Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping

Rationale Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions. Objectives The objective of the present experiments was to explore the effects of donepezil (Aricept (TM)), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction. Materials and methods The effects of donepezil were assessed in Sprague-Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests. Results Scopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (similar to 20-50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (similar to 3-10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (similar to 1% of the variance). Conclusions These results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.