Control of Sleep and Wakefulness in Health and Disease - Progress in Molecular Biology and Translational Science - page 149

alertness, but no causal mechanisms have been established. 88 Low melatonin
production also may naturally occurs in many older adults (more as a con-
sequence of being old as opposed to the aging process itself ). 89 Supplemen-
tation of this low endogenous melatonin with exogenous melatonin has had
mixed results, but may have a small impact on sleep onset mechanisms. 84 If
anything, endogenous melatonin is likely to evoke a mild hypnotic effect
predominantly at sleep onset. Mechanistically, this might occur through
suppression of a SCN-derived wake signal 90 or through modulation of ther-
moregulatory processes that are important for active heat loss at sleep
onset. 91 It must be noted, however, that the importance of melatonin to
the production of normal sleep in humans is not well established.
Another hormone that has been studied in the context of sleep regulation
is cortisol. Cortisol is produced in a highly pulsatile fashion, with low levels
in the evening and early sleep period and a rise late in the sleep period that
peaks just after habitual wake time. Cortisol, as with melatonin, is under
strong circadian control with a minor influence of sleep. 92 At physiologic
levels, there is little evidence for the relevance of cortisol to sleep regulation.
Individuals with Addison's disease, characterized by a severely diminished
capacity to produce cortisol, have relatively normal sleep. 93,94 At elevated
concentrations, cortisol may enhance the occurrence of slow wave sleep
and inhibit REMS. 93,95 Individuals with Cushing's disease, characterized
by constitutively elevated cortisol, have markedly disturbed sleep, exhibiting
increased sleep fragmentation and reduced latency to onset of REMS. 96,97
Thus, short-term elevations in cortisol may result in an increase in slowwave
sleep while, a chronic elevation in cortisol may result in a form of down-
regulation and a reduction in NREMS.
5. THE REST
There are, of course, many other components of sleep/wake regula-
tion, including other immune molecules (e.g., IL1 a , IL4, IL6), hormones
(e.g., prolactin, epinephrine, thyrotropin-releasing hormone, vasopressin,
growth hormone), peptides (e.g., cholecystokinin, vasoactive intestinal pep-
tide), and neuropeptides (e.g., neuropeptide S, cortistatin, somatostatin,
corticotropin-releasing factor). The data for these, however, are mixed
and less substantial on the role that they have in the regulation of sleep
and wake. Given that hypocretin was discovered about 15 years ago and
now considered a major regulator of sleep and wake, the roles of these