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.