Skip to main content
NCBI home page
Cellular and Molecular Neurobiology logoLink to Cellular and Molecular Neurobiology
. 1993 Jun;13(3):247–261. doi: 10.1007/BF00733753

Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA, and serotonin receptors and calcium channels in mouse brain

Dan Shi 1, Olga Nikodijević 1, Kenneth A Jacobson 1, John W Daly 1
PMCID: PMC3437321  NIHMSID: NIHMS403869  PMID: 8242688

Abstract

  1. Chronic ingestion of caffeine by male NIH strain mice alters the density of a variety of central receptors.

  2. The density of cortical A1 adenosine receptors is increased by 20%, while the density of striatal A2A adenosine receptors is unaltered.

  3. The densities of corticalβ 1 and cerebellarβ 2 adrenergic receptors are reduced byca. 25%, while the densities of corticalα 1 andα 2 adrenergic receptors are not significantly altered. Densities of striatal D1 and D2 dopaminergic receptors are unaltered. The densities of cortical 5 HT1 and 5 HT2 serotonergic receptors are increased by 26–30%. Densities of cortical muscarinic and nicotinic receptors are increased by 40–50%. The density of cortical benzodiazepine-binding sites associated with GABAA receptors is increased by 65%, and the affinity appears slightly decreased. The density of cortical MK-801 sites associated with NMDA-glutaminergic receptors appear unaltered.

  4. The density of cortical nitrendipine-binding sites associated with calcium channels is increased by 18%.

  5. The results indicate that chronic ingestion of caffeine equivalent to about 100 mg/kg/day in mice causes a wide range of biochemical alterations in the central nervous system.

Key words: caffeine, adenosine receptors, adrenergic receptors, cholinergic receptors, serotonin receptors, GABA receptors, calcium channels, dopamine receptors, NMDA receptors

