Adenosine A_2A-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 D₂ receptors on the indirect pathway neurons, with A_2A activation opposing the effect of D₂ 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.

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