Adenosine A_2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms

Objective: To investigate whether the motor and neuroprotective effects of adenosine A_2A receptor (A_2AR) antagonists are mediated by distinct cell types in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Methods: We used the forebrain A_2AR knock-out mice coupled with flow cytometric analyses and intracerebroventricular injection to determine the contribution of A_2ARs in forebrain neurons and glial cells to A_2AR antagonist-mediated motor and neuroprotective effects. Results: The selective deletion of A_2ARs in forebrain neurons abolished the motor stimulant effects of the A_2AR antagonist KW-6002 but did not affect acute MPTP neurotoxicity. Intracerebroventricular administration of KW-6002 into forebrain A_2AR knock-out mice reinstated protection against acute MPTP-induced dopaminergic neurotoxicity and attenuated MPTP-induced striatal microglial and astroglial activation. Interpretation: A_2AR activity in forebrain neurons is critical to the control of motor activity, whereas brain cells other than forebrain neurons (likely glial cells) are important components for protection against acute MPTP toxicity.