Pharmacology of Caffeine

  • John W. Daly


The widespread societal use of caffeine-containing beverages has engendered extensive interest in the pharmacological mechanisms underlying the in vivo effects of caffeine, and to a lesser extent the other naturally occurring methylxanthines, namely, theophylline and theobromine. Caffeine is ingested primarily because of mild central stimulant properties, whereby it tends to increase vigilance and defer sleep. Research, therefore, has focused primarily on the pharmacological effects of caffeine relevant to the central nervous system. The pharmacology of methylxanthines, in particular caffeine, has been reviewed in detail (Daly, 1993; Fredholm, Arslan, Johansson, Kull, & Svenningsson, 1997; Nehlig, 1994) and the present chapter will attempt only a succinct overview without extensive citations of the literature covered in those reviews.


Locomotor Activity Adenosine Receptor Endogenous Adenosine Adenosine Analog Caffeine Treatment 
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  1. Ahlijanian, M. K., and Takemori, A. E. (1986a). Cross-tolerance studies between caffeine and (−)-N6- (phenylisopropyl)adenosine (PIA) in mice. Life Sciences, 88, 577–588.CrossRefGoogle Scholar
  2. Ahlijanian, M. K., and Takemori, A. E. (19866). The effect of chronic administration of caffeine on morphine-induced analgesia, tolerance and dependence in mice. European Journal of Pharmacology, 120, 25–32.Google Scholar
  3. Anderson, R., Sheehan, M. J., and Strong, P. (1994). Characterization of the adenosine receptors mediating hypothermia in the conscious mouse. British Journal of Pharmacology, 113, 1386–1390.PubMedCrossRefGoogle Scholar
  4. Axelsson, J., and Thesleff, S. (1958). Activation of the contractile mechanism in striated muscle. Acta Physiologica Scandinavica, 44, 55–66.PubMedCrossRefGoogle Scholar
  5. Baldwin, H. A., and File, S. E. (1989). Caffeine-induced anxiogenesis: The role of the adenosine, benzodiazepine and noradrenergic receptors. Pharmacology, Biochemistry and Behavior, 32, 181–186.CrossRefGoogle Scholar
  6. Bandyopadhyay, B. C., and Poddar, M. K. (1994). Caffeine-induced increase in adenosine deaminase activity in mammalian lymphoid organs. Methods and Findings in Experimental and Clinical Pharmacology, 16, 731–733.PubMedGoogle Scholar
  7. Barraco, R. A., Coffin, V. L., Altman, H. J., and Phillis, J. W. (1983). Central effects of adenosine analogs on loco-motor activity in mice and antagonism of caffeine. Brain Research, 272, 392–395.PubMedCrossRefGoogle Scholar
  8. Berkowitz, B. A., Tarver, J. H., and Spector, S. (1970). Release of norepinephrine in the central nervous system by theophylline and caffeine. European Journal of Pharmacology, 10, 64–71.PubMedCrossRefGoogle Scholar
  9. Biaggioni, I., Paul, S., Puckett, A., and Arzubiaga, C. (1991). Caffeine and theophylline as adenosine receptor antagonists in humans. Journal of Pharmacology and Experimental Therapeutics, 258, 588–593.PubMedGoogle Scholar
  10. Bianchi, C. P. (1961). Effects of caffeine on radiocalcium movement in the frog sartorius. Journal of General Physiology, 44, 845–858.PubMedCrossRefGoogle Scholar
  11. Boulenger, J.-P., and Marangos, P. J. (1989). Caffeine withdrawal affects central adenosine receptors but not benzodiazepine receptors. Journal of Neural Transmission, 78, 9–19.PubMedCrossRefGoogle Scholar
  12. Brackett, L. E., Shamim, M. T., and Daly, J. W. (1990). Activities of caffeine, theophylline, and enprofylline analogs as tracheal relaxants. Biochemical Pharmacology, 39, 1897–1904.PubMedCrossRefGoogle Scholar
