Increased adenosine A2A receptors in the brain of Parkinson's disease patients with dyskinesias

Abstract

Brain adenosine A2A receptors have recently attracted considerable attention because of their interaction with the dopaminergic system and as potential targets for Parkinson's disease pharmacotherapy. Post mortem adenosine A2A receptor mRNA and [3H]SCH 58261-specific binding to adenosine A2A receptor were studied in the brain of Parkinson's disease patients using in situ hybridization and receptor binding autoradiography, respectively. Fourteen levodopa-treated Parkinson's disease patients, of which seven developed dyskinesias and seven did not, were compared with nine controls. Nigrostriatal denervation was similar between dyskinetic and non-dyskinetic Parkinson's disease patients, as assessed with catecholamine concentrations and [125I]RTI-121-specific binding to dopamine transporters. A2A receptor mRNA levels (+129%; P < 0.01) and [3H]SCH 58261-specific binding (+32%, P < 0.01) were increased in the putamen (lateral and medial) of dyskinetic patients compared with controls. The increase of adenosine A2A receptor mRNA in dyskinetic Parkinson's disease patients was also significant compared with non-dyskinetic Parkinson's disease patients (+60%; P < 0.05) in the lateral putamen. Moreover, [3H]SCH 58261-specific binding to adenosine A 2A receptors was increased in the external globus pallidus (+24%; P < 0.001) of Parkinson's disease patients compared with controls, regardless of the dyskinesigenic response to levodopa. No change of adenosine A 2A receptors was observed in the caudate nucleus, whereas adenosine A2A receptor protein and mRNA levels in the internal globus pallidus were not different from background. These findings suggest that increased synthesis of adenosine A2A receptors in striatopallidal pathway neurons is associated with the development of dyskinesias following long-term levodopa therapy in Parkinson's disease.