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, 33 (12), 2791-800

Association Between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety

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Association Between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety

Emma Childs et al. Neuropsychopharmacology.

Abstract

Caffeine produces mild psychostimulant and sometimes anxiogenic effects by antagonizing adenosine at A(1) and A(2A) 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 A(2A) (ADORA2A) and DRD(2) (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.

Conflict of interest statement

DISCLOSURE

All authors reported no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1
Linkage disequilibrium (D′) plot of ADORA2A in European-American participants. SNPs are shown by location as in Table 1. Squares without numbers represent D′ values of 1.0; all numbers represent the D′ value expressed as a percentile. Shaded squares represent pairs with LOD score for linkage disequilibrium of ≥2 and white squares represent LOD<2 and D′>1.0. Plots were generated using Genetix, V4.02.
Figure 2
Figure 2
Linkage disequilibrium (D′) plot of DRD2 in European-American participants. SNPs are shown by location as in Table 1. Other details are as in Figure 1.
Figure 3
Figure 3
Change in self-reported anxiety (VAS) after different doses of caffeine. Data represent mean ± SEM peak change from pre-capsule baseline in participants from all population groups. Asterisks denote significant difference from placebo (post hoc pairwise comparisons; **P<0.01).
Figure 4
Figure 4
Changes in anxiety (VAS) for genotypic groups of ADORA2A rs5751876 1976C/T, rs2298383 Intron 1a, and rs4822492 3′-flank after 150 mg caffeine in European-American participants. Bars represent mean ± SEM peak change from pre-capsule baseline. Asterisks denote significant difference between groups (post hoc multiple comparisons; *P<0.007).
Figure 5
Figure 5
Changes in anxiety (VAS) after 150 mg caffeine in European-American participants for genotypic groups at DRD2 rs1110976 Intron 6. Bars represent mean ± SEM peak change from pre-capsule baseline. The asterisk denotes a significant difference between the genotypes (P<0.006).

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