  13. Carter, A. J., O’Conner, W. T., Carter, M. J., and Ungerstedt. U. (1995). Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A, receptors. Journal Pharmacology and Experimental Therapeutics, 273, 637–642.Google Scholar
  14. Casas, M., Ferré, S., Cobos, A., Grau, J. A., and Jane, F. (1989). Relationship between rotational behavior induced by apomorphine and caffeine in rats with unilateral lesion of the nigrostriatal pathway. Neuropharmacology, 28, 407–409.PubMedCrossRefGoogle Scholar
  15. Choi, O. H., Shamim, M. T., Padgett, W. L., and Daly, J. W. (1988). Caffeine and theophylline analogues: Correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors. Life Sciences, 43, 387–398.PubMedCrossRefGoogle Scholar
  16. Chou, D. T., Khan, S., Forde, J., and Hirsh, K. R. (1985). Caffeine tolerance: Behavioral, electrophysiological and neurochemical evidence. Life Sciences, 36, 2347–2358.PubMedCrossRefGoogle Scholar
  17. Coffin, V. L., Taylor, J. A., Phillis, J. W, Altman, H. J., and Barraco, R. A. (1984). Behavioral interaction of adenosine and methylxanthines on central purinergic systems. Neuroscience Letters, 47, 91–98.PubMedCrossRefGoogle Scholar
  18. Cohen, C., Wetzel, H., and Bättig, K. (1991). Effects of nicotine, caffeine, and their combination on locomotor activity in rats. Pharmacology, Biochemistry and Behavior, 40, 121–123.CrossRefGoogle Scholar
  19. Cohen, C., Pickworth, W. B., Bunker, E. B., and Henning-field, J. E. (1994). Caffeine antagonizes EEG effects of tobacco withdrawal. Pharmacology, Biochemistry and Behavior, 47, 919–926.CrossRefGoogle Scholar
  20. Conlay, L. A., Conant, J. A., deBros, F., and Wurtman, R. (1997). Caffeine alters plasma adenosine levels. Nature, 389, 136.PubMedCrossRefGoogle Scholar
  21. Daly, J. W. (1993). Mechanism of action of caffeine. In S. Garrattini (Ed.), Caffeine, coffee and health (pp 97 – 150 ). New York: Raven.Google Scholar
  22. Daly, J. W, and Jacobson, K. A. (1995). Adenosine Receptors: Selective agonists and antagonists. In L. Belardinelli and A. Pelleg (Eds.), Adenosine and adenine nucleotides: Molecular biology to integrative physiology (pp. 157–166 ). Boston: Kluwer Academic.CrossRefGoogle Scholar
  23. Daly, J. W., Padgett, W, Shamim, M. T., Butts-Lamb, P, and Waters, J. (1985). 1,3-Dialkyl-8-(p-sulfophenyl)-xanthines: Potent water soluble antagonists for A,- and A_ adenosine receptors. Journal of Medicinal Chemistry, 28, 487–492.Google Scholar
  24. Daly, J. W., Shi, D., Nikodijevié, O., and Jacobson, K. A. (1994). The role of adenosine receptors in the central action of caffeine. Pharmacopsvchoecologia, 7, 201–213.Google Scholar
  25. Daly, J. W, Shi, D., Wong, V, and Nikodijevié, O. (1994). Chronic effects of ethanol on central adenosine function of mice. Brain Research, 650, 153–156.CrossRefGoogle Scholar
  26. Dar, M. S. (1988). The biphasic effects of centrally and peripherally administered caffeine on ethanol-induced motor incoordination in mice. Journal of Pharmacy and Pharmacology 40, 482–487.PubMedCrossRefGoogle Scholar
  27. Dar, M. S. (1990). Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. Journal of Pharmacology and Experimental Therapeutics, 255, 1202–1209.PubMedGoogle Scholar
  28. Daval, J. I., Deckert, J., Weiss, S. R. B., Post, R. M., and Marangos, P. J. (1989). Up-regulation of adenosine A, receptors and forskolin binding sites following chronic treatment with caffeine or carbamazepine: A quantitative autoradiographic study. Epilepsia, 30, 26–33.PubMedCrossRefGoogle Scholar
  29. Derlet, R. W, Tseng, J. C., and Albertson, T E. (1992). Potentiation of cocaine and d-amphetamine toxicity with caffeine. American Journal of Emergency Medicine, 10, 211–216.PubMedCrossRefGoogle Scholar
