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The Journal of Neuroscience, September 2, 2009, 29(35):11029-11037; doi:10.1523/JNEUROSCI.1653-09.2009

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Behavioral/Systems/Cognitive
The Effects of Caffeine on Sleep in Drosophila Require PKA Activity, But Not the Adenosine Receptor

Mark N. Wu,^1 * Karen Ho,^2 * Amanda Crocker,² Zhifeng Yue,³ Kyunghee Koh,² and Amita Sehgal^2,3

¹Division of Sleep Medicine, Department of Neurology, ²Department of Neuroscience, and ³Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Amita Sehgal, Department of Neuroscience/University of Pennsylvania, 232 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104. Email: amita{at}mail.med.upenn.edu

Caffeine is one of the most widely consumed stimulants in the world and has been proposed to promote wakefulness by antagonizing function of the adenosine A_2A receptor. Here, we show that chronic administration of caffeine reduces and fragments sleep in Drosophila and also lengthens circadian period. To identify the mechanisms underlying these effects of caffeine, we first generated mutants of the only known adenosine receptor in flies (dAdoR), which by sequence is most similar to the mammalian A_2A receptor. Mutants lacking dAdoR have normal amounts of baseline sleep, as well as normal homeostatic responses to sleep deprivation. Surprisingly, these mutants respond normally to caffeine. On the other hand, the effects of caffeine on sleep and circadian rhythms are mimicked by a potent phosphodiesterase inhibitor, IBMX (3-isobutyl-1-methylxanthine). Using in vivo fluorescence resonance energy transfer imaging, we find that caffeine induces widespread increase in cAMP levels throughout the brain. Finally, the effects of caffeine on sleep are blocked in flies that have reduced neuronal PKA activity. We suggest that chronic administration of caffeine promotes wakefulness in Drosophila, at least in part, by inhibiting cAMP phosphodiesterase activity.

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Received April 6, 2009; revised July 22, 2009; accepted July 23, 2009.

Correspondence should be addressed to Amita Sehgal, Department of Neuroscience/University of Pennsylvania, 232 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104. Email: amita{at}mail.med.upenn.edu

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