Circasemidian, Circadian, and Longer‐Period Activity Rhythms in Caffeine‐Treated Molecular Clock Deficient Cryptochrome (Cry) 1 and Cry 2 Double Knockout Mice

Oct 7, 2025The European journal of neuroscience

Daily and Longer Activity Patterns in Caffeine-Treated Mice Missing Key Molecular Clock Proteins Cry1 and Cry2

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Abstract

Chronic caffeine treatment extended the circadian activity period of wild-type mice for 3 weeks after cessation.

Caffeine administration in drinking water induced varied activity rhythms in clock gene deficient mice.
These rhythms included circasemidian (~12 h), circadian, and longer-period patterns under constant darkness.
Caffeine withdrawal led to spontaneous changes in activity periods, eventually resulting in arrhythmia.
In humans, rhythms shorter or longer than 24 h may contribute to sleep-wake rhythm desynchronization.
Caffeine's effects on circadian rhythms could provide insights into human rhythmic disorders.

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Mammalian circadian rhythms are driven by the transcriptional-translational feedback loop of clock genes in the hypothalamic suprachiasmatic nucleus. However, chronic methamphetamine treatment induces circadian activity rhythms in arrhythmic animals with suprachiasmatic nucleus lesions or clock gene deletions. Activation of dopaminergic neurotransmission by methamphetamine is considered to induce activity rhythms. Adenosine antagonizes the actions of dopamine at heteromers of dopamine and adenosine receptors (dopamine D1 and adenosine A1 receptors, dopamine D2 and adenosine A2A receptors). In this study, we considered that adenosine inhibition acts similarly to methamphetamine and administered an antagonist of adenosine A1 and A2A receptors, caffeine, in drinking water. Chronic caffeine treatment extended the circadian activity period of wild-type mice under constant darkness. The circadian period extension continued for 3 weeks after the replacement of caffeine with water. Chronic caffeine treatment induced circasemidian (~12 h), circadian, and longer-period activity rhythms in clock gene deficient, cryptochrome (Cry) 1 and Cry 2 double knockout mice under constant darkness. These activity rhythms changed periods spontaneously over time and became arrhythmic upon caffeine withdrawal. In humans, rhythms with periods shorter or longer than 24 h are hypothesized to cause internal desynchronization of the sleep-wake rhythm from the ~24 h body temperature rhythm under temporal isolation. Circasemidian rhythms are hypothesized to cause afternoon sleepiness and naps. Caffeine-induced rhythms may help understand rhythms with periods shorter or longer than 24 h in humans.