Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats

Rationale: Caffeine is a non-selective adenosine receptor antagonist in vitro, but involvement of different adenosine receptor subtypes, particularly adenosine A(1) and A(2A) receptors, in the central effects of caffeine remains a matter of debate. Objective: Investigate the role of adenosine A(1) and A(2A) receptors in the discriminative-stimulus effects of caffeine. Methods: Rats were trained to discriminate an injection of 30 mg/kg ( i.p.) caffeine from saline. The selective A(1) receptor antagonist CPT, the selective A(2A) receptor antagonist MSX-3 and the non-selective adenosine receptor antagonist DMPX were assessed for their ability to produce caffeine-like discriminative effects. The ability of CPT, MSX-3, the A(1) receptor agonist CPA and the A(2A) receptor agonist CGS21680 to reduce the discriminative effects of caffeine was also tested. Radioligand binding experiments with membrane preparations from rat striatum and transfected mammalian cell lines were performed to characterize binding affinity profiles of the different adenosine antagonists used in the present study ( caffeine, DMPX, CPT and MSX-3) in relation to all known adenosine receptors (A(1), A(2A), A(2B), A(3)). Results: DMPX and CPT, but not MSX-3, produced significant caffeine-like discriminative effects. MSX-3, but not CPT, markedly reduced the discriminative effects of caffeine and the caffeine-like discriminative effects of CPT. Furthermore, the A(1) receptor agonist CPA, but not the A(2A) agonist CGS21680, reduced caffeine's discriminative effects. Conclusions: Adenosine A(1) receptor blockade is involved in the discriminative-stimulus effects of behaviorally relevant doses of caffeine; A(2A) receptor blockade does not play a central role in caffeine's discriminative effects and counteracts the A(1) receptor-mediated discriminative-stimulus effects of caffeine.