1 | INTRODUCTION
Circadian physiological and behavioral rhythms in mammals are driven by
the molecular clock in the hypothalamic suprachiasmatic nucleus (SCN).
Molecular clock is a
transcriptional-translational
feedback loop of clock genes (Takahashi, 2017). CLOCK/BMAL1 heterodimer
transactivates the expression of Period (Per ) andCryptochrome (Cry ) via E-box. Periodic repression ofPer and Cry expression by their products, PER/CRY complex,
generates circadian rhythm. Clock gene deficient mice (Lowrey &
Takahashi, 2011), such as Cry1 and Cry2 double knockout
mice (CryDKO) (van der Horst et
al., 1999; Vitaterna et al., 1999), show arrhythmic behavior under
constant darkness (DD) and an increase in nighttime activity under light
dark cycle.
Chronic methamphetamine (MAP) treatment in drinking water causes the
rhythm of locomotor activity to desynchronize from the light dark cycle
and free run (Honma et al., 1986). Because MAP generates locomotor
activity rhythms even in SCN-lesioned animals (Honma
et al., 1987; Tataroglu et al.,
2006), we examined gene expression rhythms in the brain. In parallel
with locomotor activity rhythm desynchronization from the light dark
cycle by MAP, clock gene and clock controlled gene expression rhythms in
the striatum and parietal cortex desynchronized from the SCN which was
entrained to the light dark cycle (Masubuchi et al., 2000, 2007).
Because these results suggest that clock genes outside the SCN drive the
MAP-induced activity rhythm, we administered MAP to arrhythmicClock mutant mice. Contrary to expectations, locomotor activity
rhythms appeared after MAP treatment (Masubuchi et al., 2001). MAP has
also been found to induce activity rhythms in arrhythmic clock gene
deficient mice including CryDKO (Honma et al., 2008; Mohawk et al.,
2009). These results indicate that the MAP-induced locomotor rhythm is
not driven by the transcriptional-translational feedback loop of clock
genes.
In addition to MAP,
methylphenidate induces an activity rhythm in SCN-lesioned rats (Honma
& Honma, 1992). Both MAP and
methylphenidate activate dopaminergic neurotransmission by acting as
reuptake inhibitors of the dopamine released from dopaminergic neurons
(Dela Peña et al., 2015), which suggesting that the activation of
dopaminergic neurotransmission plays a role in locomotor rhythm
generation (Honma & Honma, 2009). Blum et al. (2014) demonstrated the
generation of locomotor rhythms by chemogenetic activation of
dopaminergic neurons.
Adenosine is a physiological
sleep factor (Porkka-Heiskanen & Kalinchuk, 2011). Adenosine A1 and
dopamine D1 receptors (A1AR and
D1R), and adenosine A2A and
dopamine D2 receptors (A2AAR and D2R) form heteromers (A1AR/D1R and
A2AAR/D2R). Adenosine antagonizes dopamine activity at the A1AR/D1R and
A2AAR/D2R sites. These heteromers are involved in the pathophysiology of
various diseases, including Parkinson’s disease, schizophrenia, drug
addiction, and restless legs syndrome (Fuxe et al., 2010; Nazario et
al., 2017; Cortés et al., 2019). Caffeine is a psychostimulant that acts
as an A1AR and A2AAR antagonist
(Ferré, 2016). We expected that caffeine would act similarly to the
dopamine stimulant MAP and generate activity rhythm. Here, we
demonstrate that chronic caffeine administration in drinking water,
similar to MAP (Masubuchi et al., 2001) generates activity rhythms in
CryDKO.