Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease

Studies in animal models of Parkinson's disease (PD) and preliminary clinical trials have shown that adenosine A2A antagonists might be useful in the treatment of the disease. In order to study the effect of A2A blockade on parkinsonian tremor and on long-term modifications produced by chronic L-DOPA, we have evaluated: (I) the effect of the A2A antagonist SCH 58261 on jaw tremor induced by tacrine; (II) glutamic acid decarboxylase (GAD 67) mRNA in basal ganglia, by in situ hybridization in 6-hydroxydopamine (6-OHDA) lesioned rats chronically treated with SCH 58261+L-DOPA or L-DOPA alone, as model of dyskinesia. (I) Intact rats receiving tacrine display bursts of jaw movements, which were counteracted by parenteral, and intrastriatal administration of A2A antagonists. (II) Acute administration of SCH 58261+L-DOPA, potentiates the rotational behavior induced by L-DOPA indicating anti PD activity of A2A antagonists. Chronic administration of SCH 58261 plus L-DOPA, produced minimal changes in GAD67 mRNA in the striatum and globus pallidus whereas L-DOPA alone increased GAD67 mRNA in both structures. Moreover, in the substantia nigra, GAD67 mRNA was significantly decrease after L-DOPA alone while SCH 58261 plus LLDOPA brought the GAD67 mRNA level increased by the lesion, to the same level of the intact substantia nigra. Antagonism of A2A receptors effectively counteracts the motor impairment and tremor, which characterize PD, and produces little or no long-term changes in basal ganglia activity, suggesting that this treatment has low dyskinetic potential