Effects of the adenosine A 2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefron
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ORIGINAL INVESTIGATION
Effects of the adenosine A2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex Takako Kadowaki Horita & Minoru Kobayashi & Akihisa Mori & Peter Jenner & Tomoyuki Kanda
Received: 21 February 2013 / Accepted: 20 May 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract 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 T. Kadowaki Horita : T. Kanda (*) Pharmacological Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan e-mail: [email protected] M. Kobayashi Project Management Department, Development Division, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan A. Mori Strategic Product Planning Department, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan P. Jenner Neurodegenerative Diseases Research Centre, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King’s College, London, UK
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. Keywords Cognition . Working memory . Dopamine . Adenosine A2A receptor . Istradefylline Abbreviations 6-OHDA 6-Hydroxydopamine PFC Prefrontal cortex PD Parkinson’s disease
Introduction Parkinson’s disease (PD) is primarily characterised by motor abnormalities, but cognitive changes also occur both in the early and later stages of the disease process. In late-stage disease, cognitive decline and dementia occur in up to 80 % of older individuals, and this presum
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