  30. Dixon, A. K., Widdowson, L., and Richardson, P. J. (1997). Desensitization of the adenosine A, receptor by the A,A receptor in the rat striatum. Journal of Neurochemistry, 69, 315–3321.Google Scholar
  31. Durcan, M., and Morgan, P. F. (1989). Evidence for A, receptor involvement in the hypomotility effects of adenosine analogs in mice. European Journal of Pharmacology, 168, 285–290.PubMedCrossRefGoogle Scholar
  32. Durcan, M. J., and Morgan, P. F. (1991). Hypothermic effects of alkylxanthines: Evidence for a calcium-independent phosphodiesterase action. European Journal of Pharmacology, 204, 15–20.PubMedCrossRefGoogle Scholar
  33. Ehrlich, B. E., Kaftan, E., Bezprozvannayan, S., and Bezprozvanny, I. (1994). The pharmacology of intracellular Ca-’-release channels. Trends in Pharmacological Sciences, 15, 145–148.PubMedCrossRefGoogle Scholar
  34. Estler, C. J. (1973). Effect of a-and ß-adrenergic blocking agents and parachlorophenylalanine on morphine-and caffeine-stimulated locomotor activity of mice. Psychopharmacologia, 28, 261–268.PubMedCrossRefGoogle Scholar
  35. Ferré, S., von Euler, G., Johansson, B., Fredholm, B. B., and Fuxe, K. (1991). Stimulation of high affinity A, receptors decreases the affinity of dopamine D, receptors in rat striatal membranes. Proceedings of the National Academy of Sciences USA, 88, 7237–7241.Google Scholar
  36. Ferré, S., Fuxe, K., von Euler, G., Johansson, B., and Fredholm, B. B. (1992). Adenosine-dopamine interactions in the brain. Neuroscience. 51, 501–512.Google Scholar
  37. Ferré, S., O’Conner, W. T., Svenningsson, P., Bjorklund, L., Lindberg, J., Tinner, B., Stromberg, I., Goldstein, M., Ogren, S. O., Ungerstedt, U., Fredholm, B. B., and Fuxe, K. (1996). Dopamine D, receptor-mediated facilitation of GABAergic neurotransmission in the rat strioentopenduncular pathway and its modulation by adenosine A, receptor-mediated mechanisms. European Journal of Neuroscience, 8, 1545–1553.PubMedCrossRefGoogle Scholar
  38. Ferré, S., Popoli, P., Tinner-Staines, B., and Fuxe, K. (1996). Adenosine A, receptor-dopamine interaction in the rat limbic system: Modulation of dopamine D, receptor antagonist binding sites. Neuroscience Letters, 208, 109–112.PubMedCrossRefGoogle Scholar
  39. Finn, l. B., and Holtzman, S. G. (1987). Pharmacologic specificity of tolerance to caffeine-induced stimulation of locomotor activity. Psychopharmacology, 93, 428–434.PubMedCrossRefGoogle Scholar
  40. Finn, 1. B., luvone, P. M., and Holtzman, S. G. (1990). Depletion of catecholamines in the brain of rats differentially affects stimulation of locomotor activity by caffeine, D-amphetamine, and methylphenidate. Neuropharmacology, 29, 625–631.PubMedCrossRefGoogle Scholar
  41. Francis, A., and Fochtmann, L. (1994). Caffeine augmentation of electroconvulsive seizures. Psychopharmacology, 110, 320–323.CrossRefGoogle Scholar
  42. Frank, G. B. (1960). Effect of changes in extracellular calcium concentration on the potassium-induced contracture of frog’s skeletal muscle. Journal of Physiology, 151, 518–538.PubMedGoogle Scholar
  43. Fredholm, B. B., and Lindgren, E. (1983). Inhibition of soluble 5’-nucleotidase from rat brain by different xanthine derivatives. Biochemical Pharmacology, 32, 2832–2834.PubMedCrossRefGoogle Scholar
  44. Fredholm, B. B., Herrara-Marschwitz, M., Jonzon, B., Lindstrom, K., and Ungerstedt, U. (1983). On the mechanism by which methylxanthines enhance apomorphine-induced rotation in the rat. Pharmacology, Biochemistry and Behavior; 19, 535–54.CrossRefGoogle Scholar
  45. Fredholm, B. B., Jonzon, B., and Lindgren, E. (1984). Changes in noradrenaline release and in beta receptor number in rat hippocampus following long-term treatment with theophylline or L-phenylisopropyladenosine. Acta Physiologica Scandinavica, 122, 55–59.PubMedCrossRefGoogle Scholar
