Abstract
Rationale
There is no consensus on the contribution of adenosine A1 and A2A receptor blockade to motor-activating effects of caffeine.
Objective
Our aim was to use a detailed and continuous observational method to compare the motor effects induced by caffeine with those induced by selective A1 and A2A receptor antagonists.
Methods
The behavioral repertoire induced by systemic administration of caffeine (3, 10, and 30 mg/kg), A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.2, 4.8 and 7.2 mg/kg), and A2A receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3; 1, 3, and 10 mg/kg) was analyzed. The effects of pretreatment with the selective A1 receptor agonist N 6-cyclopentyladenosine (CPA; 0.1 mg/g) and the selective A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxyamidoadenosine (CGS 21680; 0.2 mg/kg) on the pattern of motor activation induced by caffeine, CPT, or MSX-3 were also examined.
Results
The pattern of behavioral activation induced by caffeine was better mimicked by CPT than by MSX-3. Coadministration of CPT and MSX-3 gave different results depending on the dose and the type of behavioral response. CPA was more effective at decreasing the activating effects of caffeine and CPT than those of CGS 21680. On the other hand, CGS 21680 was more effective at decreasing the activating effects of MSX-3 than those of caffeine or CPT. Factor analysis revealed a complex three-dimensional behavioral profile for caffeine that was similar to the profile for CPT and was different from the profile for MSX-3.
Conclusions
The results indicate a predominant role for A1 receptors in the motor-activating effects of acutely administered caffeine.
Similar content being viewed by others
References
Andresen BT, Gillespie DG, Mi Z, Dubey RK, Jackson EK (1999) Role of adenosine A(1) receptors in modulating extracellular adenosine levels. J Pharmacol Exp Ther 291:76–80
Antoniou K, Kafetzopoulos E (1996) The pattern of locomotor activity after cocaine treatment in the rat. Behav Pharmacol 7:237–244
Antoniou K, Kafetzopoulos E, Papadopoulou-Daifoti Z, Hyphantis T, Marselos M (1998a) d-amphetamine, cocaine and caffeine: a comparative study of acute effects on locomotor activity and behavioural patterns in rats. Neurosci Biobehav Rev 23:189–196
Antoniou K, Papadopoulou-Daifotis Z, Kafetzopoulos E (1998b) Differential alterations in basal and d-amphetamine-induced behavioural pattern following 6-OHDA or ibotenic acid lesions into the dorsal striatum. Behav Brain Res 97:3–28
Barraco RA, Martens KA, Parizon M, Normile HJ (1993) Adenosine A2a receptors in the nucleus accumbens mediate locomotor depression. Brain Res Bull 31:397–404
Baumgold J, Nikodijevic O, Jacobson KA (1992) Penetration of adenosine antagonists into mouse brain as determined by ex vivo binding. Biochem Pharmacol 43:889–894
Conlay LA, Conant JA, deBros F, Wurtman R (1997) Caffeine alters plasma adenosine levels. Nature 389:136
Daly JW, Fredholm BB (1998) Caffeine—an atypical drug of dependence. Drug Alcohol Depend 51:199–206
El Yacoubi M, Ledent C, Menard JF, Parmentier M, Costentin J, Vaugeois JM (2000) The stimulant effects of caffeine on locomotor behaviour in mice are mediated through its blockade of adenosine A(2A) receptors. Br J Pharmacol 129:1465–1473
Ferré S, Fuxe K, von Euler G, Johansson B, Fredholm BB (1992) Adenosine–dopamine interactions in the brain. Neuroscience 51:501–512
Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133
Fredholm BB, Irenius E, Kull B, Schulte G (2001) Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 61:443–448
Gasior M, Jaszyna M, Peters J, Goldberg SR (2000) Changes in the ambulatory activity and discriminative stimulus effects of psychostimulant drugs in rats chronically exposed to caffeine: effect of caffeine dose. J Pharmacol Exp Ther 295:1101–1111
Goldberg SR, Prada JA, Katz JL (1985) Stereoselective behavioral effects of N 6-phenylisopropyl-adenosine and antagonism by caffeine. Psychopharmacology 87:272–277
Halldner L, Lozza G, Lindstrom K, Fredholm BB (2000) Lack of tolerance to motor stimulant effects of a selective adenosine A(2A) receptor antagonist. Eur J Pharmacol 406:345–354
Halldner L, Aden U, Dahlberg V, Johansson B, Ledent C, Fredholm BB (2004) The adenosine A1 receptor contributes to the stimulatory, but not the inhibitory effect of caffeine on locomotion: a study in mice lacking adenosine A1 and/or A2A receptors. Neuropharmacology 46:1008–1017
Howell LL, Coffin VL, Spealman RD (1997) Behavioral and physiological effects of xanthines in nonhuman primates. Psychopharmacology (Berl) 129:1–14
