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 A 2A 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 A 2A 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