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Effects of Long-Term Caffeine Consumption on the Adenosine A1 Receptor in the Rat Brain: an In Vivo PET Study with [18F]CPFPX

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Abstract

Purpose

Caffeine, a nonselective antagonist of adenosine receptors, is the most popular psychostimulant worldwide. Recently, a protective role of moderate chronic caffeine consumption against neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease has been discussed. Thus, aim of the present study was an in vivo investigation of effects of long-term caffeine consumption on the adenosine A1 receptor (A1AR) in the rat brain.

Procedures

Sixteen adult, male rats underwent five positron emission tomography (PET) scans with the highly selective A1AR radioligand [18F]CPFPX in order to determine A1AR availability. After the first baseline PET scan, the animals were assigned to two groups: Caffeine treatment and control group. The caffeine-treated animals received caffeinated tap water (30 mg/kg bodyweight/day, corresponding to 4–5 cups of coffee per day in humans) for 12 weeks. Subsequently, caffeine was withdrawn and repeated PET measurements were performed on day 1, 2, 4, and 7 of caffeine withdrawal. The control animals were measured according to the same time schedule.

Results

At day 1, after 4.4 h of caffeine withdrawal, a significant decrease (− 34.5%, p < 0.001) of whole brain A1AR availability was observed. Unlike all other investigated brain regions in caffeine-treated rats, the hypothalamus and nucleus accumbens showed no significant intraindividual differences between baseline and first withdrawal PET scan. After approximately 27 h of caffeine withdrawal, the region- and group-specific effects disappeared and A1AR availability settled around baseline.

Conclusions

The present study provides evidence that chronic caffeine consumption does not lead to persistent changes in functional availability of cerebral A1ARs which have previously been associated with neuroprotective effects of caffeine. The acute and region-specific decrease in cerebral A1AR availability directly after caffeine withdrawal is most likely caused by residual amounts of caffeine metabolites disguising an unchanged A1AR expression at this early time-point.

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References

  1. Fredholm BB, Ijzerman AP, Jacobson KA et al (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

    CAS  PubMed  Google Scholar 

  2. Fastbom J, Pazos A, Palacios JM (1987) The distribution of adenosine A1 receptors and 5′-nucleotidase in the brain of some commonly used experimental animals. Neuroscience 22:813–826

    Article  CAS  PubMed  Google Scholar 

  3. Fastbom J, Pazos A, Probst A et al (1987) Adenosine A1 receptors in the human brain: a quantitative autoradiographic study. Neuroscience 22:827–839

    Article  CAS  PubMed  Google Scholar 

  4. Gessi S, Merighi S, Varani K et al (2011) Adenosine receptors in health and disease. Adv Pharamacol 61:41–75

    Article  CAS  Google Scholar 

  5. Paul S, Elsinga HP, Ishiwata K et al (2016) Adenosine A(1) receptors in the central nervous system: their functions in health and disease, and possible elucidation by PET imaging. Curr Med Chem 18:4820–4835

    Article  Google Scholar 

  6. Holschbach MH, Olsson RA, Bier D et al (2002) Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX): a potent and selective A1-adenosine receptor antagonist for in Vivo imaging. J Med Chem 45:5150–5156

    Article  CAS  PubMed  Google Scholar 

  7. Elmenhorst D, Kroll T, Wedekind F et al (2013) In vivo kinetic and steady-state quantification of [18F]-CPFPX binding to rat cerebral A1 adenosine receptors: validation by displacement and autoradiographic experiments. J Nucl Med 54:1–9

    Article  Google Scholar 

  8. Bauer A, Holschbach MH, Meyer PT et al (2003) In vivo imaging of adenosine A1 receptors in the human brain with [18F]CPFPX and positron emission tomography. NeuroImage 19:1760–1769

    Article  PubMed  Google Scholar 

  9. Fredholm BB, Bättig K, Holmén J et al (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133

    CAS  PubMed  Google Scholar 

  10. Nehlig A, Daval JL, Debry G (1992) Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev 17:139–170

    Article  CAS  PubMed  Google Scholar 

  11. Addicott MA, Laurienti PJ (2009) A comparison of the effects of caffeine following abstinence and normal caffeine use. Psychopharmacology 207:423–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. James JE, Rogers PJ (2005) Effects of caffeine on performance and mood: withdrawal reversal is the most plausible explanation. Psychopharmacology 182:1–8

