Journal of Alzheimer’s Disease 27 (2011) 477–482 DOI 10.3233/JAD-2011-110650 IOS Press 477 Short Communication Memantine Affects Cognitive Flexibility in the Morris Water Maze Bechara J. Saab a,b,∗ , Ruxandra M. Luca b,1 , Wing B. Yuen b,1 , Adam M.P. Saab b,c and John C. Roder a,b a Department of Molecular and Medical Genetics, Program in Neuroscience, University of Toronto, Toronto, Canada b Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada c University of British Columbia, Okanagan Campus, Kelowna, Canada Accepted 10 July 2011 Abstract. Alzheimer’s disease (AD) is multi-factorial mental disorder characterized by a copious array of congruent features cumulating in disrupted memory and dysthymia. Though the mechanism remains elusive, the highly unspecific pharmaceutical, memantine, provides modest benefits for patients with moderate-to-severe AD. A greater understanding of how memantine affects cognitive function promises to facilitate the search for better therapeutics. We therefore examined cognitive flexibility of mice following 5 and 10mg/kg memantine administration using a platform re-location water maze. Strikingly, subjects receiving memantine demonstrated memory impairment relative to controls when re-trained off drug, revealing a novel and unusual disruption of cognitive flexibility. Keywords: Alzheimer’s disease, cognitive disorder, cognitive flexibility, dopamine, excitotoxicity, GABA(A), hippocampus, learning and memory, memantine, mental flexibility, mice, mouse, muscarinic cholinergic system, neurotoxicity, NMDAR, platform re-location water maze, prefrontal cortex Alzheimer’s disease (AD) is a common and complex mental disorder of severe retrograde and anterograde amnesia, further complicated by high comorbidity with depression [1–5], itself a mental illness asso- ciated with impaired learning, memory, and general cognition [6]. Memantine, a relatively recent and widely prescribed pharmaceutical for treatment of moderate-to-severe AD, was found to have benefi- cial effects on AD patients following the serendipitous discovery over twenty years ago that amantadine, an amino-adamantine structurally similar to memantine, benefited Parkinsonian symptoms in patients receiving the drug as an anti-viral agent [7]. How memantine pro- vides partial relief of AD symptoms remains a mystery. 1 These authors contributed equally to the manuscript. ∗ Correspondence to: Bechara J. Saab, Brain Research Institute, Swiss Federal Institute of Technology, University of Zurich, Win- terthurerstrasse 190, CH-8057 Zurich, Switzerland. Tel.: +41 44 635 3309; Fax: +41 44 635 3303; E-mail: saab@hifo.uzh.ch. It is well known, however, that memantine modulates the function of many brain receptors [8]. Potentially of considerable clinical importance, memantine acts as a cholinergic stimulant in the hippocampus [9], and blocks 7 nicotinic acetylcholine receptors at concentrations lower than those required for meman- tine to antagonize the N-methyl-D-aspartate receptor (NMDAR) [10]. Interestingly from a patient outcome point of view, memantine also stimulates dopamine release in the prefrontal cortex [11, 12] and attenuates GABA(A) receptor activation [13]. In rats, meman- tine induces a neurotoxic effect further augmented by co-administration of the cholinesterase inhibitor, donepezil [14], while in contrast, experiments using acute hippocampal slices suggest memantine may protect against NMDAR-induced excitotoxicity [15]. At clinical doses, however, memantine does not induced the common negative peripheral side effects of other NMDAR antagonists, such as MK-801 [16], ISSN 1387-2877/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved