Cholinesterase Inhibitors Improve Both Memory and Complex Learning in Aged Beagle Dogs

Article type: Research Article

Authors: Araujo, Joseph A.^{a; b; c; *} | Greig, Nigel H.^d | Ingram, Donald K.^e | Sandin, Johan^f | de Rivera, Christina^{a; b} | Milgram, Norton W.^{a; b; g}

Affiliations: [a] Department of Pharmacology, University of Toronto, Toronto, ON, Canada | [b] CanCog Technologies Inc., Toronto, ON, Canada | [c] InterVivo Solutions Inc., Toronto, ON, Canada | [d] Drug Design and Development Section, Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD, USA | [e] Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, USA | [f] AstraZeneca R&D Södertälje, Department of Neuroscience, Södertälje, Sweden | [g] Division of Life Sciences, University of Toronto at Scarborough Campus, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Joseph A. Araujo, InterVivo Solutions Inc., 120 Carlton St., Suite 203, Toronto, ON M5A 4 K2, Canada. Tel.: +1 416 677 6085; Fax: +1 416 920 1876; E-mail: josepha@intervivosolutions.com.

Abstract: Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline.

Keywords: Alzheimer's disease, cholinesterase inhibitor, dog, donepezil, learning, memory, phenserine

DOI: 10.3233/JAD-2011-110005

Journal: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 143-155, 2011