e rat basal forebrain, Moreover, this treatment led to the appearance of th e p65 subunit of NF-kappaB in the nucleus, as determined by western blot an alysis of nuclear proteins. This contrasted with undetectable levels in the sleeping controls. A concomitant disappearance of I-kappaB in cytoplasm su ggested the degradation of this inhibitor of NF-kappaB. In the acute in vit ro basal forebrain slice preparation, perfusion of adenosine increased NF-k appaB DNA binding while pretreatment of the slices with the A(1) adenosine receptor antagonist, cyclopentyl-1-3-dimethylxanthine, significantly reduce d NF-K-B DNA binding. These results are compatible with the hypothesis that increases in the leve ls of adenosine in the basal forebrain. that occur during prolonged wakeful ness, act through an Al adenosine receptor and a second messenger system to increase the activity of the transcription factor NF-kappaB. We further hy pothesize that some of the long duration effects of prolonged wakefulness/s leep deprivation on performance and physiology, often termed 'sleep debt'. might be mediated through adenosine and its activation of NF-kappaB, which is known to alter the expression of several behavioral state regulatory fac tors. Published by Elsevier Science Ltd on behalf of IBRO.