Abstract
Caffeine produces mild psychostimulant and sometimes anxiogenic effects by antagonizing adenosine at A1 and A2A receptors, and perhaps through interactions with other transmitter systems. Adenosine receptors are colocalized and functionally interact with dopamine receptors in the brain. Thus, functional polymorphisms in the genes for either adenosine or dopamine receptors may affect responses to caffeine. In this study, we examined associations between self-reported anxiogenic effects of caffeine and variation in the genes for A2A (ADORA2A) and DRD2 (DRD2) receptors. Healthy male and female individuals (n=102), who consumed less than 300 mg caffeine per week, ingested capsules containing 0, 50, 150, and 450 mg caffeine under double-blind conditions in four separate experimental sessions. Subjective anxiety was measured before and at repeated times after capsules were consumed. At the 150 mg dose of caffeine, we found a significant association between caffeine-induced anxiety (Visual Analog Scales, VAS) and ADORA2A rs5751876 (1976C/T), rs2298383 (intron 1a) and rs4822492 (3′-flank), and DRD2 rs1110976 (intron 6). Caffeine-induced anxiety (VAS) was also associated with two-loci interactions of selected ADORA2A and DRD2 polymorphisms. The lowest dose of caffeine did not increase ratings of anxiety while the highest dose increased anxiety in the majority of subjects. These findings provide support for an association between an ADORA2A polymorphism and self-reported anxiety after a moderate dose of caffeine. It is likely that other ADORA2A and DRD2 polymorphisms also contribute to responses to caffeine.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Alsene K, Deckert J, Sand P, de Wit H (2003). Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 28: 1694–1702.
Arinami T, Gao M, Hamaguchi H, Toru M (1997). A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet 6: 577–582.
Barrett JC, Fry B, Maller J, Daly MJ (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265.
Chen JF, Moratalla R, Impagnatiello F, Grandy DK, Cuellar B, Rubinstein M et al (2001). The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice. Proc Natl Acad Sci USA 98: 1970–1975.
Childs E, de Wit H (2006). Subjective, behavioral, and physiological effects of acute caffeine in light, nondependent caffeine users. Psychopharmacology (Berl) 185: 514–523.
Comings DE, MacMurray JP (2000). Molecular heterosis: a review. Mol Genet Metab 71: 19–31.
Conde L, Vaquerizas JM, Dopazo H, Arbiza L, Reumers J, Rousseau F et al (2006). PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes. Nucleic Acids Res 34: W621–W625.
Cornelis MC, El-Sohemy A, Campos H (2007). Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption. Am J Clin Nutr 86: 240–244.
Culverhouse R, Klein T, Shannon W (2004). Detecting epistatic interactions contributing to quantitative traits. Genet Epidemiol 27: 141–152.
Daly JW, Fredholm BB (1998). Caffeine—an atypical drug of dependence. Drug Alcohol Depend 51: 199–206.
Deckert J, Nothen MM, Franke P, Delmo C, Fritze J, Knapp M et al (1998). Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease. Mol Psychiatry 3: 81–85.
Deckert J, Nothen MM, Rietschel M, Wildenauer D, Bondy B, Ertl MA et al (1996). Human adenosine A2a receptor (A2aAR) gene: systematic mutation screening in patients with schizophrenia. J Neural Transm 103: 1447–1455.
Dews PB, Curtis GL, Hanford KJ, O’Brien CP (1999). The frequency of caffeine withdrawal in a population-based survey and in a controlled, blinded pilot experiment. J Clin Pharmacol 39: 1221–1232.
Dudbridge F (2003). Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25: 115–121.
Enoch MA, Shen PH, Xu K, Hodgkinson C, Goldman D (2006). Using ancestry-informative markers to define populations and detect population stratification. J Psychopharmacol 20: 19–26.
Evans SM, Griffiths RR (1991). Dose-related caffeine discrimination in normal volunteers: individual differences in subjective effects and self-reported cues. Behav Pharmacol 2: 345–356.
Finckh U, Giraldo-Velasquez M, Pelz J, Otto G, Sander T, Schmidt LG et al (1996). Dopamine D2 receptor gene (DRD2) haplotypes in Caucasians. Gene 179: 251–255.
Folstein MF, Luria R (1973). Reliability, validity, and clinical application of the visual analogue mood scale. Psychol Med 3: 479–486.
Fuxe K, Agnati LF, Jacobsen K, Hillion J, Canals M, Torvinen M et al (2003). Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson's disease. Neurology 61: S19–S23.
Fuxe K, Ferre S, Canals M, Torvinen M, Terasmaa A, Marcellino D et al (2005). Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function. J Mol Neurosci 26: 209–220.
Gelernter J, Kranzler H, Cubells JF, Ichinose H, Nagatsu T (1998). DRD2 allele frequencies and linkage disequilibria, including the -141CIns/Del promoter polymorphism, in European-American, African-American, and Japanese subjects. Genomics 51: 21–26.
Goni JR, de la Cruz X, Orozco M (2004). Triplex-forming oligonucleotide target sequences in the human genome. Nucleic Acids Res 32: 354–360.
