Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists

The selective localization of adenosine A2A receptors to the striatopallidal system suggested a new therapeutic approach to the management of Parkinson's disease (PD). The results of behavioral studies using A2A receptor-specific agents in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys highlight the therapeutic potential of A2A antagonists as a novel treatment for PD. However, little is known about the role of A2A receptors in basal ganglia function or their pathophysiologic role in PD. Recently, the authors found that presynaptic A2A receptors modulate GABAergic synaptic transmission in the striatum and globus pallidus (GP), suggesting an A2A receptor-mediated dual modulation of the striatopallidal system. Striatal A2A receptors may increase the excitability of medium spiny neurons (MSNs) by modulating an intrastriatal GABAergic network. In addition, pallidal modulation occurs at striatopallidal MSN terminals located at the GP, enhancing GABA release onto GP projection neurons and directly suppressing their activity. Blockade of these modulatory functions by A2A antagonists could counteract excessive striatopallidal neuronal activity provoked by striatal dopamine depletion in patients with PD, leading to a reversal of parkinsonian motor deficits.