Cholinomimetic actions of memantine on learning and hippocampal plasticity

The non-competitive NMDA receptor antagonist memantine, currently prescribed for the treatment of Alzheimer's disease, is assumed to prevent the excitotoxicity implicated in neurodegenerative processes. Here, we investigated the actions of memantine on hippocampal function and signalling. In behavioural experiments using the water maze, we observed that memantine (at 2 mg/kg) reversed scopolamine-induced learning deficits in mice. When acutely applied to mouse hippocampal slices, memantine caused a significant upward shift in the population spike input-output relationship at 10 and 100 μM, and a corresponding downward shift in latency, indicative of overall enhanced synaptic transmission. This action was blocked by the muscarinic antagonist scopolamine (10 μM) but not by the NMDA antagonist MK-801 (10 μM) or the GABA antagonist bicuculline (20 μM). Further, memantine occluded potentiation induced by 50 nM carbachol (CCh), while enhancing inhibitory actions of CCh at 1 μM, suggesting additive actions. As anticipated for an NMDA antagonist, 100 μM (but not 10 μM) memantine also inhibited tetanus-induced long-term potentiation (LTP), and NMDA-induced Ca ²⁺ signals were blocked in cultured hippocampal neurones at 10 μM (by 88%). Overall, our data suggest actions of memantine beyond NMDA receptor antagonism, including stimulating effects on cholinergic signalling via muscarinic receptors. These interactions with the cholinergic system are likely to contribute to memantine's therapeutic potential.