Griffiths RR, Evans SM, Heishman SJ, Preston KL, Sannerud CA, Wolf B et al (1990). Low-dose caffeine discrimination in humans. J Pharmacol Exp Ther 252: 970–978.
Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, Hodge SE et al (2004). Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacology 29: 558–565.
Hart P, Farrell GC, Cooksley WG, Powell LW (1976). Enhanced drug metabolism in cigarette smokers. BMJ 2: 147–149.
Hohoff C, McDonald JM, Baune BT, Cook EH, Deckert J, de Wit H (2005). Interindividual variation in anxiety response to amphetamine: possible role for adenosine A2A receptor gene variants. Am J Med Genet B Neuropsychiatr Genet 139: 42–44.
Hughes R (1996). Drugs which induce anxiety: caffeine. N Z J Psychol 25: 36–42.
James JE, Rogers PJ (2005). Effects of caffeine on performance and mood: withdrawal reversal is the most plausible explanation. Psychopharmacology (Berl) 182: 1–8.
Jonsson EG, Nothen MM, Grunhage F, Farde L, Nakashima Y, Propping P et al (1999). Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 4: 290–296.
Kidd KK, Morar B, Castiglione CM, Zhao H, Pakstis AJ, Speed WC et al (1998). A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus. Hum Genet 103: 211–227.
Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF et al (2003). Catechol o-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100: 6186–6191.
McNair D, Lorr M, Droppleman L (1971). Profile of Mood States. Educational and Industrial Testing Service: San Diego.
Millstein J, Conti DV, Gilliland FD, Gauderman WJ (2006). A testing framework for identifying susceptibility genes in the presence of epistasis. Am J Hum Genet 78: 15–27.
Neville MJ, Johnstone EC, Walton RT (2004). Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat 23: 540–545.
Parsian A, Cloninger CR, Zhang ZH (2000). Functional variant in the DRD2 receptor promoter region and subtypes of alcoholism. Am J Med Genet 96: 407–411.
Peroutka SJ, Price SC, Wilhoit TL, Jones KW (1998). Comorbid migraine with aura, anxiety, and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles. Mol Med 4: 14–21.
Powell KR, Koppelman LF, Holtzman SG (1999). Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats. Behav Pharmacol 10: 707–716.
Ritchie T, Noble EP (2003). Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res 28: 73–82.
Shi MM, Myrand SP, Bleavins MR, de la Iglesia FA (1999). High throughput genotyping for the detection of a single nucleotide polymorphism in NAD(P)H quinone oxidoreductase (DT diaphorase) using TaqMan probes. Mol Pathol 52: 295–299.
Storey J (2002). A direct approach to false discovery rates. J R Statist Soc B 64: 479–498.
Swanson JA, Lee JW, Hopp JW (1994). Caffeine and nicotine: a review of their joint use and possible interactive effects in tobacco withdrawal. Addict Behav 19: 229–256.
Torvinen M, Kozell LB, Neve KA, Agnati LF, Fuxe K (2004). Biochemical identification of the dopamine D2 receptor domains interacting with the adenosine A2A receptor. J Mol Neurosci 24: 173–180.
Yu L, Frith MC, Suzuki Y, Peterfreund RA, Gearan T, Sugano S et al (2004). Characterization of genomic organization of the adenosine a2a receptor gene by molecular and bioinformatics analyses. Brain Res 1000: 156–173.
Zahniser NR, Simosky JK, Mayfield RD, Negri CA, Hanania T, Larson GA et al (2000). Functional uncoupling of adenosine A(2A) receptors and reduced response to caffeine in mice lacking dopamine D2 receptors. J Neurosci 20: 5949–5957.
Acknowledgements
This research was supported by NIDA (DA02812) and the General Clinical Research Center (USPHS MO1RR000555). We thank Michelle Dassinger, Liz Young, Lisa Vicini, Maliha Darugar, and Kathrin Schwarte for their technical assistance.
Author information
Authors and Affiliations
Corresponding author
Additional information
DISCLOSURE
All authors reported no biomedical financial interests or potential conflicts of interest.
Rights and permissions
About this article
Cite this article
Childs, E., Hohoff, C., Deckert, J. et al. Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety. Neuropsychopharmacol 33, 2791–2800 (2008). https://doi.org/10.1038/npp.2008.17
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2008.17
Keywords
This article is cited by
-
Brain activity during a working memory task after daily caffeine intake and caffeine withdrawal: a randomized double-blind placebo-controlled trial
Scientific Reports (2023)
-
International society of sports nutrition position stand: caffeine and exercise performance
Journal of the International Society of Sports Nutrition (2021)
-
Novel insights on caffeine supplementation, CYP1A2 genotype, physiological responses and exercise performance
European Journal of Applied Physiology (2021)
-
Experimental study of pre- and postnatal caffeine exposure and its observable effects on selected neurotransmitters and behavioural attributes at puberty
Metabolic Brain Disease (2021)
-
Neferine and lianzixin extracts have protective effects on undifferentiated caffeine-damaged PC12 cells
BMC Complementary Medicine and Therapies (2020)
