Such threats also require adaptive plastic changes in neuronal circuits, which may explain the increased extracellular formation of ATP-derived adenosine by ecto-nucleotidases, with a burst of its rate-limiting step—ecto-5′-nucleotidase or CD73 (Cunha, 2001)—under noxious brain conditions to sustain an overfunction of A2AR that contributes to synaptotoxicity and neurotoxicity in different brain diseases (Cunha, 2016). This evidence concerns the gene ADORA2A and brain disorder.