References

  1. Abbracchio, M. P., Fogliatto, G., Paoletti, A. M., Rovati, G. E., and Cattabeni, F. (1992). Prolonged in vitro exposure of rat brain slices to adenosine analogues: selective desensitization of adenosine A1 but not A2 receptors.Eur. J. Pharmacol.227317–324. [DOI] [PubMed] [Google Scholar]
  2. Ahlijanian, M. K., and Takemori, A. E. (1986). Cross-tolerance studies between caffeine and (−)-N6-(phenylisopropyl)-adenosine (PIA) in mice.Life Sci.88577–588. [DOI] [PubMed] [Google Scholar]
  3. Bartrup, J. T., and Stone, T. W. (1990). Activation of NMDA receptor coupled channels suppresses the inhibitory action of adenosine on hippocampal slices.Brain Res.530330–334. [DOI] [PubMed] [Google Scholar]
  4. Berkowitz, B. A., and Spector, S. (1971). The effect of caffeine and theophylline on the disposition of brain serotonin in the rat.Eur. J. Pharmac.16322–325. [DOI] [PubMed] [Google Scholar]
  5. Berkowitz, B. A., Tarver, J. H., and Spector, S. (1970). Release of norepinephrine in the central nervous system by theophylline and caffeine.Eur. J. Pharmac.1064–71. [DOI] [PubMed] [Google Scholar]
  6. Boulenger, J.-P., Patel, J., Post, R. M., Parma, A. M., and Marangos, P. J. (1983). Chronic caffeine consumption increases the number of brain adenosine receptors.Life Sci.321135–1142. [DOI] [PubMed] [Google Scholar]
  7. Bruns, R. F., Daly, J. W., and Snyder, S. H. (1980). Adenosine receptor in brain membranes: binding of N6-cyclohexyl-[3H]adenosine and 1,3-diethyl-8-[3H]phenylxanthine.Proc. Natl. Acad. Sci. USA775547–5551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bylund, D. B., and Snyder, S. H. (1976). Beta adrenergic receptor binding in membrane preparations from mammalian brain.Mol. Pharmacol.12568–580. [PubMed] [Google Scholar]
  9. Chipkin, R. E., McQuade, R. D., and Iorio, L. C. (1987). D1 and D2 dopamine binding site up-regulation and apomorphine-induced stereotypy.Pharmacol. Biochem. Behav.28477–482. [DOI] [PubMed] [Google Scholar]
  10. Corrodi, H., Fuxe, K., and Jonsson, G. (1972). Effects of caffeine on central monoamine neurons.J. Pharm. Pharmac.24155–158. [DOI] [PubMed] [Google Scholar]
  11. Daly, J. W. (1993). Mechanism of action of caffeine. In Garattini, S. (ed.),Caffeine, Coffee and Health, Raven Press Ltd., New York, pp. 97–149. [Google Scholar]
  12. Daval, J. L., Deckert, J., Weiss, S. R. B., Post, R. M., and Marangos, P. J. (1989). Upregulation of adenosine A1 receptors and forskolin binding sites following chronic treatment with caffeine or carbamazepine: a quantitative autoradiographic study.Epilepsia3026–33. [DOI] [PubMed] [Google Scholar]
  13. Dolin, S., Little, H., Hudspith, M., Pagonis, C., and Littleton, J. (1987). Increased dihydropyridine-sensitive calcium channels in rat brain may underlie ethanol physical dependence.Neuropharmacology26275–279. [DOI] [PubMed] [Google Scholar]
  14. Ehlert, F. J., Roeske, W. R., Itoga, E., and Yamamura, H. I. (1982). The binding of [3H]nitrendipine to receptors for calcium channel antagonists in the heart, cerebral cortex, and ileum of rats.Life Sci.302192–2202. [DOI] [PubMed] [Google Scholar]
  15. Ferré, S., Fuxe, K., Von Euler, G., Johansson, B., and Fredholm, B. B. (1992). Adenosine-dopamine interactions in the brain.Neuroscience51501–512. [DOI] [PubMed] [Google Scholar]
  16. Ferretti, C., Blengio, M., Vigna, I., Ghi, P., and Genazzini, E. (1992). Effects of estradiol on the ontogenesis of striatal D1 and D2 receptor sites in male and female rats.Brain Res.571212–217. [DOI] [PubMed] [Google Scholar]
  17. Fredholm, B. B. (1982). Adenosine actions and adenosine receptors after 1 week treatment with caffeine.Acta Physiol. Scand.115283–286. [DOI] [PubMed] [Google Scholar]
  18. 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 Physiol. Scand.12255–59. [DOI] [PubMed] [Google Scholar]
  19. Glossmann, H. and Hornung, R. (1980).α-Adrenoceptors in rat brain: sodium changes the affinity of agonists for prazosin sites.Eur. J. Pharmacol.61407–408. [DOI] [PubMed] [Google Scholar]
  20. Goldberg, M. R., Curatolo, P. W., Tung, C.-S., and Robertson, D. (1982). Caffeine down-regulatesβ adrenoreceptors in rat forebrain.Neuroscience Lett.3147–52. [DOI] [PubMed] [Google Scholar]
  21. Green, R. M., and Stiles, G. L. (1986). Chronic caffeine ingestion sensitized the A1 adenosine receptor-adenylate cyclase system in rat cerebral cortex.J. Clin. Invest.77222–227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hadfield, M. G., and Milio, C. (1989). Caffeine and regional brain monoamine utilization in mice.Life Sci.452637–2644. [DOI] [PubMed] [Google Scholar]
