Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine


Caffeine, a component of tea, coffee and cola, induces wakefulness. It binds to adenosine A1 and A2A receptors as an antagonist, but the receptor subtype mediating caffeine-induced wakefulness remains unclear. Here we report that caffeine at 5, 10 and 15 mg kg−1 increased wakefulness in both wild-type mice and A1 receptor knockout mice, but not in A2A receptor knockout mice. Thus, caffeine-induced wakefulness depends on adenosine A2A receptors.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Time course of changes in wakefulness after caffeine (15 mg kg−1) treatment.
Figure 2: Total time of wakefulness for 3 h after caffeine injection.


  1. 1

    Porkka-Heiskanen, T. et al. Science 276, 1265–1268 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Fredholm, B.B., Ijzerman, A.P., Jacobson, K.A., Klotz, K.N. & Linden, J. Pharmacol. Rev. 53, 527–552 (2001).

    CAS  PubMed  Google Scholar 

  3. 3

    Basheer, R., Strecker, R.E., Thakkar, M.M. & McCarley, R.W. Prog. Neurobiol. 73, 379–396 (2004).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Hayaishi, O., Urade, Y., Eguchi, N. & Huang, Z.L. Arch. Ital. Biol. 142, 533–539 (2004).

    CAS  PubMed  Google Scholar 

  5. 5

    Porkka-Heiskanen, T., Alanko, L., Kalinchuk, A. & Stenberg, D. Sleep Med. Rev. 6, 321–332 (2002).

    Article  PubMed  Google Scholar 

  6. 6

    Fredholm, B.B., Chen, J.F., Masino, S.A. & Vaugeois, J.M. Annu. Rev. Pharmacol. Toxicol. 45, 385–412 (2005).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Satoh, S., Matsumura, H., Suzuki, F. & Hayaishi, O. Proc. Natl. Acad. Sci. USA 93, 5980–5984 (1996).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Scammell, T.E. et al. Neuroscience 107, 653–663 (2001).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Hong, Z.Y. et al. J. Neurochem. 92, 1542–1549 (2005).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Fredholm, B.B., Battig, K., Holmen, J., Nehlig, A. & Zvartau, E.E. Pharmacol. Rev. 51, 83–133 (1999).

    CAS  PubMed  Google Scholar 

  11. 11

    El Yacoubi, M., Ledent, C., Parmentier, M., Costentin, J. & Vaugeois, J.M. Neuropharmacology 45, 977–985 (2003).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Fisone, G., Borgkvist, A. & Usiello, A. Cell. Mol. Life Sci. 61, 857–872 (2004).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Rainnie, D.G., Grunze, H.C., McCarley, R.W. & Greene, R.W. Science 263, 689–692 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Mignot, E., Taheri, S. & Nishino, S. Nat. Neurosci. 5 (suppl.), 1071–1075 (2002).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Stenberg, D. et al. J. Sleep Res. 12, 283–290 (2003).

    Article  PubMed  Google Scholar 

Download references


This study was supported in part by grants-in-aid for scientific research from the Japan Society for the Promotion of Science (O.H., Z.-L.H.), the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN; Y.U.), Takeda Pharmaceutical Company Limited (O.H.) and Osaka City. This manuscript is dedicated to the late S. Fink to acknowledge his many scientific contributions to adenosine studies.

Author information



Corresponding author

Correspondence to Osamu Hayaishi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Huang, ZL., Qu, WM., Eguchi, N. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 8, 858–859 (2005).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing