Adenosine-dopamine interactions: development of a concept and some comments on therapeutic possibilities

This brief review presents a personal perspective on the historical development of the current knowledge about the biologically important concept of functional antagonism between adenosine A2A and dopamine D2 receptors in caudate-putamen, accumbens, and tuberculum olfactorium. In the 1970s, studies of dopamine actions suggested an unexpected role of adenosine. Developments during the next decade substantiated this finding and demonstrated that a subform of adenosine A2 receptors was enriched in the basal ganglia. Cloning of adenosine receptors provided better tools for cellular localization and showed that A2A receptors are closely associated with D2 receptors. Distinct functional interactions at several levels were discovered, and there is now strong evidence that A2A receptors are tonically active and modified by dopamine acting at D2 receptors. Development of selective antagonists and knockout mice have highlighted the potential usefulness of A2A antagonists in decreasing symptoms and progression of Parkinson's disease-something that has also been vindicated by careful epidemiologic studies. There are issues of efficacy and potential side effects that need to be resolved, but the future looks bright.