Role of adenosine A_2A receptors in motor control: relevance to Parkinson's disease and dyskinesia

Adenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A_2A subtype are highly enriched in the caudate-putamen, which is richly innervated by dopamine. Moreover, several studies in experimental animals have consistently demonstrated that the pharmacological antagonism of A_2A receptors has a facilitatory influence on motor behavior. Taken together, these findings have envisaged A_2A receptors as a promising target for symptomatic therapies aimed at ameliorating motor deficits. Accordingly, A_2A receptor antagonists have been extensively studied as new agents for the treatment of Parkinson's disease (PD), the epitome of motor disorders. In this review, we provide an overview of the effects that adenosine A_2A receptor antagonists elicit in rodent and primate experimental models of PD, with regard to the counteraction of motor deficits as well as to manifestation of dyskinesia and motor fluctuations. Moreover, we briefly present the results of clinical trials of A_2A receptor antagonists in PD patients experiencing motor fluctuations, with particular regard to dyskinesia. Finally, we discuss the interaction between A_2A receptor antagonists and serotonin receptor agonists, since combined administration of these drugs has recently emerged as a new potential therapeutic strategy in the treatment of dyskinesia.