    Article  CAS  PubMed  Google Scholar 

  13. Eskelinen MH, Ngandu T, Toumilehto J et al (2009) Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J Alzheimers Dis 16:85–91

    Article  CAS  PubMed  Google Scholar 

  14. Qi H, Li S (2014) Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson’s disease. Geriatr Gerontol Int 14:430–439

    Article  PubMed  Google Scholar 

  15. Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55

    Article  CAS  PubMed  Google Scholar 

  16. Boulenger G, Marangos PJ (1989) Caffeine withdrawal affects central adenosine receptors but not benzodiazepine receptors. J Neural Transm Gen Sect 78:9–15

    Article  CAS  PubMed  Google Scholar 

  17. Daval JL, Deckert J, Weiss SR et al (1989) Upregulation of adenosine A1 receptors and forskolin binding sites following chronic treatment with caffeine or carbamazepine: a quantitative autoradiographic study. Epilepsia 30:26–33

    Article  CAS  PubMed  Google Scholar 

  18. Ramkumar V, Bumgarner JR, Jacobson KA et al (1988) Multiple components of the A1 adenosine receptor-adenylate cyclase system are regulated in rat cerebral cortex by chronic caffeine ingestion. J Clin Invest 82:242–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Espinosa J, Rocha A, Nunes F et al (2013) Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia. J Alzheimers Dis 34:509–518

    CAS  PubMed  Google Scholar 

  20. Georgiev V, Johansson B, Fredholm BB (1993) Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without changes in adenosine A1 receptor number. Brain Res 612:271–277

    Article  CAS  PubMed  Google Scholar 

  21. Johansson B, Georgiev V, Kuosmanen T et al (1996) Long-term treatment with some methylxanthines decreases the susceptibility to bicuculline- and pentylenetetrazol-induced seizures in mice. Relationship to c-ios expression and receptor binding. Eur J Neurosci 8:2447–2458

    Article  CAS  PubMed  Google Scholar 

  22. Marangos PJ, Boulenger G, Patel J (1984) Effects of chronic caffeine on brain adenosine receptors: regional and ontogenetic studies. Life Sci 34:899–907

    Article  CAS  PubMed  Google Scholar 

  23. Boulenger G, Patel J, Post RM et al (1983) Chronic caffeine consumption increases the number of brain adenosine receptors. Life Sci 32:1135–1142

    Article  CAS  PubMed  Google Scholar 

  24. Sengupta P (2013) The laboratory rat: relating its age with human’s. Int J Prev Med 4:624–630

    PubMed  PubMed Central  Google Scholar 

  25. Elmenhorst D, Meyer PT, Matusch A et al (2012) Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with [18F]-CPFPX and PET. J Nucl Med 53:1723–1729

    Article  CAS  PubMed  Google Scholar 

  26. Kaplan GB, Greenblatt DJ, Kent MA et al (1993) Caffeine treatment and withdrawal in mice: relationships between dosage, concentrations, locomotor activity and A1 adenosine receptor binding. J Pharamcol Exp Ther 266:1563–1572

    CAS  Google Scholar 

  27. Kroll T, Elmenhorst D, Weisshaupt A et al (2014) Reproducibility of non-invasive A1 adenosine receptor quantification in the rat brain using [18F]CPFPX and positron emission tomography. Mol Imag Biol 16:699–709

    Article  Google Scholar 

  28. Innis RB, Cunningham VJ, Delforge J et al (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539

    Article  CAS  PubMed  Google Scholar 

  29. Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. NeuroImage 4:153–158

    Article  CAS  PubMed  Google Scholar 

  30. Shukitt-Hale B, Miller MG, Chu YF et al (2013) Coffee, but not caffeine, has positive effects on cognition and psychomotor behavior in aging. Age (Dordr) 35:2183–2192

