Adenosine A2A receptors and Parkinson's disease

The drug treatment of Parkinson's disease (PD) is accompanied by a loss of drug efficacy, the onset of motor complications, lack of effect on non-motor symptoms, and a failure to modify disease progression. As a consequence, novel approaches to therapy are sought, and adenosine A(2A) receptors (A(2A)ARs) provide a viable target. A(2A)ARs are highly localized to the basal ganglia and specifically to the indirect output pathway, which is highly important in the control of voluntary movement. A(2A)AR antagonists can modulate gamma-aminobutyric acid (GABA) and glutamate release in basal ganglia and other key neurotransmitters that modulate motor activity. In both rodent and primate models of PD, A(2A)AR antagonists produce alterations in motor behavior, either alone or in combination with dopaminergic drugs, which suggest that they will be effective in the symptomatic treatment of PD. In clinical trials, the A(2A)AR antagonist istradefylline reduces "off" time in patients with PD receiving optimal dopaminergic therapy. However, these effects have proven difficult to demonstrate on a consistent basis, and further clinical trials are required to establish the clinical utility of this drug class. Based on preclinical studies, A(2A)AR antagonists may also be neuroprotective and have utility in the treatment of neuropsychiatric disorders. We are only now starting to explore the range of potential uses of A(2A)AR antagonists in central nervous system disorders, and their full utility is still to be uncovered.