IMR Press / FBL / Volume 13 / Issue 6 / DOI: 10.2741/2852

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.


Adenosine A1-A2A receptor heteromers: new targets for caffeine in the brain

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1 National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, U.S.A.
2 Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
3 Department of Psychology, Dalhousie University, Halifax, NS B3H 4J1, Canada
4 Institut de Biologie et Physiologie Cellulaires, Centre National de la Reserche Scientifique-6187, University of Poitiers, 86022 Poitiers, France
5 Drug Dependence and Behavioral Neurochemistry Department, Psychiatry-CEDD, GlaxoSmithKline S.p.A. Medicine Research Center, 37135 Verona, Italy
6 Department of Pharmacology, Medical School, University of Ioannina, 45110 Ioannina, Greece

*Author to whom correspondence should be addressed.

Academic Editor: John Salamone

Front. Biosci. (Landmark Ed) 2008, 13(6), 2391–2399;
Published: 1 January 2008
(This article belongs to the Special Issue Adenosine A2A receptors in motor function and dysfunction)

The contribution of blockade of adenosine A1 and A2A receptor to the psychostimulant effects of caffeine is still a matter of debate. When analyzing motor activity in rats, acutely administered caffeine shows a profile of a non-selective adenosine receptor antagonist, although with preferential A1 receptor antagonism. On the other hand, tolerance to the effects of A1 receptor blockade seems to be mostly responsible for the tolerance to the motor-activating effects of caffeine, while the residual motor-activating effects of caffeine in tolerant individuals seem to involve A2A receptor blockade. These behavioral studies correlate with in vivo microdialysis experiments that suggest that A1 receptor-mediated modulation of striatal glutamate release is involved in the psychostimulant effects of caffeine. Experiments in transfected cells demonstrate the ability of A1 receptors to heteromerize with A2A receptors and the A1-A2A receptor heteromer can be biochemically identified in the striatum, in striatal glutamatergic terminals. The striatal A1-A2A receptor heteromer provides a "concentration-dependent switch" mechanism by which low and high concentrations of synaptic adenosine produce the opposite effects on glutamate release. The analysis of the function of A1-A2A receptor heteromers during chronic treatment with caffeine gives new clues about the well-known phenomenon of tolerance to the psychostimulant effects of caffeine.

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