Jacobson KA, Nikodijevic O, Padgett WL, Gallo-Rodriguez C, Maillard M, Daly JW (1993) 8-(3-Chlorostyryl)caffeine (CSC) is a selective A2-adenosine antagonist in vitro and in vivo. FEBS Lett 323:141–144
Karcz-Kubicha M, Antoniou K, Terasmaa A, Quarta D, Solinas M, Justinova Z, Pezzola A, Reggio R, Muller CE, Fuxe K, Goldberg SR, Popoli P, Ferré S (2003) Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration. Neuropsychopharmacology 28:1281–1291
Katz JL, Goldberg SR (1987) Psychomotor stimulant effects of caffeine alone and in combination with an adenosine analog in the squirrel monkey. J Pharmacol Exp Ther 242:179–187
Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, Costentin J, Heath JK, Vassart G, Parmentier M (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388:674–678
Lindskog M, Svenningsson P, Pozzi L, Kim Y, Fienberg AA, Bibb JA, Fredholm BB, Nairn AC, Greengard P, Fisone G (2002) Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. Nature 418:774–778
Maemoto T, Finlayson K, Olverman HJ, Akahane A, Horton RW, Butcher SP (1997) Species differences in brain adenosine A1 receptor pharmacology revealed by use of xanthine and pyrazolopyridine based antagonists. Br J Pharmacol 122:1202–1208
Marston HM, Finlayson K, Maemoto T, Olverman HJ, Akahane A, Sharkey J, Butcher SP (1998) Pharmacological characterization of a simple behavioral response mediated selectively by central adenosine A1 receptors, using in vivo and in vitro techniques. J Pharmacol Exp Ther 285:1023–1030
Mueller K, Hollingsworth EM, Cross DR (1989) Another look at amphetamine-induced stereotyped locomotor activity in rats using a new statistic to measure locomotor stereotypy. Psychopharmacology (Berl) 97:74–79
Nikodijevic O, Sarges R, Daly JW, Jacobson KA (1991) Behavioral effects of A1- and A2-selective adenosine agonists and antagonists: evidence for synergism and antagonism. J Pharmacol Exp Ther 259:286–294
Quarta D, Ferré S, Solinas M, You ZB, Hockemeyer J, Popoli P, Goldberg SR (2004a) Opposite modulatory roles for adenosine A1 and A2A receptors on glutamate and dopamine release in the shell of the nucleus accumbens. Effects of chronic caffeine exposure. J Neurochem 88:1151–1158
Quarta D, Borycz J, Solinas M, Patkar K, Hockemeyer J, Ciruela F, Lluis C, Franco R, Woods AS, Goldberg SR, Ferré S (2004b) Adenosine receptor-mediated modulation of dopamine release in the nucleus accumbens depends on glutamate neurotransmission and N-methyl-d-aspartate receptor stimulation. J Neurochem 91:873–880
Sauer R, Maurinsh J, Reith U, Fulle F, Klotz KN, Muller CE (2000) Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A(2A)-selective adenosine receptor antagonists. J Med Chem 43:440–448
Snyder SH, Katims JJ, Annau Z, Bruns RF, Daly JW (1981) Adenosine receptors and behavioral actions of methylxanthines. Proc Natl Acad Sci U S A 78:3260–3264
Solinas M, Ferré S, You ZB, Karcz-Kubicha M, Popoli P, Goldberg SR (2002) Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci 22:6321–6324
Solinas M, Ferré S, Antoniou K, Quarta D, Justinova Z, Hockemeyer J, Pappas LA, Segal PN, Wertheim C, Muller CE, Goldberg SR (2005) Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats. Psychopharmacology 179:576–586
Spruijt BM, Gispen WH (1984) Behavioral sequences as an easily quantifiable parameter in experimental studies. Physiol Behav 32:707–710
Svenningsson P, Nomikos GG, Fredholm BB (1995) Biphasic changes in locomotor behavior and in expression of mRNA for NGFI-A and NGFI-B in rat striatum following acute caffeine administration. J Neurosci 15:7612–7624
Svenningsson P, Nomikos GG, Ongini E, Fredholm BB (1997) Antagonism of adenosine A2A receptors underlies the behavioural activating effect of caffeine and is associated with reduced expression of messenger RNA for NGFI-A and NGFI-B in caudate–putamen and nucleus accumbens. Neuroscience 79:753–764
Waldeck B (1975) Effect of caffeine on locomotor activity and central catecholamine mechanisms: a study with special reference to drug interaction. Acta Pharmacol Toxicol 36:1–23
Acknowledgements
We would like to thank Mrs. Olga Tsoumami for technical assistance. National Institute on Drug Abuse Intramural Research Program funds supported this research.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Antoniou, K., Papadopoulou-Daifoti, Z., Hyphantis, T. et al. A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors. Psychopharmacology 183, 154–162 (2005). https://doi.org/10.1007/s00213-005-0173-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-005-0173-6