  46. Fredholm, B. B., Arslan, G., Johansson, B., Kull, B., and Svenningsson, P. (1997). Adenosine A,A receptors and the actions of caffeine. In Y. Okada (Ed.), The role of adenosine in the nervous system (pp. 51–74 ). Amsterdam: Elsevier Science.Google Scholar
  47. Fuxe, K., Ferré, S., Snaprud, P., von Euler, G., Johansson, B., and Fredholm, B. B. (1993). Antagonistic A JD, receptor interactions in the striatum as a basis for adenosine/dopamine interactions in the central nervous system. Drug Development Research, 28, 374–380.CrossRefGoogle Scholar
  48. Garrett, B. E., and Holtzman, S. G. (1994a). Caffeine cross-tolerance to selective dopamine D, and D, receptor agonists but not to their synergistic interaction. European Journal of Pharmacology, 262, 65–75.PubMedCrossRefGoogle Scholar
  49. Garrett, B. E., and Holtzman, S. G. (19946). D, and D, dopamine receptor antagonists block caffeine-induced stimulation of locomotor activity in rats. Pharmacology, Biochemistry and Behavior, 47, 89–94.Google Scholar
  50. Garrett, B. E., and Holtzman, S. G. (1995). Does adenosine receptor blockade mediate caffeine-induced rotational behavior? Journal of Pharmacology and Experimental Therapeutics, 274, 207–214.PubMedGoogle Scholar
  51. Georgiev, V., Johansson, B., and Fredholm, B. B. (1993). Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without a change in adenosine A, receptor number. Brain Research, 612, 271–277.PubMedCrossRefGoogle Scholar
  52. Goldberg, M. R., Curatolo, P. W., and Robertson, D. (1982). Caffeine down regulates 3-adrenoceptors in rat forebrain. Neuroscience Letters, 31, 47–51.PubMedCrossRefGoogle Scholar
  53. Griffiths, R. R., and Mumford, G. K. (1996). Caffeine reinforcement, discrimination, tolerance and physical dependence in laboratory animals and humans. In C. R. Schuster and M. J. Kuhar (Eds.), Handbook of experimental pharmacology (pp. 315–341 ). Heidelberg, Germany: Springer-Verlag.Google Scholar
  54. Holloway, F. A., Modrow, H. E., and Michaelis, R. C. (1985). Methylxanthine discrimination in the rat: Possible benzodiazepine and adenosine mechanisms. Pharmacology, Biochemistry and Behavior, 22, 815824.Google Scholar
  55. Holtzman, S. G. (1986). Discriminative stimulus properties of caffeine in the rat: Noradrenergic mediation. Journal of Pharmacology and Experimental Therapeutics, 239, 706–714.PubMedGoogle Scholar
  56. Holtzman, S. G., Mante, S., and Minneman, K. P. (1991). Role of adenosine receptors in caffeine tolerance. Journal of Pharmacology and Experimental Therapeutics, 256, 62–68.Google Scholar
  57. Horger, B. A., Wellman, P. J., Morten, A., Davies, B. T., and Schenk, S. (1991). Caffeine exposure sensitizes rats to the reinforcing effects of cocaine. Neuroreport, 2, 53–56.PubMedCrossRefGoogle Scholar
  58. lmaizumi, M., Miyazaki, S., and Onodera, K. (1994). Effects of xanthine derivatives in a light/dark test in mice and contribution of adenosine receptors. Methods and Findings in Experimental and Clinical Pharmacology, 16, 639–644.Google Scholar
  59. Jacobson, K. A., Von Lubitz, D. K. J. E., Daly, J. W., and Fredholm, B. B. (1996). Adenosine receptor ligands: Differences with acute versus chronic treatment. Trends in Pharmacological Sciences, 17, 108–113.PubMedCrossRefGoogle Scholar
  60. Jain, N., Kemp, N., Adeyemo, O., Buchanan, P., and Stone, T. W. (1995). Anxiolytic activity of adenosine receptor activation in mice. British Journal of Pharmacology, 116, 2127–2133.PubMedCrossRefGoogle Scholar
