4 | DISCUSSION
The extension of the activity
period in WT by chronic caffeine
treatment continued for at least 3 weeks after caffeine removal. This
means that temporal caffeine exposure brought about extension of period
of the biological clock. Chronic MAP treatment extended the circadian
activity period and induced
activity rhythms with approximately 30 h period in wild-type Balb/c mice
(Masubuchi et al., 2001). Data obtained from this study show that after
MAP withdrawal, the activity period was significantly longer than that
before MAP (23.8±0.0 h vs
23.4±0.071 h, n=4, P=0.001).
Period extensions after chronic caffeine or MAP administration suggest
their similar effects on the circadian period. After-effect is long
lasting circadian period change
after exposure to various
environmental lights (Pittendrigh & Daan, 1976). We showed that PH
domain and leucine rich repeat protein phosphatase 1 (PHLPP1) is
involved in after-effect of activity rhythm by light induced phase shift
(Masubuchi et al., 2010).
Although the
mechanism of
after-effect is not well known,
it is possible that a common mechanism drives after-effect by light and
after-effect by non-photic intervention, that is, the period extension
after temporal caffeine treatment.
Activity rhythm generation by chronic
caffeine administration in CryDKO
supports the idea that caffeine acts as an inhibitor of adenosine at
A1AR/D1R and A2AAR/D2R heteromers and acts similarly to the dopamine
increase in the synaptic cleft by MAP. D1R, D2R, and A2AAR are strongly
expressed in the striatum, whereas A1AR is widely expressed in the brain
(Fuxe et al., 2010; Mishra et
al., 2018). If MAP- and caffeine-induced rhythms are driven by a common
system that acts through A1AR/D1R and/or A2AAR/D2R, it may also involve
the striatum.
Caffeine induced activity rhythms
with various periods, including circasemidian and circadian rhythms, and
longer periods in CryDKO. In addition to circadian rhythm, rhythms with
a period longer or shorter than 24 h have been hypothesized in human
physiology. Internal desynchronization of biological rhythms is known
under isolated constant condition. The period of the sleep-wake rhythm
becomes either much longer or shorter than 24 h, whereas the period of
the body temperature rhythm
remains close to 24 h (Aschoff et al., 1967; Wever, 1979). Dissociation
of two oscillators, a circadian
oscillator and an oscillator with
a period longer or shorter than 24 h, is considered to cause internal
desynchronization. Analyzing caffeine-induced rhythms with longer and
shorter periods than 24 h may be important for clarifying the mechanism
of internal desynchronization.
The caffeine-induced rhythms spontaneously changed over
time. Interestingly, the long
period in CryDKO#07 (29.25 h, Figure 3a) and #10 (28.33 h, Figure 3b)
quickly became approximately half the
(circasemidian) period (13.33 h,
17.16 h) and returned to a long period (30.00 h, 30.91 h). In humans,
sleep propensity increases not only at night, but also in the afternoon.
2 per day sleep/wake regulation
is thought to cause afternoon sleepiness and nap. The harmonics of
circadian oscillators, circadian oscillator splitting into 2 antiphase
circadian oscillators, model, and the independent circasemidian
oscillator model are hypothesized to cause 2 per day regulation. The
former does not account for the fact that naps are often skipped
(Broughton & Mullington, 1992). The short-term appearance and
disappearance of the circasemidian rhythm, as observed in CryDKO#07 and
#10, may account for the skipping of naps and variable afternoon
sleepiness.
Caffeine is the most consumed psychoactive drug in the world (Ferré,
2016). Caffeine at bedtime has significant effects on sleep disturbance
(Drake et al., 2013). However, rhythm induction by caffeine provides a
possibility that caffeine is useful not only to increase wakefulness but
also to control the sleep-wake rhythm.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS
SM designed research. SM, TY, and KK performed experiments. KI, TT, and
WN contributed new reagents/analytic tools. SM wrote the manuscript. TY,
KK, KI, TT, and WN reviewed the manuscript.
CONSENT FOR PUBLICATION
The authors consent to the publication of this manuscript.
DATA AVAILABILITY STATEMENT
All data and materials are available for review
ORCID
Satoru Masubuchihttps://orcid.org/0000-0003-0377-088X
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