Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety

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 ¼ 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 0 -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.

Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption

“…In addition, for certain analyses of the effects of caffeine vs placebo on anxiety, baseline (pretreatment) anxiety score was also included as a covariate. This is similar to the approach of calculating change from baseline scores (Childs et al, 2008), and was done to control for preexisting individual differences in anxiety in these analyses. Baseline differences in anxiety as a function of consumer status and genotype group were small (see Results).…”

“…Single nucleotide polymorphism selection was based on previous studies (Alsene et al, 2003;Childs et al, 2008;Deckert et al, 1998), and their regulatory potential (UCSC, http://genome.ucsc.edu), linkage disequilibrium (LD) and tagging capabilities (Hapmap, http://www.hapmap.org), and minor allele frequencies. Eight SNPs were selected to cover the 25 kb ADORA2A variant resulting in mRNA X68486 (rs5751862, rs5760405, New3, rs11704959, rs2298383, rs3761422, rs2267076, and rs5751876), and nine SNPs were selected to cover the 76 kb ADORA1 variant resulting in mRNA L22214 (rs9660662, rs1874142, rs10920568, rs12135643, rs3766566, rs3766560, rs3753472, rs16851030, and rs12744240).…”

“…It is possible, for example, that the experience of increased anxiety after caffeine may cause vulnerable individuals to avoid caffeine subsequently (cf Evans and Griffiths, 1992;Stern et al, 1989), so that actually there are rather few such individuals among populations of frequent caffeine consumers. Indeed, even among infrequent consumers of caffeine a minority (19-29%) carry the rs5751876 TT genotype (Alsene et al, 2003;Childs et al, 2008). Furthermore, anxiety effects of caffeine might be diminished with frequent consumption due to tolerance.…”

“…Consistent with this, recent studies have discovered an association between caffeine-induced anxiety and a single nucleotide polymorphism (SNP) in the gene coding for the adenosine A 2A receptor (ADORA2A). Specifically, it was found that 150 mg caffeine (equivalent to the amount of caffeine present in, eg, 1 1 2 cups of ground coffee) increased anxiety in individuals carrying the TT genotype of the ADORA2A SNP rs5751876, but not in the CT and CC genotype groups (Alsene et al, 2003;Childs et al, 2008).…”

“…Associations between both the anxiogenic and alerting effects of caffeine and other ADORA2A SNPs and ADORA1 SNPs were also examined. These further SNPs were selected according to their potential functional relevance, and to extend the findings of Alsene et al (2003) and Childs et al (2008). A secondary objective of the study was to test the withdrawal reversal hypothesis (James and Rogers, 2005), alluded to above, which predicts that administration of caffeine to frequent caffeine consumers after acute (overnight) caffeine deprivation will increase their alertness, but not to above the level of alertness experienced by infrequent caffeine consumers not given caffeine.…”