The NMDA receptor antagonist memantine impairs hippocampal plasticity during declarative learning

Purpose: Memantine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD), is thought to decelerate declarative memory decline by ameliorating NMDAR overactivation. However, no consensus has yet evolved on potential procognitive effects of a single clinical dose of memantine on declarative learning in healthy individuals. The purpose of the present study was therefore to investigate the effects of a 20-mg dose of memantine on the neural and behavioral indices of declarative learning.

Materials and Methods: We combined functional magnetic resonance imaging (fMRI) with a declarative learning task and cytoarchitectonic probabilistic mapping of the hippocampus and its major subdivisions in 39 healthy volunteers administered either a 20-mg single oral dose of memantine or placebo.

Results: In controls, performance improved across the declarative learning task. This facilitation on the behavioral level was paralleled by a decrease in hippocampal responses on the neural level, an effect that was probabilistically mapped to the left cornu ammonis (CA). In memantine-treated subjects, however, hippocampal responses increased across the declarative learning task, while performance remained constant.

Conclusion: In healthy individuals, a 20-mg single clinical dose of memantine impairs hippocampal plasticity during declarative learning, which argues against a procognitive effect of the agent in nonpatient populations.