  23. Hammer, R., Berrie, C. P., Birdsall, N. J. M., Burgen, A. S. V. and Hulme (1980). Pirenzipine distinguishes between different subclasses of muscarinic receptors.Nature28390–93. [DOI] [PubMed] [Google Scholar]
  24. Hawkins, M., Dugich, M. M., Porter, N. M., Urbancic, M., and Radulovacki, M. (1988). Effects of chronic administration of caffeine on adenosine A1 and A2 receptors in rat brain.Brain Res. Bull.21479–482. [DOI] [PubMed] [Google Scholar]
  25. Hillard, C. J., and Pounds, J. J. (1993) Effects of chronic nicotine treatment on the accumulation of [3H]tetraphenylphosphonium by cerebral cortical synaptosomes.J. Neurochem.60687–695. [DOI] [PubMed] [Google Scholar]
  26. Holtzman, S. G., Mante, S., and Minneman, K. P. (1991). Role of adenosine receptors in caffeine tolerance.J. Pharmacol. Exp. Therap.25662–68. [PubMed] [Google Scholar]
  27. Jarvis, M. F., Schulz, K., Hutchison, A. J., Do, U. H., Sills, M. A., and Williams, M. (1989). [3H]CGS 21680: A selective A2 adenosine receptor agonist directly labels A2 receptors in rat brain.J. Pharmacol. Exp. Ther.251888–893. [PubMed] [Google Scholar]
  28. Josselyn, S. A., and Beninger, R. J. (1991). Behavioral effects of intrastriatal caffeine mediated by adenosinergic modulation of dopamine.Pharmacol. Biochem. Behav.3997–103. [DOI] [PubMed] [Google Scholar]
  29. Ksir, C., Hakan, R., Hall, D. P., and Kellar, K. J. (1985) Exposure to nicotine enhances the behavioral stimulant effect of nicotine and increases the binding of [3H]acetylcholine to nicotine receptors.Neuropharmacology24527–531. [DOI] [PubMed] [Google Scholar]
  30. Leysen, J. E., Gompel, P. V., Gommeren, W., Woestenborghs, R., and Janssen, P. A. J. (1986). Down regulation of serotonin-S2 receptor sites in rat brain by chronic treatment with the serotonin-S2 antagonists: ritanserin and setoperone.Psychopharmacology88434–444. [DOI] [PubMed] [Google Scholar]
  31. Lin, Y., and Phillis, J. W. (1990). Chronic caffeine exposure reduces the excitant action of acetylcholine on cerebral cortical neurons.Brain Res.524316–318. [DOI] [PubMed] [Google Scholar]
  32. Lowenstein, P. R., Vacas, M. I., and Cardinali, D. P. (1982). Effect of pentoxifylline onα- andβ-adrenoceptor sites in cerebral cortex, medial basal hypothalamus and pineal gland of the rat.Neuropharmacology21243–248. [DOI] [PubMed] [Google Scholar]
  33. Lupica, C. R., Berman, F. R., and Jarvis, M. F. (1991). Chronic theophylline treatment increases adenosine A1, but not A2, receptor binding in the rat brain; an autoradiographic study.Synapse9 95–102. [DOI] [PubMed] [Google Scholar]
  34. Marks, M. J., Stitzel, J. A., Romm, E., Wehner, J. M., and Collins, A. C. (1986). Nicotine binding sites in rat and mouse brain: comparison of acetylcholine, nicotine, andα-bungarotoxin.Mol. Pharmacol.30427–436. [PubMed] [Google Scholar]
  35. Martino-Barows, A. M., and Kellar, K. J. (1986). [3H]Acetyl-choline and [3H](−)nicotine label the same recognition site in rat brain.Mol. Pharmacol.31169–174. [PubMed] [Google Scholar]
  36. Michaluk, J., Antkiewizc-Michaluk, L., Roskosz-Pelc, A., Sansone, M., Oliver, A., and Vetulani, J. (1982). Dopamine receptor in the striatum and limbic system of various strains of mice: Relation to difference in responses to apomorphine.Pharmacol. Biochem. Behav.171115–1118. [DOI] [PubMed] [Google Scholar]
  37. Munson, P. J., and Rodbard, D. (1980). LIGAND: A versatile computerized approach for characterization of ligand-binding systems.Anal. Biochem.107220–239. [DOI] [PubMed] [Google Scholar]
  38. Nagaoka, H., Sakurada, S., Sakurada, T., Takeda, S., Nakagawa, Y., Kisara, K., and Arai, Y. (1993). Theophylline-induced nociceptive behavioral response in mice: possible indirect interaction with spinal N-methyl-D-aspartate receptors.Neurochem. Int.2269–74. [DOI] [PubMed] [Google Scholar]
  39. Nehlig, A., Daval, J.-L., and Debry, G. (1992). Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic, and psychostimulant effects.Brain Res. Rev.17139–170. [DOI] [PubMed] [Google Scholar]
  40. Nehlig, A., Daval, J.-L., Pereira de Vasconcelos, A., and Boyet (1987). Caffeine-diazepam interaction and local cerebral glucose utilization in the conscious rat.Brain Res. Rev.419272–278. [DOI] [PubMed] [Google Scholar]
