title: Adenosine A2A-receptor antagonism and pathophysiology of Parkinson's disease and drug-induced movement disorders.
abstract: Parkinson's disease and drug-induced movement disorders (DIMDs) have commonalities in etiology based on impaired dopamine-based neurotransmission. Adenosine A(2A)-receptor antagonism may provide a new mechanism through which these disorders can be managed. In the motor circuit, tonic output from the globus pallidus and substantia nigra regulates movement via opposing excitatory and inhibitory inputs to the cerebral cortex through the direct and indirect pathways. Increased activity of the direct pathway increases movement via an inhibitory effect on thalamocortical projection neurons; increased activity of the indirect pathway has the opposite effect. Regulation of these pathways is mediated primarily by reciprocal inhibitory interactions between dopamine and adenosine receptors on neurons of these pathways. Adenosine A(2A) receptors are colocalized with dopamine D(2) receptors on the indirect pathway neurons, with A(2A) activation opposing the effect of D(2) activation. The A(2A) receptors' role in the pathophysiology of Parkinson's disease and DIMDs is evidenced by the upregulation of A(2A) receptors in patients with Parkinson's disease and patients receiving long-term administration of dopamine blockers. Further, A(2A)-receptor antagonists are effective in reversing parkinsonian motor deficits and extrapyramidal symptoms in animal models of Parkinson's disease and DIMDs. Understanding the role of A(2A)-receptor antagonism in the pathophysiology of Parkinson's disease and DIMD has therapeutic implications.
authors: Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Institute of Biomedical Research Barcelona, Spain. jkulisevsky@santpau.cat
authors: Jaime
authors: J
authors: Kulisevsky
authors: Michael
authors: M
authors: Poyurovsky
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000627:therapeutic use*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A