  61. Johansson, B., Ahlberg, S., van der Ploeg, I., Brene, S., Lindefors, N., Persson, H., and Fredholm, B. B. (1993). Effect on long term caffeine treatment on A, and A, adenosine receptor binding and on mRNA levels in rat brain. Naunyn-Schmidebergs Archives of Pharmacology, 347, 407–414.CrossRefGoogle Scholar
  62. Joyce, E. M., and Koob, G. E. (1981). Amphetamine-, scopolamine-and caffeine-induced locomotor activity following 6-hydroxydopamine lesions in the mesolimbic dopamine system. Psychopharmacology, 73, 311–313.PubMedCrossRefGoogle Scholar
  63. Kaplan, G. B., Greenblatt, D. J., Kent, M. A., Cotreau, M. M., Arcelin, G., and Shader, R. I. (1992). Caffeine-induced behavioral stimulation is dose-dependent and associated with A, adenosine receptor occupancy. Neuropsychopharmacology, 6, 145–153.PubMedGoogle Scholar
  64. Kaplan, G. B., Greenblatt, D. J., Kent, M. A., and CotreauBibbo, M. M. (1993). Caffeine treatment and withdrawal in mice: Relationships between dosage, concentrations, locomotor activity and A, adenosine receptor binding. Journal of Pharmacology and Experimental Therapeutics, 266, 1563–1572.PubMedGoogle Scholar
  65. Kaplan, G. B., Greenblatt, D. J., Leduc, B. W, Thompson, M. L., and Shader, R. I. (1989). Relationship of plasma and brain concentrations of caffeine and metabolites to benzodiazepine receptor binding and locomotor activity. Journal of Pharmacology and Experimental Therapeutics, 248, 1078–1083.PubMedGoogle Scholar
  66. Katims, J. J., Annau, Z., and Snyder, S. H. (1983). Interactions in the behavioral effects of methylxanthines and adenosine derivatives. Journal of Pharmacology and Experimental Therapeutics, 227, 167–173.PubMedGoogle Scholar
  67. Kuribara, H. (1994). Caffeine enhances the stimulant effects of methamphetamine, but may not affect induction of methamphetamine sensitization of ambulation in mice. Psychopharmacology, 116, 125–129.PubMedCrossRefGoogle Scholar
  68. Kuribara, H. (1995). Caffeine enhances acute stimulant effect of morphine but inhibits morphine sensitization when assessed by ambulation of mice. Progress Neuropsychopharmacology, 19, 313–321.CrossRefGoogle Scholar
  69. Kuribara, H., and Tadokoro, S. (1992). Behavioral effects of cocoa and its main active compound theobromine: Evaluation by ambulatory activity and discrete avoidance in mice. Japanese Journal ofAlcohol and Drug Dependence, 27, 168–179.Google Scholar
  70. LeBlanc, J., Richard, D., and Racotta, I. S. (1995). Metabolic and hormone-related responses to caffeine in rats. Pharmacological Research, 32, 129–134.PubMedCrossRefGoogle Scholar
  71. Lin, M. T., Chandra, A., and Lui, G. G. (1980). The effects of theophylline and caffeine on thermoregulatory functions of rats at different ambient temperatures. Journal of Pharmacy and Pharmacology, 32, 204–208.PubMedCrossRefGoogle Scholar
  72. Lin, Y., and Phillis, J. W (1990a). Chronic caffeine exposure enhances adenosinergic inhibition of cerebral cortical neurons. Brain Research, 520, 322–323.PubMedCrossRefGoogle Scholar
  73. Lin, Y., and Phillis, J. W. (1990b). Chronic caffeine exposure reduces the excitant action of acetylcholine on cerebral cortical neurons. Brain Research, 524, 316–318.PubMedCrossRefGoogle Scholar
  74. Lopez, F., Miller, L. G., Greenblatt, D. J., Kaplan, G. B., and Shader, R. I. (1989). Interaction of caffeine with the GABAA receptor complex: Alterations in receptor function but not ligand binding. European Journal of Pharmacology, 172, 453–459.PubMedCrossRefGoogle Scholar
  75. MacKenzie, T. B., Popkin, M. K., Dziubinski, J., and Sheppard, J. R. (1981). Effects of caffeine withdrawal on isoproterenol-stimulated cyclic adenosine monophosphate. Clinical Pharmacology and Therapeutics, 30, 436–438.PubMedCrossRefGoogle Scholar
