Both selective A2AR antagonists and the non-selective adenosine receptor antagonist caffeine (Fredholm et al., 1999), can control mood and memory alterations in rodents exposed to repeated stress (Yamada et al., 2013; Kaster et al., 2015), as per the mood normalizing properties afforded by the intake of caffeine in humans (reviewed in Grosso et al., 2016) and the association of A2AR polymorphisms with anxiety and depression (Hamilton et al., 2004; Hohoff et al., 2010; Oliveira et al., 2019). This evidence concerns the gene ADORA2A and major depressive disorder.