Role of adenosine receptors in caffeine tolerance

SG Holtzman, S Mante and KP Minneman

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia.

Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N- ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine- induced stimulation of locomotor activity.

Volume 256, Issue 1, pp. 62-68, 01/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				M. A. Schwarzschild, K. Xu, E. Oztas, J. P. Petzer, K. Castagnoli, N. Castagnoli Jr., and J.-F. Chen Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of Parkinson's disease Neurology, December 9, 2003; 61(90116): S55 - 61. [Abstract] [Full Text]

				M. Tarnopolsky and C. Cupido Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers J Appl Physiol, November 1, 2000; 89(5): 1719 - 1724. [Abstract] [Full Text] [PDF]

				K. Varani, F. Portaluppi, S. Gessi, S. Merighi, E. Ongini, L. Belardinelli, and P. A. Borea Dose and Time Effects of Caffeine Intake on Human Platelet Adenosine A2A Receptors : Functional and Biochemical Aspects Circulation, July 18, 2000; 102(3): 285 - 289. [Abstract] [Full Text] [PDF]

				P. Svenningsson, G. G. Nomikos, and B. B. Fredholm The Stimulatory Action and the Development of Tolerance to Caffeine Is Associated with Alterations in Gene Expression in Specific Brain Regions J. Neurosci., May 15, 1999; 19(10): 4011 - 4022. [Abstract] [Full Text] [PDF]

				B. B. Fredholm, K. Battig, J. Holmen, A. Nehlig, and E. E. Zvartau Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use Pharmacol. Rev., March 1, 1999; 51(1): 83 - 133. [Abstract] [Full Text] [PDF]

				S. R. Dager, M. E. Layton, W. Strauss, T. L. Richards, A. Heide, S. D. Friedman, A. A. Artru, C. E. Hayes, and S. Posse Human Brain Metabolic Response to Caffeine and the Effects of Tolerance Am J Psychiatry, February 1, 1999; 156(2): 229 - 237. [Abstract] [Full Text]

				L. L. Howell and A. M. Landrum Effects of Chronic Caffeine Administration on Respiration and Schedule-Controlled Behavior in Rhesus Monkeys J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 190 - 199. [Abstract] [Full Text]