  76. Marangos, P. J., Paul, S. M., Parma, A. M., Goodwin, F. K., Syapin, P., and Skolnick, P. (1979). Purinergic inhibition of diazepam binding to rat brain (in vitro). Life Sciences, 24, 851–858.PubMedCrossRefGoogle Scholar
  77. Marangos, P. J., Martino, A. M., Paul, S. M., and Skolnick, P. (1981). The benzodiazepines and inosine antagonize caffeine induced seizures. Psychopharmacology, 72, 269–273.PubMedCrossRefGoogle Scholar
  78. Marcuson, D. E., Myers, J. P., and Johnson, D. A. (1994). The role of caffeine in the modulation of neurotransmission in the brain. Pharmacopsvchoecologia, 7, 109–117.Google Scholar
  79. Marks, M. J., Grady, S. R., and Collins, A. C. (1993). Down regulation of nicotinic receptor function after chronic nicotine infusion. Journal of Pharmacology and Experimental Therapeutics, 266, 1268–1276.PubMedGoogle Scholar
  80. Mehta, A. K., and Kulkarni, S. K. (1983). Effect of purinergic substances on rectal temperature in mice: Involvement of Pl-purinoceptors. Archives Internationales de Pharmacodynamie et de Therapie, 264, 180–186.PubMedGoogle Scholar
  81. Misra, A. L., Vadlamani, N. L., and Pontani, R. B. (1984). Effect of caffeine on cocaine locomotor stimulant activity in rats. Pharmacology, Biochemistry and Behavior, 24, 761–764.CrossRefGoogle Scholar
  82. Miyamoto, K., Kurita, M., Ohmae, S., Sakai, R., Sanae, E, and Takagi, K. (1994). Selective tracheal relaxation and phosphodiesterase-1V inhibition by xanthine derivatives. European Journal of Pharmacology, 267, 317–322.PubMedCrossRefGoogle Scholar
  83. Moraidis, I., and Bingmann, D. (1994). Epileptogenic actions of xanthines in relation to their affinities for adenosine A, receptors in CA3 neurons of hippocampal slices (guinea pigs). Brain Research, 640, 140145.Google Scholar
  84. Morton, R. A., and Davies, C. H. (1997). Regulation of muscarinic acetylcholine receptor-mediated synaptic responses by adenosine in the rat hippocampus. Journal of Physiology (London), 502, 75–90.Google Scholar
  85. Mueller, K., Saboda, S., Palmour, R., and Nyhan, W. L. (1982). Self-injurious behavior produced in rats by daily caffeine and continuous amphetamine. Pharmacology, Biochemistry and Behavior, 17, 613–617.CrossRefGoogle Scholar
  86. Mukhopadhyay, S., and Poddar, J. K. (1995). Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosine interaction. Neurochemical Research, 20, 39–44.PubMedCrossRefGoogle Scholar
  87. Müller, C. E., and Daly, J. W. (1993). Stimulation of calcium release by caffeine analogs in pheochromocytoma cells. Biochemical Pharmacology, 46, 1825–1829.PubMedCrossRefGoogle Scholar
  88. Nehlig, A. (1994). Caffeine, brain energy metabolism and blood flow: A basis for understanding the behavioral effects of the methylxanthines. Pharmacopsvchoecologia, 7, 97–107.Google Scholar
  89. Nehlig, A., Daval, J.-L., Boyet, S., and Vert, P. (1986). Comparative effects of acute and chronic administration of caffeine on local cerebral glucose utilization in the conscious rat. European Journal of Pharmacology, 129, 93–103.PubMedCrossRefGoogle Scholar
  90. Nehlig, A., Daval, J.-L., and Debry, G. (1992). Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Research Reviews, 17, 139–170.PubMedCrossRefGoogle Scholar
  91. Nikodijevié, O., Sarges, R., Daly, J. W, and Jacobson, K. A. (1991). Behavioral effects of A,- and A2-selective adenosine agonists and antagonists: Evidence for synergism and antagonism. Journal of Pharmacology and Experimental Therapeutics, 259, 286–294.Google Scholar
  92. Nikodijevié, O., Jacobson, K. A., and Daly, J. W. (1993a). Acute treatment of mice with high doses of caffeine: An animal model for choreiform movement. Drug Development Research, 30, 121–128.CrossRefGoogle Scholar
