Pharmacological Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan.
Psychopharmacology (Berl). 2013 Dec;230(3):345-52. doi: 10.1007/s00213-013-3158-x. Epub 2013 Jun 10.
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.
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.
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.
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.
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.
认知功能改变是帕金森病（PD）早期和晚期的共同特征，涉及皮质多巴胺含量的改变。腺苷 A2A 拮抗剂，如伊曲茶碱，可改善 PD 的运动功能，但它们对认知障碍的影响尚未确定。
本研究旨在探讨伊曲茶碱是否可以逆转由于前额叶皮质（PFC）多巴胺能传入减少引起的工作记忆损伤。我们还评估了 A2A 拮抗剂给药是否调节 PFC 中的多巴胺水平。
使用 6-羟多巴胺（6-OHDA）在大鼠中产生 PFC 多巴胺能传入的双侧损伤。使用物体识别任务和延迟交替任务评估认知表现。检查了伊曲茶碱、多奈哌齐和苯丙胺对认知表现的影响。此外，还研究了伊曲茶碱对 PFC 细胞外多巴胺水平的影响。
PFC 多巴胺水平和认知表现因 6-OHDA 损伤而显著降低。伊曲茶碱、多奈哌齐和苯丙胺改善了 PFC 损伤大鼠的认知表现。伊曲茶碱增加了正常和 PFC 损伤大鼠 PFC 中的多巴胺水平。
PFC 多巴胺能传入在工作记忆表现中起重要作用。使用伊曲茶碱阻断 A2A 受体可逆转认知功能的变化，这可能是由于 PFC 多巴胺含量的增加。腺苷 A2A 受体拮抗剂不仅改善 PD 中的运动性能，而且可能导致认知改善。
