Neuropsychologia 46 (2008) 2476–2484 Contents lists available at ScienceDirect Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia Specific impairments in visuospatial working and short-term memory following low-dose scopolamine challenge in healthy older adults Elizabeth Thomas a , Peter J. Snyder b,c , Robert H. Pietrzak d,e , Colleen E. Jackson f , Martin Bednar g , Paul Maruff e,h,∗ a Department of Psychology, University of Melbourne, Australia b Department of Clinical Neurosciences, Warren Alpert Medical School of Brown University, Providence, RI, USA c Child Study Center, Yale University School of Medicine, New Haven, CT, USA d Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA e CogState Ltd., Melbourne, Australia f Department of Psychology, University of Connecticut, Storrs, CT, USA g Pfizer Global Research and Development, Groton, CT, USA h Centre for Neuroscience, University of Melbourne, Australia article info Article history: Received 31 August 2007 Received in revised form 15 April 2008 Accepted 16 April 2008 Available online 22 April 2008 Keywords: Scopolamine Donepezil cognitive function Spatial working memory abstract Scopolamine-induced deficits in cognitive and motor processes have been widely demonstrated in ani- mals and humans, although the role of acetylcholine in working memory is not as well understood. This study examined the role of acetylcholine neurotransmission in visuospatial short term and work- ing memory using the Groton Maze Learning Test (GMLT). The GMLT is a computerized hidden maze learning test that yields measures of component cognitive processes such as spatial memory, working memory, and visuomotor function, as well as their integration in trial-and-error problem solving. Healthy older adults were administered scopolamine (0.3mg subcutaneous), the acetlycholinesterase inhibitor donepezil (5 mg oral), scopolamine with donepezil, or placebo. Compared to placebo, low-dose scopo- lamine led to performance deficits on all measures of the GMLT. The greatest scopolamine-induced deficits were observed in errors reflecting working memory processes (e.g., perseverative errors d = -2.98, and rule-break errors d = -2.49) and these impairments remained robust when statistical models accounted for scopolamine-related slowing in visuomotor speed. Co-administration of donepezil partially amelio- rated scopolamine-related impairments and this effect was greatest for measures of working memory than short-term memory. By itself, donepezil was associated with a small improvement in visuomotor function. These results suggest that scopolamine disrupts processes required for rule maintenance and performance monitoring, in combination with visuomotor slowing and sequential location learning. © 2008 Elsevier Ltd. All rights reserved. 1. Introduction The role of the dopaminergic (DA) system in frontal cortex activ- ity and working memory functions associated with the frontal cortex has been widely investigated. Animal experiments and recent pharmacological research in humans also suggests a role of the cholinergic system in working memory (Hasselmo & Stern, 2006). In humans, cholinergic neurotransmission has been widely implicated in sensory processing, attention, and memory encoding functions (Giocomo & Hasselmo, 2007). Although working memory and short-term memory impairments have been observed fol- ∗ Corresponding author at: Level 7, 21 Victoria Street, Melbourne, Victoria 3000, Australia. Tel.: +61 3 9664 1300; fax: +61 3 9664 1301. E-mail address: pmaruff@cogstate.com (P. Maruff). lowing administration of cholinergic antagonists in humans, this has been demonstrated mainly within the verbal domain (Curran, Schifano, & Lader, 1991; Ebert, Siepman, Oertel, Wesnes, & Kirch, 1998; Eddington & Rusted, 2003; Ellis et al., 2006; Mintzer & Griffiths, 2003; Tariot, Patel, Cox, & Henderson, 1996). It is not clear from these studies the degree to which working memory impair- ments produced by cholinergic antagonists are a consequence of attentional, sensory, or short-term memory impairments, and are consistent with spatial working memory deficits observed in ani- mal studies. This study was designed to investigate the changes in short-term learning and memory, and working memory asso- ciated with modulation of central nervous system acetylcholine transmission in healthy older adults. We expected that administra- tion of a muscarinic acetylcholine agonist (donepezil), antagonist (scopolamine), their co-administration, or placebo would produce different, but well-ordered performance profiles on a computerized 0028-3932/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2008.04.010