  93. Nikodijevié, O., Jacobson, K. A., and Daly, J. W. (1993b). Effects of combinations of methylxanthines and adenosine analogs on locomotor activity in control and chronic caffeine-treated mice. Drug Development Research, 30, 104–110.CrossRefGoogle Scholar
  94. Nikodijevié, O., Jacobson, K. A., and Daly, J. W. (1993c). Locomotor activity in mice during chronic treatment with caffeine and withdrawal. Pharmacology, Biochemistry and Behavior, 44, 199–216.CrossRefGoogle Scholar
  95. Oliverio, A., Castellano, C., Parone, F., and Vetulani, J. (1983). Caffeine interferes with morphine-induced hyperactivity but not analgesia. Polish Journal of Pharmacology and Pharmacy, 35, 336–346.Google Scholar
  96. Poisner, A. M. (1973). Caffeine-induced catecholamine secretion: Similarity to caffeine-induced muscle contraction. Proceedings of the Society for Experimental Biology and Medicine, 142, 102–105.Google Scholar
  97. Popoli, P., Giménez-Llort, L., Pezzola, A., Reggio, R., Martinez, E., Fuxe, K., and Ferré, S. (1996). Adenosine A, receptor blockade selectivity potentiates the motor effects induced by dopamine D, receptor stimulation in rodents. Neuroscience Letters, 218, 209–213.PubMedCrossRefGoogle Scholar
  98. Rall, T. W, and Sutherland, E. W. (1958). Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. Journal of Biological Chemistry, 232, 1077–1091.PubMedGoogle Scholar
  99. Ray, S. K., and Poddar, M. K. (1990). Role of central serotonin in caffeine-induced stimulation of locomotor activity in rat. BiogenicAnrines, 7, 153–164.Google Scholar
  100. Riedel, W. Hogervorst., E., Leboux, R., Verhey, F., van Praag, L., and Jollos, J. (1995). Caffeine alters scopolamine-induced memory impairment in humans. Psychopharmacology, 122, 158–168.Google Scholar
  101. Roca, D. J., Schiller, G. D., and Farb, D. H. (1988). Chronic caffeine or theophylline exposure reduces y-aminobutyric acid/benzodiazepine receptor site interactions. Molecular Pharmacology, 33, 481–485.PubMedGoogle Scholar
  102. Rudolphi, K. A., Keil, M., Fastbom, J., and Fredholm, B. B. (1989). lschaemic damage in gerbil hippocampus is reduced following up-regulation of adenosine (A,) receptors by caffeine treatment. Neuroscience Letters, 103, 275–280.Google Scholar
  103. Sansone, M., Battaglia, M., and Castellano, C. (1994). Effect of caffeine and nicotine on avoidance learning in mice: Lack of interaction. Journal of Pharmacy and Pharmacology, 46, 765–767.PubMedCrossRefGoogle Scholar
  104. Sattin, A., and Ralf, T. W. (1970). The effect of adenosine and adenine nucleotides on the cyclic adenosine 3’,5’-phosphate content of guinea pig cerebral cortex slices. Molecular Pharmacology, 6, 13–23.PubMedGoogle Scholar
  105. Sawynok, J., and Reid, A. (1996). Caffeine antinociception: Role of formalin concentration and A, and A2 receptors. European Journal of Pharmacology 298, 105–111.PubMedCrossRefGoogle Scholar
  106. Sawynok, J., and Yaksh, T. L. (1993). Caffeine as an analgesic adjuvant: A review of pharmacology and mechanisms of action. Pharmacological Reviews, 45, 43–85.Google Scholar
  107. Seale, T. W, Abla, K. A., Shamim, M. T., Carney, J. M., and Daly, J. W. (1988). 3,7-Dimethyl-l-propargylxanthine: A potent and selective in vivo antagonist of adenosine analogs. Life Sciences, 43, 1671–1684.Google Scholar
  108. Shi, D., Nikodijevié, O., Jacobson, K. A., and Daly, J. W (1993). Chronic caffeine alters the density ofA,-adenosine, 3-adrenergic, serotonin, cholinergic, and GABA, receptors and calcium channels in mouse brain. Cellular and Molecular Neurobiology 13, 247–261.PubMedCrossRefGoogle Scholar
