Uncovering Caffeine’s Adenosine A(2A) Receptor Inverse Agonism in Experimental Parkinsonism

[Image: see text] Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A(2A) receptor (A(2A)R) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A(2A)R inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A(2A)R agonist, of the receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A(2A)R inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.