  41. Nikodijević, O., Jacobson, K. A., and Daly, J. W. (1993). Locomotor activity in mice during chronic treatment with caffeine and withdrawal.Pharmacol. Biochem. Behav.44199–216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Nikodijević, O., Sarges, R., Daly, J. W., and Jacobson, K. A. (1991). Behavioral effects of A1- and A2-selective adenosine agonists and antagonists: Evidence for syntergism and antagonism.J. Pharmacol. Exp. Therap.259286–294. [PMC free article] [PubMed] [Google Scholar]
  43. Pedigo, N. W., Yamamura, H. I., and Nelson, D. L. (1981). Discrimination of multiple [3H]5-hydroxytryptamine binding sites by the neuroleptic spiperone in rat brain.J. Neurochem.36220–226. [DOI] [PubMed] [Google Scholar]
  44. Phillis, J. W., Jiang, Z. G., Chelack, B. J., and Wu, P. H. (1980). The effect of morphine on purine and acetylcholine release from rat cerebral cortex: Evidence for a purinergic component in morphine's action.Pharmacol. Biochem. Behav.13421–427. [DOI] [PubMed] [Google Scholar]
  45. Porter, N. M., Radulovacki, M., and Green, R. D. (1988). Desensitization of adenosine and dopamine receptors in rat brain after treatment with adenosine analogs.J. Pharmacol. Exp. Therap.244218–225. [PubMed] [Google Scholar]
  46. Ramkumar, V., Bumgarner, J. R., Jacobson, K. A., and Stiles, G. L. (1988). Multiple components of the A1 adenosine-adenylate cyclase system are regulated in rat cerebral cortex by chronic caffeine ingestion.J. Clin. Invest.82242–247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rudolphi, K. A., Kell, M., Fastbom, J., and Fredholm, B. B. (1989). Ischaemic damage in gerbil hippocampus is reduced following upregulation of adenosine (A1) receptors by caffeine treatment.Neurosci. Lett.103275–280. [DOI] [PubMed] [Google Scholar]
  48. Schultz, J. E., and Schmidt, B. H. (1986). Rolipram, a stereospecific inhibitor of calmodulin-independent phosphodiesterase, causesβ-adrenoceptor subsensitivity in rat cerebral cortex.Naunyn-Schmiedeberg's Arch. Pharmacol.33323–30. [DOI] [PubMed] [Google Scholar]
  49. Siggins, G. R., Hoffer, B. J., and Ungerstedt, U. (1974). Electrophysiological evidence for the involvement of cyclic adenosine monophosphate in dopamine responses of caudate neurons.Life Sci.16779–792. [DOI] [PubMed] [Google Scholar]
  50. Szot, P., Sanders, R. C., and Murray, T. F. (1987). Theophylline-induced upregulation of A1-adenosine receptors associated with reduced sensitivity to convulsants.Neuropharmacology26 1173–1180. [DOI] [PubMed] [Google Scholar]
  51. U'Prichard, D. C., Greenberg, D. A., and Snyder, S. H. (1977). Binding characteristics of a radiolabeled agonist and antagonist at central nervous system alpha noradrenergic receptors.Mol. Pharmacol.13454–473. [PubMed] [Google Scholar]
  52. Valzelli, L., and Bernasconi, S. (1973). Behavioral and neurochemical effects of caffeine in normal and aggressive mice.Pharmacol. Biochem. Behav.1251–254. [DOI] [PubMed] [Google Scholar]
  53. Williams, M. (1987). Purine receptors in mammalian tissues: pharmacology and functional significance.Ann. Rev. Pharmacol. Toxicol.27315–345. [DOI] [PubMed] [Google Scholar]
  54. Wong, E. H. F., Knight, A. R., and Woodruff, G. N. (1988). [3H]MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat brain membranes.J. Neurochem.50 274–281. [DOI] [PubMed] [Google Scholar]
  55. Wu, P. H., and Coffin, V. L. (1984). Up-regulation of brain [3H]diazepam binding sites in chronic caffeine-treated rats.Brain Res.294186–189. [DOI] [PubMed] [Google Scholar]
  56. Wu, P. H., and Phillis, J. W. (1986). Up-regulation of brain [3H]diazepam binding sites in chronic caffeine-treated rats.Gen. Pharmacol.17501–503. [DOI] [PubMed] [Google Scholar]
  57. Yamamura, H. I., and Snyder S. H. (1974). Muscarinic cholinergic binding in rat brain.Proc. Nat. Acad. Sci. USA711725–1729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Yarbrough, G. G. (1975). Supersensitivity of caudate neurons after repeated administration of haloperidol.Eur. J. Pharmacol.31367–369. [DOI] [PubMed] [Google Scholar]
  59. Zielke, C. L., and Zielke, H. R. (1987). Chronic exposure to subcutaneously implanted methylxanthines. Differential elevation of A1-adenosine receptors in mouse cerebellar and cerebral cortical membranes.Biochem. Pharmacol.362533–2538. [DOI] [PubMed] [Google Scholar]

Articles from Cellular and Molecular Neurobiology are provided here courtesy of Springer

RESOURCES