FIGURE 8.

Investigations of the role of adenosine (AD) as a neuromodulatory sleep factor. A: extracellular AD concentrations in the feline basal forebrain (BF) for 10-min consecutive samples from an individual animal, showing elevated levels during wakefulness. Labels indicate behavioral state: W, wakefulness; S, slow wave (NREM) sleep; R, REM sleep. [Adapted from Porkka-Heiskanen et al. (1018). Reprinted with permission from AAAS.] B: AD concentrations in the feline BF rise during 6 h of sleep deprivation (SD) and decrease towards baseline levels during 3 h of spontaneous recovery sleep. [Adapted from Porkka-Heiskanen et al. (1018). Reprinted with permission from AAAS.] C: AD and nitric oxide (NOx, red) concentrations in the rat BF rise during 11 h of SD. The rise of NOx during SD precedes the rise of AD. AD levels are significantly elevated by hour 2 of SD and remain elevated until recovery sleep, when levels fall towards baseline levels. Levels are normalized to baseline levels in the 2 h preceding SD. [Adapted from Kalinchuk et al. (591), with permission from John Wiley and Sons.] D: AD and NOx levels in the rat frontal cortex also rise during SD. Again, the rise of NOx during SD precedes the rise of AD. The rise of AD is significant by hour 6 of SD and is delayed compared with the rise seen in BF, as shown in C. Levels are normalized to baseline levels in the 2 h preceding SD. [Adapted from Kalinchuk et al. (591), with permission from John Wiley and Sons.] E: graphic depiction of the intracellular signaling pathway of the AD A1 receptor in BF observed following sleep deprivation in rats. Steps of the pathway: 1) AD binds to the A1 receptor; 2) activation of PLC pathway, releasing inositol 1,4,5-trisphosphate (IP₃); 3) IP₃ receptor-mediated intracellular calcium mobilization and activation of protein kinase C; 4) phosphorylation of Iκ-B and release of nuclear factor-κB (NF-κB) dimer; 5) nuclear translocation of NF-κB dimer; 6) promoter DNA binding of NF-κB and transcriptional activation of target genes including A1 receptor; 7) protein synthesis (A₁ receptor synthesis). This signaling cascade appears to be confined to cholinergic neurons of BF. (Adapted from Basheer et al. Neuroscience 104: 731–739, 2001, with permission from Elsevier.