Adenosine, prolonged wakefulness, and A1-activated NF-kappaB 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 into the basal forebrain decreased wakefulness. Furthermore, prolonged wakefulness resulted in increased levels of extracellular adenosine in the basal forebrain of cats and rats. However, the longer-term consequences of prolonged wakefulness and increased adenosine are largely unknown. We report here an increase in the DNA binding activity of the transcription factor, nuclear factor-kappa B (NF-kappaB) following 3 h of sustained wakefulness in the rat basal forebrain. Moreover, this treatment led to the appearance of the p65 subunit of NF-kappaB in the nucleus, as determined by western blot analysis of nuclear proteins. This contrasted with undetectable levels in the sleeping controls. A concomitant disappearance of I-kappaB in cytoplasm suggested the degradation of this inhibitor of NF-kappaB. In the acute in vitro basal forebrain slice preparation, perfusion of adenosine increased NF-kappaB DNA binding while pretreatment of the slices with the A1 adenosine receptor antagonist, cyclopentyl-1-3-dimethylxanthine, significantly reduced NF-kappaB DNA binding. These results are compatible with the hypothesis that increases in the levels of adenosine in the basal forebrain, that occur during prolonged wakefulness, act through an A1 adenosine receptor and a second messenger system to increase the activity of the transcription factor NF-kappaB. We further hypothesize that some of the long duration effects of prolonged wakefulness/sleep 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 factors.
Basheer
R
R
Department of Psychiatry, Havard Medical School and VA Medical Center, Brockton, MA 02401, USA.
Rainnie
D G
DG
Porkka-Heiskanen
T
T
Ramesh
V
V
McCarley
R W
RW
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002451:Cell Compartmentation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D004247:DNA / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D020318:Rats, Long-Evans; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014851:Wakefulness / Q000502:physiology*
D016328:NF-kappa B; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D004247:DNA; D000241:Adenosine