Acute cognitive effects of donepezil in young, healthy volunteers Ana LC Zaninotto 1 , Orlando FA Bueno 1 , Ma ´rcia Pradella-Hallinan 1 , Se ´rgio Tufik 1 , Jenny Rusted 2 , Con Stough 3 and Sabine Pompe ´ia 1 * 1 Departamento de Psicobiologia, Universidade Federal de Sa ˜o Paulo (UNIFESP), Sa ˜o Paulo, Brazil 2 Department of Psychology, Sussex University, Brighton, BN, UK 3 Brain Sciences Institute, Swinburne University of Technology, Melbourne, Australia Objective The acute nootropic potential of donepezil in young healthy volunteers has not been adequately investigated mainly because in previous studies: (1) effects were assessed before peak-plasma concentration (Tmax) was reached; (2) only a few cognitive processes were assessed. Here we investigated a myriad of cognitive effects of augmentation of acetylcholine using an acute dose of donepezil in healthy adults at theoretical Tmax. Methods This was a double-blind, placebo controlled, parallel group design study of cognitive effects of acute oral donepezil (5 mg). Subjects were tested twice after donepezil ingestion: 90 min (time that coincides with previous testing in the literature) and 210 min. (theoretical Tmax). The test battery included tasks that tap cognitive domains that are sensitive to acetylcholine manipulations. Results At both testing times donepezil improved long-term recall of prose, objects recall, recall of spatial locations, and integration of objects with their locations, some effects having been related to self-reported mood enhancement. However, improvement of performance in the central executive measure (backward digit span) occurred only at Tmax. Conclusion Positive cognitive effects of acute donepezil can be observed in various cognitive domains including mood, but its full nootropic potential is more clearly found close to theoretical peak-plasma concentration. Copyright # 2009 John Wiley & Sons, Ltd. key words — donepezil; acetylcholinesterase inhibitor; memory; cognition; working memory; performance INTRODUCTION Donepezil is a potent, specific, non-competitive, and reversible inhibitor of acetylcholinesterase (AChEI) (Shigeta and Homma, 2001; Jann et al., 2002) that is currently used to improve cognition in patients with a wide range of clinical disorders (Shigeta and Homma, 2001). Donepezil has also been shown to have nootropic effects after chronic use in healthy young (Gro ¨n et al., 2005) and elderly volunteers (FitzGerald et al., 2008). Studies such as these, however, shed little light on the role of acetylcholine on cognition because the status of the cholinergic system in these populations is altered by age, pathologies (Gro ¨n et al., 2005), and/or chronic use (Poirier, 2002). For this purpose, it is therefore ideal to administer single doses to healthy young adults in whom the cholinergic system is intact. Yet, in healthy young adults positive cognitive effects were not always found after acute doses of donepezil, despite various reports of acute cognitive improvement by other AChEIs and acetylcholine agonists in the same type of participants (e.g., Warburton and Rusted, 1993; Thompson et al., 2002, Thiel et al., 2005; Furey et al., 2008a,b). Nathan et al. (2001) showed no acute effect of donepezil in attention, motor speed, and working memory measures (digit span forward and backwards), while Hutchison et al. (2001) reported improvement in visual inspection time (IT), a physiological marker of functional status of the cholinergic system that is impaired in Alzheimer’s disease (Nathan and Stough, 2001) and that indicates speed of visual information processing abilities (Garaas and Pomplun, 2008). Also, the same acute dose of donepezil led to partial reversal of acute mecamyla- mine-induced deficits in IT (Thompson et al., 2000), lending some support to the cognitive enhancing properties of this drug in young, healthy individuals. Differently, it is clear that explicit/declarative episodic memory (see Squire, 1986) is impaired by acute administration of anticholinergics in healthy adults (e.g., Broocks et al., 1998; Curran et al., 1998; Curran, 2000; Ellis et al., 2006). Also, performance is altered by these drugs in some of the subsystem of the multiple component model of working memory human psychopharmacology Hum. Psychopharmacol Clin Exp 2009; 24: 453–464. Published online 28 July 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hup.1044 * Correspondence to: S. Pompe ´ia, Departamento de Psicobiologia, Uni- versidade Federal de Sa ˜o Paulo (UNIFESP), R. Napolea ˜o de Barros 925, 04024-002 Sa ˜o Paulo, SP, Brazil. Tel:/Fax: 55 11 2149-0155. E-mail: spompeia@gmail.com Copyright # 2009 John Wiley & Sons, Ltd. Received 24 December 2008 Accepted 27 May 2009