Control of Sleep and Wakefulness in Health and Disease - Progress in Molecular Biology and Translational Science - page 145

awake. 50,51 The role of adenosine in wake regulation is well established by
the ubiquitous use of caffeine as a wake-promoting agent—at physiologic
concentrations, the main effect of caffeine is to block adenosine receptors. 52
A recent study has proposed that the wake-promoting effects of caffeine are
due to specific blockade of adenosine A2A receptors in the shell of the
nucleus accumbens. 53 The role of the nucleus accumbens in sleep regulation
and how adenosine regulation in this nucleus compares with adenosine reg-
ulation in the basal forebrain are yet to be discovered.
The homeostatic and circadian systems interact to create single, daily
periods of stable sleep and wake. As the waking day goes on, the homeostatic
drive for sleep increases and is offset by an increasing circadian drive for
wake, resulting in stable wakefulness for about 16 h. Around habitual bed-
time, the homeostatic drive for sleep begins to overwhelm the circadian
drive for wake, which has now begun to dissipate, and sleep begins. As sleep
continues, the homeostatic drive for sleep is quenched, but the circadian
drive for sleep offsets this decline and sleep is maintained for about 8 h.
When there is a mismatch between the timing of homeostasis and the cir-
cadian system, such as occurs during jet lag or shift work, sleep and wake
disruptions become evident (see Chapter 7 ) with potentially significant
effects on physical and mental well-being (see Chapters 7 , 9 , 10 , 11 ). This
type of sleep and wake fragmentation is caused by controllable behavioral
influences. In normal aging, there appears to be a decline in the strength
of the consolidation of both sleep and wake. Healthy older adults will often
nap during the daytime and have fragmented sleep at night. Of course, these
two behaviors are somewhat reciprocal in that reduced sleep at night will
cause tiredness and napping during the day, which decreases homeostatic
pressure for sleep and increases awakening at night and so on. Even when
kept awake all day, there is an increased sleep fragmentation in healthy older
adults. 54 In pathological states of aging, such as AD, there can be even greater
fragmentation of sleep and wake. About half of individuals with AD will
have nearly a complete loss of sleep and wake consolidation. 55 In other
words, the occurrence of sleep and wake becomes nearly random across
the day and night. In many epidemiologic studies, this sleep/wake fragmen-
tation is the top- or second-most cited reasons for institutionalization of
older adults with AD (with incontinence being similarly ascribed). 27,56 It
is possible that a decline of hypocretin release (i.e., modeled as a decline
in the circadian wake drive) within the normal physiologic range may be
partially responsible for this decline in wake consolidation and that repletion
of this peptide might reverse this effect. 57