Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats.
BACKGROUND
Caffeine is a non-selective adenosine receptor antagonist in vitro, but involvement of different adenosine receptor subtypes, particularly adenosine A1 and A 2A receptors, in the central effects of caffeine remains a matter of debate.


OBJECTIVE
Investigate the role of adenosine A1 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 A1 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 A1 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 (A1, A 2A, A 2B, A3).


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 A1 receptor agonist CPA, but not the A 2A agonist CGS21680, reduced caffeine's discriminative effects.


CONCLUSIONS
Adenosine A1 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 A1 receptor-mediated discriminative-stimulus effects of caffeine.
Solinas
Marcello
M
Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, NIDA-IRP, NIH, DHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Ferré
Sergi
S
Antoniou
Katerina
K
Quarta
Davide
D
Justinova
Zuzana
Z
Hockemeyer
Jörg
J
Pappas
Lara A
LA
Segal
Pavan N
PN
Wertheim
Carrie
C
Müller
Christa E
CE
Goldberg
Steven R
SR
D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002110:Caffeine / Q000737:chemistry / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D043682:Receptor, Adenosine A1 / Q000502:physiology*
D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D002110:Caffeine