    Article  CAS  Google Scholar 

  31. Wu PH, Coffin VL (1984) Up-regulation of brain [3H]diazepam binding sites in chronic caffeine-treated rats. Brain Res 294:186–189

    Article  CAS  PubMed  Google Scholar 

  32. Bonati M, Latini R, Galletti F et al (1982) Caffeine disposition after oral doses. Clin Pharmacol Ther 32:98–106

    Article  CAS  PubMed  Google Scholar 

  33. Bortolotti A, Traina GL, Guaitani A et al (1990) In vivo and perfused liver caffeine kinetics in the rat. Res Commun Chem Pathol Pharmacol 69:285–295

    CAS  PubMed  Google Scholar 

  34. Liu X, Smith BJ, Chen C et al (2005) Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium: an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding. J Pharmacol Exp Ther 313:1254–1262

    Article  CAS  PubMed  Google Scholar 

  35. Wang Y, Lau CE (1998) Caffeine has similar pharmacokinetics and behavioral effects via the i.p. and p.o. routes of administration. Pharmacol Biochem Behav 60:271–278

    Article  PubMed  Google Scholar 

  36. Daly JW, Butts-Lamb P, Padgett W (1983) Subclasses of adenosine receptors in the central nervous system: interaction with caffeine and related methylxanthines. Cell Mol Neurobiol 3:69–80

    Article  CAS  PubMed  Google Scholar 

  37. Gasior M, Jaszyna M, Munzar P et al (2002) Caffeine potentiates the discriminative-stimulus effects of nicotine in rats. Psychopharmacology 162:385–395

    Article  CAS  PubMed  Google Scholar 

  38. Liu X, Smith BJ, Chen C et al (2006) Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration. Drug Metab Dispos 34:1443–1447

    Article  CAS  PubMed  Google Scholar 

  39. Hawkins M, Dugich MM, Porter NM et al (1988) Effects of chronic administration of caffeine on adenosine A1 and A2 receptors in rat brain. Brain Res Bull 21:479–482

    Article  CAS  PubMed  Google Scholar 

  40. Elmenhorst D, Meyer PT, Matusch A et al (2007) Test-retest stability of cerebral A1 adenosine receptor quantification using [18F]CPFPX and PET. Eur J of Nucl Med Mol Imaging 34:1061–1070

    Article  CAS  Google Scholar 

  41. Green RM, Stiles GL (1986) Chronic caffeine ingestion sensitizes the A1 adenosine receptor-adenylate cyclase system in rat cerebral cortex. J Clin Invest 77:222–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Tim Urbansky, Andrea Radermacher, Sylvia Köhler-Dibowski, Stefanie Krause, and Dorothe Krug are gratefully acknowledged for excellent technical assistance. We thank Daniela Schneider for analyzing plasma caffeine concentrations, Nikola Kornadt-Beck for fruitful discussions and valuable support, and Johannes Ermert and Bernd Neumaier for radioligand supply.

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Authors and Affiliations

  1. Institute of Neuroscience and Medicine (INM-2), Forschungszentrum Jülich GmbH, Jülich, Germany

    Danje Nabbi-Schroeter, David Elmenhorst, Angela Oskamp, Stefanie Laskowski, Andreas Bauer & Tina Kroll

  2. Psychiatry and Psychotherapy, Medical Psychology, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany

    David Elmenhorst

  3. Neurological Department, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Andreas Bauer

Authors
  1. Danje Nabbi-Schroeter
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  2. David Elmenhorst
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  3. Angela Oskamp
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  4. Stefanie Laskowski
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  5. Andreas Bauer
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  6. Tina Kroll
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Corresponding author

Correspondence to Tina Kroll.

Ethics declarations

All experiments were approved by the regional authorities and conducted in accordance with the German Animal Protection Act.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Nabbi-Schroeter, D., Elmenhorst, D., Oskamp, A. et al. Effects of Long-Term Caffeine Consumption on the Adenosine A1 Receptor in the Rat Brain: an In Vivo PET Study with [18F]CPFPX. Mol Imaging Biol 20, 284–291 (2018). https://doi.org/10.1007/s11307-017-1116-4

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  • DOI: https://doi.org/10.1007/s11307-017-1116-4

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