1. ¹Preclinical Pharmacology Section, Behavioral Neuroscience Branch, NIDA, NIH, IRP, Department of Health and Human Services, Baltimore, MD, USA
2. ²Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
3. ³Department of Pharmacology, Istituto Superiore di Sanita, Rome, Italy
4. ⁴Pharmaceutical Institute, University of Bonn, Bonn, Germany

Correspondence: Dr Sergi Ferré, Preclinical Pharmacology Section, NIDA, NIH, IRP, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. Tel: +1 410 550 1586; Fax: +1 410 550 1648; E-mail: sferre@intra.nida.nih.gov

Received 18 September 2002; Revised 10 January 2003; Accepted 14 January 2003; Published online 9 April 2003.

Abstract

The involvement of adenosine A₁ 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 A₁ receptor agonist CPA and the A_2A receptor agonist CGS 21680 by caffeine, the selective A₁ 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 A₁ 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 A₁ 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.