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Adenosine–dopamine interactions

Development of a concept and some comments on therapeutic possibilities

From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

Address correspondence and reprint requests to Dr. Bertil B. Fredholm, Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden; e-mail: Bertil.Fredholm{at}fyfa.ki.se

Abstract

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 A_2A 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 A_2A receptors are closely associated with D₂ receptors. Distinct functional interactions at several levels were discovered, and there is now strong evidence that A_2A 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 A_2A 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.