Featured Article Reversal of scopolamine-induced deficits with a single dose of donepezil, an acetylcholinesterase inhibitor Peter J. Snyder a,b, *, Martin M. Bednar b , Jennifer R. Cromer a , Paul Maruff c,d a Department of Psychology, University of Connecticut, 406 Babbidge Road, Unit 1020, Storrs, CT, 06269-1020, USA b Pfizer Global Research & Development, Groton, CT USA c CogState Ltd, Melbourne, Australia d School of Psychological Science, LaTrobe University, Melbourne, Australia Received 4 August 2005; received in revised form 12 September 2005; accepted 14 September 2005 Abstract Background: To develop a more rapid screening paradigm for novel cognitive enhancers, the authors sought to determine the utility of a well-known pharmacologic model of induced dementia (scopolamine challenge), paired with a sensitive neuropsychological test, for assessing the ability of a single oral dose of a current treatment for Alzheimer’s disease (donepezil) to improve cognitive performance in healthy elderly subjects. Methods: Thirty-two (4 groups of 8) healthy elderly volunteers were put randomly into a double-blind, placebo-controlled, modified crossover design study. In Part 1, 16 subjects received donepezil (5 mg) or placebo separately in a crossover fashion. In Part 2, the remaining 2 groups of 8 subjects received scopolamine (0.3 mg subcutaneously) with each group then were assigned randomly to receive donepezil (5 mg) or placebo (in a crossover fashion) 3 hours postbaseline. A novel measure of visuospatial working memory and executive controls, the Groton Maze Learning Test (GMLT), was administered to each subject at baseline and at 2.5, 4, 5.5, 7, and 9 hours after dosing of donepezil. Results: With scopolamine, subjects showed slower psychomotor speed, reduced accuracy and learning efficiency, and longer time required to navigate a hidden maze. Concurrent administration of donepezil significantly reversed these deficits and resulted in a faster recovery time. In addition, single doses of donepezil alone led to improved psychomotor speed, accuracy, and learning efficiency. Conclusions: Robust effects of single-dose donepezil on cognition can be readily observed, with the use of a complex hidden maze learning task, both with and without a scopolamine-induced deficit model in healthy elderly adults. © 2005 The Alzheimer’s Association. All rights reserved. Keywords: Acetylcholinesterase inhibitor; Donepezil; Scopolamine; Cognition; Neuropsychological test; Maze learning; Working memory; Sensitivity of measurement 1. Introduction The cholinergic neurotransmitter system is involved in the storage and retrieval of new learning [1], as well as playing an important role in other aspects of cognition (eg, information processing speed) [2]. The storage and retrieval of new learning is supported by a complex circuit that involves large numbers of cholinergic projections from the nucleus basalis of Meynert (NbM) to the hippocampus, amygdala, and throughout the cortex. It is well known that lesions to these mesial temporal and basal forebrain cholin- Conflict of Interest Disclosure: Dr. Snyder was a staff clinician-scien- tist at Pfizer Inc., the manufacturer of donepezil, throughout the design and conduct of this study (he is presently at the University of Connecticut). Dr. Bednar is a staff clinician-scientist employed by Pfizer Inc. Dr. Maruff is the Chief Scientific Officer of CogState, Ltd. (www.cogstate.com), a di- agnostic test company that maintains several contractual agreements with Pfizer Inc., for the provision of their clinical tests. The Groton Maze Learning Test (GMLT) was developed by Dr. Snyder, and is licensed for commercial distribution by CogState, Ltd *Corresponding author. Tel: (860) 715-2195. E-mail address: peter.snyder@uconn.edu Alzheimer’s & Dementia 1 (2005) 126 –135 1552-5260/05/$ – see front matter © 2005 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2005.09.004