Reversal of scopolamine-induced deficits with a single dose of donepezil, an acetylcholinesterase inhibitor.

Background: To develop a more rapid screening paradigm for novel cognitive enhancers, the authors sought to determine the utility of a well-known pharmacologic model of induced dementia (scopolamine challenge), paired with a sensitive neuropsychological test, for assessing the ability of a single oral dose of a current treatment for Alzheimer's disease (donepezil) to improve cognitive performance in healthy elderly subjects.

Methods: Thirty-two (4 groups of 8) healthy elderly volunteers were put randomly into a double-blind, placebo-controlled, modified crossover design study. In Part 1, 16 subjects received donepezil (5 mg) or placebo separately in a crossover fashion. In Part 2, the remaining 2 groups of 8 subjects received scopolamine (0.3 mg subcutaneously) with each group then were assigned randomly to receive donepezil (5 mg) or placebo (in a crossover fashion) 3 hours postbaseline. A novel measure of visuospatial working memory and executive controls, the Groton Maze Learning Test (GMLT), was administered to each subject at baseline and at 2.5, 4, 5.5, 7, and 9 hours after dosing of donepezil.

Results: With scopolamine, subjects showed slower psychomotor speed, reduced accuracy and learning efficiency, and longer time required to navigate a hidden maze. Concurrent administration of donepezil significantly reversed these deficits and resulted in a faster recovery time. In addition, single doses of donepezil alone led to improved psychomotor speed, accuracy, and learning efficiency.

Conclusions: Robust effects of single-dose donepezil on cognition can be readily observed, with the use of a complex hidden maze learning task, both with and without a scopolamine-induced deficit model in healthy elderly adults.