Differential muscarinic and NMDA contributions to visuo-spatial paired-associate learning in rhesus monkeys

Rationale: Early, accurate detection of degenerative neurological disorders such as Alzheimer's disease (AD) is essential for therapies designed to slow disease progression. Performance of a touch-screen mediated visuo-spatial paired-associates learning (vsPAL) task predicts neurocognitive decline in elderly populations presenting with mild cognitive impairment and distinguishes AD patients from elderly depressed individuals. Translation of this cognitive task to a non-human model may therefore provide an improved tool for study of the etiology and treatment of dementia. Objective: The goal of the current study was to contrast cholinergic and glutamatergic contributions to performance of this AD-sensitive task by challenging rhesus monkeys performing vsPAL with muscarinic antagonist and non-competitive NMDA antagonist drugs. Methods: Seven monkeys were trained to perform vsPAL and then serially challenged with acute doses of scopolamine (3, 10, 17 µg/kg, IM) and ketamine (0.3, 1.0, 1.78 mg/kg, IM). Results: Scopolamine produced a dose×difficulty related impairment of both recognition memory and incremental acquisition aspects of task performance. In contrast, ketamine administration resulted in a dose-dependent impairment of recognition memory but not incremental acquisition. Conclusions: Monkeys' performance of a task sensitive to AD in humans was impaired by two classic pharmacological models of cognitive impairment, therefore supporting the use of this nonhuman model to explore mechanisms of AD-associated cognitive decline. The differential pattern of impairment observed is consistent with a hypothesis that muscarinic mechanisms are required for linking external events with an existing internal representation, whereas NMDA mechanisms are required for the formation/strengthening of such an internal representation.