1.9 Chronobiology
91
The decompressed bimodal structure of human sleep during
long nights indicates that the length of natural sleep is related to
the length of the night. Potentially, a two-oscillator system could
function to maintain proper sleep patterns during changing pho-
toperiods. Such a proposed system would consist of an evening
oscillator that tracks the transition from day to night (dusk) and
a morning oscillator that tracks the transition from night to day
(dawn). The relative phase differences between these oscillators
may encode the changing day lengths associated with the pass-
ing of the seasons. Biological evidence for a two-oscillator sys-
tem exists in rodents and humans.
The melatonin profile of many vertebrates, including some
humans, is bimodal, with evening and morning peaks. In
rodents, metabolic and electrophysiological studies of the SCN
typically have been done in brain slices cut in the coronal plane.
Results of electrophysiological studies conducted in brain slices
cut in the horizontal plane have provided new insights. The
action potential frequency in SCN neurons from horizontally
cut preparations is bimodal, with peaks in the early and late sub-
jective day. Furthermore, the interpeak interval varies as a func-
tion of the photoperiod in which the animal was housed. These
studies lend credence to long-standing suspicions that the SCN
of seasonally breeding mammals and, perhaps, nonseasonal
mammals harbor a morning and evening oscillator that interact
to convey day-length information.
Effect of Aging
In general, as humans age, the circadian period shortens, the
circadian phase advances resulting in earlier waking times and
bedtimes, the amplitudes of most circadian rhythms decrease,
and dramatic phase shifts such as those caused by jet-lag are less
tolerated. Again, a mouse model has provided interesting insight
into the interaction of the aging process and the circadian clock.
The effect of chronic jet-lag on aged mice has dramatic conse-
quences on mortality. About half of aged mice forced to phase
advance 6 hours once per week survive this treatment compared
with an 83 percent survival rate in unshifted age-matched mice.
Aged mice subjected to weekly 6-hour phase delays show an
intermediate survival of 68 percent. These profound effects of
phase shifting are not observed in younger mice. The pathogen-
esis of chronic jet-lag remains to be determined. Of interest,
these mice did not have an increased rate of tumorigenesis. It
is likely that in humans, as in mice, the internal desynchrony of
oscillators that result from a rotating light schedule may have
dire consequences that may be exacerbated by aging.
Circadian Rhythms and
Pharmacotherapy
Circadian rhythmicity can be affected by drugs, and conversely,
the circadian clock can modulate the efficacy of drugs through-
out the course of the day. A better understanding of these inter-
actions will lead to more effective pharmacotherapies. Some
of the best-studied interactions between medications and the
circadian clock have included the circadian effects of antide-
pressants. Elevated nocturnal body temperature is a common
feature among depressed patients. This effect may be due to
a reduced amplitude of the master circadian oscillator in the
hypothalamus that drives body temperature. Tricyclic antide-
pressants (TCAs) and selective serotonin reuptake inhibitors
(SSRIs) reduce elevated nocturnal body temperature while
simultaneously enhancing circadian amplitude. Similarly,
many depressed patients exhibit a dampened amplitude in daily
activity rhythms. Like body temperature, the amplitude in daily
activity cycles of depressed individuals may be augmented
by TCA or SSRI therapy.
The use of lithium to treat bipolar disorder has been long
established. However, lithium also affects the circadian system,
resulting in a lengthening of circadian period. The molecular
mechanism by which this occurs remains unknown. Glycogen
synthase kinase 3
b
(GSK3
b
) has been implicated in participat-
ing within the molecular clock mechanism. Of interest, GSK3
b
is inhibited by lithium. In cell culture, GSK3
b
has been shown to
stabilize the negative clockwork regulator REV-ERB
a
via phos-
phorylation. REV-ERB
a
typically represses the transcription of
the
BMAL1
gene. In the presence of lithium, however, GSK3
b
is inhibited, thereby preventing the phosphorylation and stabi-
lization of REV-ERB
a
,
which as a consequence is targeted for
proteasomal degradation. The degradation of REV-ERB
a
results
in the de-repression of
BMAL1
transcription. Whether lithium’s
influence on circadian behavior is attributable to its inhibitory
effect on
GSK3
b
-
mediated stabilization of REV-ERB
a
remains
to be determined.
Short-acting benzodiazepines (e.g., triazolam [Halcion] and
brotizolam [Lendormin]) also exert chronobiological effects. In
hamsters, triazolam or brotizolam administered during the mid-
dle of the subjective day induces circadian phase advances in
activity. Brotizolam has been shown to reduce the light-induced
expression of clock genes
Per1
and
Per2
in the SCN. Although
benzodiazepines are allosteric modulators of
g
-aminobutyric
acid A receptors (GABA
A
), several lines of evidence indicate
that the circadian effects of short-acting benzodiazepines require
an intact serotonergic system. When the 5-HT
1A/7
receptor ago-
nist 8-hydroxy-2-(di-
n
-propylamino)-tetralin (8-OH-DPAT) is
injected into hamsters at subjective midday, phase advances
in locomotor behavior and SCN neuronal activity are observed
in addition to a reduction in
Per1
and
Per2
gene expression in
the SCN. Recreational drugs of abuse also affect the circadian
system. 3,4-Methylenedioxymethamphetamine (MDMA), or
“ecstasy,” can act as a serotonin neurotoxin. Hamsters treated
with MDMA showed reduced triazolam-induced phase shifts
in circadian locomotor activity and a diminished ability to
reentrain rhythms posttreatment. MDMA-treated animals
exhibited a reduction of serotonergic axonal terminals in the
SCN, again emphasizing the importance of an intact seroto-
nergic system in the regulation of the circadian axis. Recre-
ational use of methamphetamine has increased dramatically.
Chronic administration of methamphetamine disorganizes
rodent activity rhythms. However, administration of metham-
phetamine to rodents rendered arrhythmic through ablation of
the SCN results in a reemergence of rhythmicity. The mecha-
nism involved in the rescue of rhythmicity or site of action
remains unknown.
The efficacy and toxicity of many pharmacotherapeutics
vary as a function of circadian phase. Daily variations in fixed-
dose lethal toxicity have been appreciated in rodents for years.
Many anticancer drugs, ranging in mechanism from antimetab-
olites to deoxyribonucleic acid (DNA) intercalators to mitotic
inhibitors, have been shown to have 2- to 10-fold changes in
