ADORA2A and Parkinson disease: In the same PD animal model, the A2AR demonstrated a significant constitutive activity and this uncontrolled activity was blocked by caffeine and other prototypic A2AR inverse agonists.59 Therefore, we assumed that the striatal A2AR-D2R heteromer disruption observed in this PD animal model, and the expected loss of the negative canonical and allosteric control by the D2R was behind the gain of A2AR constitutive activity, which could be involved in the striatal neurodegeneration of PD (Fig. 1D).