title: Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration.
abstract: The involvement of adenosine A(1) and A(2A) receptors in the motor effects of caffeine is still a matter of debate. In the present study, counteraction of the motor-depressant effects of the selective A(1) receptor agonist CPA and the A(2A) receptor agonist CGS 21680 by caffeine, the selective A(1) receptor antagonist CPT, and the A(2A) receptor antagonist MSX-3 was compared. CPT and MSX-3 produced motor activation at the same doses that selectively counteracted motor depression induced by CPA and CGS 21680, respectively. Caffeine also counteracted motor depression induced by CPA and CGS 21680 at doses that produced motor activation. However, caffeine was less effective than CPT at counteracting CPA and even less effective than MSX-3 at counteracting CGS 21680. On the other hand, when administered alone in habituated animals, caffeine produced stronger motor activation than CPT or MSX-3. An additive effect on motor activation was obtained when CPT and MSX-3 were coadministered. Altogether, these results suggest that the motor-activating effects of acutely administered caffeine in rats involve the central blockade of both A(1) and A(2A) receptors. Chronic exposure to caffeine in the drinking water (1.0 mg/ml) resulted in tolerance to the motor effects of an acute administration of caffeine, lack of tolerance to amphetamine, apparent tolerance to MSX-3 (shift to the left of its 'bell-shaped' dose-response curve), and true cross-tolerance to CPT. The present results suggest that development of tolerance to the effects of A(1) receptor blockade might be mostly responsible for the tolerance to the motor-activating effects of caffeine and that the residual motor-activating effects of caffeine in tolerant individuals might be mostly because of A(2A) receptor blockade.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Branch, NIDA, NIH, IRP, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Marzena
authors.initials: M
authors.lastname: Karcz-Kubicha
authors.forename: Katerina
authors.initials: K
authors.lastname: Antoniou
authors.forename: Anton
authors.initials: A
authors.lastname: Terasmaa
authors.forename: Davide
authors.initials: D
authors.lastname: Quarta
authors.forename: Marcello
authors.initials: M
authors.lastname: Solinas
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.forename: Antonella
authors.initials: A
authors.lastname: Pezzola
authors.forename: Rosaria
authors.initials: R
authors.lastname: Reggio
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.forename: Patrizia
authors.initials: P
authors.lastname: Popoli
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D002110:Caffeine / Q000008:administration & dosage*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule / Q000662:veterinary; D004347:Drug Interactions; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010627:Phenethylamines / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014227:Triazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics; D014970:Xanthines / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000697:Central Nervous System Stimulants; C113602:MSX 3 compound; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D014316:Tritium; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C053907:8-cyclopentyl-1,3-dimethylxanthine; D002110:Caffeine; C048599:N(6)-cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000661:Amphetamine; D000241:Adenosine