title: Adenosine A1-A2A receptor heteromers: new targets for caffeine in the brain.
abstract: 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.
authors.affiliation: National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA. sferre@intra.nida.nih.gov
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferre
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.forename: Janusz
authors.initials: J
authors.lastname: Borycz
authors.forename: Marcello
authors.initials: M
authors.lastname: Solinas
authors.forename: Davide
authors.initials: D
authors.lastname: Quarta
authors.forename: Katerina
authors.initials: K
authors.lastname: Antoniou
authors.forename: Cesar
authors.initials: C
authors.lastname: Quiroz
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.forename: Carme
authors.initials: C
authors.lastname: Lluis
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects; D019281:Dimerization; D006801:Humans; D008954:Models, Biological; D009043:Motor Activity; D043682:Receptor, Adenosine A1 / Q000737:chemistry / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D002110:Caffeine; D000241:Adenosine