ADORA2A Gene Variation, Caffeine, and Emotional Processing: A Multi-level Interaction on Startle Reflex

Abstract

There is converging evidence for genetic, biochemical, and neuropsychological factors to increase the risk for anxiety and anxiety disorders. The pathogenesis of anxiety disorders is assumed to be influenced by a complex interaction of these individual risk factors on several levels, affecting intermediate phenotypes of anxiety such as the startle reflex. Thus, in the present double-blind, placebocontrolled study we attempted to paradigmatically investigate a multi-level pathogenetic model of anxiety by testing the effect of 300 mg caffeine citrate as an antagonist at the adenosine A2A receptor vs placebo on the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) startle reflex in 110 healthy individuals (male ¼ 56, female ¼ 54) stratified for the adenosine A2A receptor (ADORA2A) 1976T4C polymorphism (rs5751876). In addition to the expected main effect of picture category (highest startle amplitude for unpleasant, lowest for pleasant pictures) groups across all ADORA2A 1976T4C genotype and intervention (caffeine vs placebo) groups, an interaction effect of genotype, intervention, and picture category was discerned: In ADORA2A 1976TT risk genotype carriers, highest startle magnitudes were observed after caffeine administration in response to unpleasant pictures, with this effect arising particularly from the female subgroup. Our data point to a complex, multi-level, and potentially gender-specific pathogenetic model of anxiety, with genetic and biochemical factors interactively increasing the risk of maladaptive emotional processing and thereby possibly also anxiety disorders. The present findings may eventually aid in improving primary and secondary prevention by sharpening the risk profiles of anxiety-prone individuals.

PharmGKB summary

“…A recent study in White healthy volunteers did not replicate this association, although the authors state that this may have been because of differences between the American and German anxiety measurement assessment scales or dose of caffeine [30]. They did observe qualitative differences in startle reflex that were more pronounced in women and involved the interaction of rs5751876 genotype, caffeine, and type of stimuli, although they did not compare genotype groups directly [30]. ADORA2A rs5751876 is not associated with vasodilator response when exposed to adenosine and caffeine [32].…”

Modification of caffeine effects on the affect-modulated startle by neuropeptide S receptor gene variation

“…Also, although the present results have been controlled for a potential impact of the ADORA2A 1976 T > C (rs5751876) variant, which has previously been found to be associated with anxiety-related phenotypes (Deckert et al 1998;Freitag et al 2010;Hamilton et al 2004;Hohoff et al 2009;Hohoff et al 2010) and subjective as well as psychophysiological anxiety responses to caffeine (Alsene et al 2003;Childs et al 2008;Rogers et al 2010;Domschke et al 2012), an influence of further anxietyrelevant genetic background, e.g., the dopamine D2 receptor (DRD2) (see Childs et al 2008), which has been suggested to play a role in setting up adaptive responses to cope with aversive environmental stimuli (de la Mora et al 2010), cannot be excluded. Finally, IAPS pictures used in the present study were matched regarding arousal level of unpleasant and pleasant pictures, but valence was higher for unpleasant as compared to pleasant pictures, which could have influenced our results.…”

“…Strom, unpublished data, http://ihg.gsf.de/cgi-bin/hw/hwa1.pl), were fulfilled for NPSR genotype distribution in the present sample (T/T, 20.2 %; A/T, 50.8 %; A/A, 29.0 %; p00.85). Given previous association findings of a silent polymorphism in exon 2 of the ADORA2A gene (rs5751876, 1976 T > C, formerly 1083 T > C, Tyr/Tyr) with anxiety-related phenotypes (Deckert et al 1998;Freitag et al 2010;Hamilton et al 2004;Hohoff et al 2009;Hohoff et al 2010) and subjective as well as psychophysiological anxiety responses to caffeine (Alsene et al 2003;Childs et al 2008;Rogers et al 2010;Domschke et al 2012), the present results were controlled for ADORA2A 1976 T > C genotype distribution (C/C, 23.3 %; C/T, 36.2 %; T/T, 40.5 %; for genotyping conditions, see Deckert et al (1998)). …”

“…A blood sample (20 ml EDTA blood) was taken for genetic analyses. From this larger pool of probands, a subsample of 124 subjects was recruited for the presently applied affect-modulated startle experiment as described in detail by Domschke et al (2012). Additional exclusion criteria were caffeine or lactose intolerance, high and frequent caffeine consumption (more than three cups of coffee per day), lower than high school education, or breast feeding.…”

“…In turn, NPS injections have been observed to reduce cumulative burying behavior, which is increased by caffeine (Vitale et al 2008), while a NPSR receptor antagonist did not affect the hyperlocomotor effect of caffeine in mice (Ruzza et al 2010). In summary, as the neuropeptide S system seems to closely interact with the adenosine system and as caffeine has previously been shown to influence anxiety-related measures as well as the affect-modulated startle reflex (Alsene et al 2003;Childs et al 2008;Domschke et al, 2012;Rogers et al 2010), investigation of the interactive effects of NPSR gene variation and caffeine on startle response to emotional stimuli might aid in further elucidating the complex interplay between the neuropeptide S and adenosine systems in the human model. Thus, given evidence from animal and human studies for the neuropeptide S system to (1) partly mediate the acoustic startle reflex, (2) influence emotional processing, and (3) interact with the adenosinergic system, the present studybased on our previous study setting of a double-blind, placebo-controlled caffeine administration prior to measurement of the affect-modulated startle response ) -for the first time aims at investigating the impact of NPSR A/T (Asn 107 Ile; rs324981) genotype on the startle reflex and its modulation by emotional stimuli and caffeine in human probands.…”