Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration.
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.
Karcz-Kubicha
Marzena
M
Preclinical Pharmacology Section, Behavioral Neuroscience Branch, NIDA, NIH, IRP, Department of Health and Human Services, Baltimore, MD, USA.
Antoniou
Katerina
K
Terasmaa
Anton
A
Quarta
Davide
D
Solinas
Marcello
M
Justinova
Zuzana
Z
Pezzola
Antonella
A
Reggio
Rosaria
R
Müller
Christa E
CE
Fuxe
Kjell
K
Goldberg
Steven R
SR
Popoli
Patrizia
P
Ferré
Sergi
S
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
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