  109. Shi, D., Nikodijevié, O., Jacobson, K. A., and Daly, J. W. (1994). Effects of chronic caffeine on adenosine, dopamine and acetylcholine systems in mice. Archives Internationales de Pharmacodynamie et de Therapie, 328, 261–287.PubMedGoogle Scholar
  110. Snyder, S. H., Katims, J. J., Annau, Z., Bruns, R. F., and Daly, J. W. (1981). Adenosine receptors and behavioral actions of methylxanthines. Proceedings of the National Academy of Sciences USA, 78, 3260–3264.CrossRefGoogle Scholar
  111. Svenningsson, P., Strom, A., Johansson, B., and Fredholm, B. B. (1995). Increased expression of C fun, jun B, AP-1 and preproenkephalin mRNA in rat striatum following a single injection of caffeine. Journal of Neuroscience, 15, 3583–3593.PubMedGoogle Scholar
  112. Svenningsson, P., LeMoine, C., Kull, B., Sunahara, R., Bloch, B., and Fredholm, B. B. (1997). Antagonism of adenosine A2n receptors underlies the behavioral activating effect of caffeine and is associated with reduced expression of messenger RNA for NGFI-A and NGF1-B in caudate-putamen and nucleus accumbens. Neuroscience, 79, 753–764.PubMedCrossRefGoogle Scholar
  113. Swanson, J. A., Lee, J. W., and Hopp, J. W. (1994). Caffeine and nicotine. A review of their joint use and possible interactive effects in tobacco withdrawal. Addictive Behavior, 19, 229–256.CrossRefGoogle Scholar
  114. Toray, S. N., and Kulkarni, S. K. (1991). Antagonism of caffeine-induced convulsions by ethanol and dizocilpine (MK-801) in mice. Methods and Findings in Experimental and Clinical Pharmacology, 13, 413–417.Google Scholar
  115. Traversa, U., Rosati, A. M., Florio, C., and Vertua, R. (1994). Effects of chronic administration of adenosine antagonists on adenosine A, and AZA receptors in mouse brain. In Vivo, 8, 1073–1078.PubMedGoogle Scholar
  116. Ukena, D., Schudt, C., and Sybrecht, G. W. (1993). Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes. Biochemical Pharmacology, 45, 847–851.PubMedCrossRefGoogle Scholar
  117. Virus, R. M., Ticho, S., Pildtich, M., and Radulovacki, M. (1990). A comparison of the effects of caffeine, cyclopentyltheophylline, and alloxazine on sleep in rats: Possible roles of central nervous system adenosine receptors. Neuropsychopharmacology, 3, 243–249.PubMedGoogle Scholar
  118. Von Borstel, R. W., Wurtman, R. J., and Conlay, L. A. (1983). Chronic caffeine consumption potentiates the hypotensive action of circulating adenosine. Life Sciences, 32, 1151–1158.CrossRefGoogle Scholar
  119. Von Lubitz, D. K. J. E., Paul, I. A., Bartus, R. T., and Jacobson, K. A. (1993). Effects of chronic administration of adenosine A, receptor agonist and antagonist on spatial learning and memory. European Journal of Pharmacology, 249, 271–280.CrossRefGoogle Scholar
  120. White, J. M. (1994). Behavioral effects of caffeine coadministered with nicotine, benzodiazepines and alcohol. Pharmacopsychoecologia, 7, 119–126.Google Scholar
  121. Wu, P. H., and Coffin, V. L. (1984). Up-regulation of brain [3H]diazepam binding sites in chronic caffeine-treated rats. Brain Research, 294, 186–189.PubMedCrossRefGoogle Scholar
  122. Wu, P. H., and Phillis, J. W. (1988). Up-regulation of brain [3H]diazepam binding sites in chronic caffeine treated rats. General Pharmacology, 17, 501–503.Google Scholar
  123. Zhang, Y., and Wells, J. M. (1990). Effects of chronic administration on peripheral adenosine receptors. Journal of Pharmacology and Experimental Therapeutics, 254, 270–276.Google Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • John W. Daly
    • 1
  1. 1.National Institutes of HealthBethesdaUSA

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