title: The adenosine A1 receptor contributes to the stimulatory, but not the inhibitory effect of caffeine on locomotion: a study in mice lacking adenosine A1 and/or A2A receptors.
abstract: Caffeine has biphasic effects on locomotion, and blockade of the adenosine A(2A) receptor (A2AR) is necessary for the stimulatory effect of low doses of caffeine, but not for the locomotor depressant effect observed at high doses. We wanted to elucidate the role of the adenosine A(1) receptor (A1R) in mediating the locomotor effects of increasing doses of caffeine using wild-type mice (A1R(WT)), mice heterozygous for (A1R(HET)), and mice lacking the adenosine A(1) receptor (A1R(KO)). Caffeine had the typical biphasic dose-effect relationship in all three genotypes, but the stimulatory action of caffeine was facilitated in the A1R(KO) mice. In order to investigate the interaction between blockade of A1Rs and A2ARs, mice lacking both receptors (A1R(KO)/A2AR(KO)) were tested. Regardless of A1R genotype, animals lacking A2AR were not stimulated by caffeine, whereas animals heterozygous for A2AR were. As expected, the A1R is not crucial for the stimulatory effect of caffeine, but seems to modulate the effect of caffeine exerted via A2AR blockade. Furthermore, these results suggest that the inhibitory effect of high doses of caffeine is due neither to blockade of the A1R, nor of the A2AR, and an effect independent of these adenosine receptors is likely.
authors.affiliation: Department of Physiology and Pharmacology, Section of Molecular Pharmacology, Karolinska Institutet, Nanna Svartz vag 2, S-171 77 Stockholm, Sweden. linda.halldner@fyfa.ki.se
authors.forename: Linda
authors.initials: L
authors.lastname: Halldner
authors.forename: Ulrika
authors.initials: U
authors.lastname: Adén
authors.forename: Viktoria
authors.initials: V
authors.lastname: Dahlberg
authors.forename: Björn
authors.initials: B
authors.lastname: Johansson
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Fredholm
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D043682:Receptor, Adenosine A1 / Q000172:deficiency* / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000172:deficiency* / Q000235:genetics
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D002110:Caffeine