RATIONALE: Altered cognitive function is a common feature of both the early and 
later stages of Parkinson's disease (PD) that involves alterations in cortical 
dopamine content. Adenosine A2A antagonists, such as istradefylline, improve 
motor function in PD, but their effect on cognitive impairment has not been 
determined.
OBJECTIVE: The present study investigated whether impairment of working memory 
due to the loss of dopaminergic input into the prefrontal cortex (PFC) is 
reversed by administration of istradefylline. We also evaluated whether A2A 
antagonist administration modulates dopamine levels in the PFC.
METHODS: Bilateral lesions of the dopaminergic input to the PFC were produced in 
rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using 
an object recognition task and delayed alternation task. The effects of 
istradefylline, donepezil and methamphetamine on cognitive performance were 
examined. In addition, the effect of istradefylline on extracellular dopamine 
levels in the PFC was studied.
RESULTS: PFC dopamine levels and cognitive performance were significantly 
reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine 
improved cognitive performance of PFC-lesioned rats. Istradefylline increased 
dopamine levels in the PFC in both normal and PFC-lesioned rats.
CONCLUSIONS: PFC dopaminergic input plays an important role in working memory 
performance. Blockade of A2A receptors using istradefylline reverses the changes 
in cognitive function, and this may be due to an increase in PFC dopamine 
content. Adenosine A2A receptor antagonists not only improve motor performance 
in PD but may also lead to improved cognition.