Memantine acts as a cholinergic stimulant in the mouse hippocampus

Benjamin D. Drever, William George Anderson, Helena Louise Johnson, Matthew O'Callaghan, Sangwon Seo, Deog-Young Choi, Gernot Riedel, Bettina Platt

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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 mu M, and a corresponding downward shift in latency, indicative of overall enhanced synaptic transmission. This action was blocked by the muscarinic antagonist scopolamine (10 mu M) but not by the NMDA antagonist MK-801 (10 mu M) or the GABA antagonist bicuculline (20 mu M). Further, memantine occluded potentiation induced by 50 nM carbachol (CCh), while enhancing inhibitory actions of CCh at 1 mu M, suggesting additive actions. As anticipated for an NMDA antagonist, 100 mu M (but not 10 mu M) memantine also inhibited tetanus-induced long-term potentiation (LTP), and NMDA-induced Ca2+ signals were blocked in cultured hippocampal neurones at 10 mu M (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.

Original languageEnglish
Pages (from-to)319-333
Number of pages15
JournalJournal of Alzheimer's Disease
Volume12
Issue number4
Publication statusPublished - Dec 2007

Keywords

  • Alzheimer's disease
  • NMDA
  • neuroprotection
  • learning
  • synaptic transmission
  • LTP
  • acetylcholine
  • muscarinic
  • long-term potentiation
  • NMDA-receptor antagonists
  • nicotinic acetylcholine-receptors
  • open-channel blockers
  • D-aspartate receptors
  • rat hippocampal
  • Alzheimers-disease
  • synaptic-transmission
  • muscarinic receptors
  • nucleus basalis

Cite this

Drever, B. D., Anderson, W. G., Johnson, H. L., O'Callaghan, M., Seo, S., Choi, D-Y., ... Platt, B. (2007). Memantine acts as a cholinergic stimulant in the mouse hippocampus. Journal of Alzheimer's Disease, 12(4), 319-333.

Memantine acts as a cholinergic stimulant in the mouse hippocampus. / Drever, Benjamin D.; Anderson, William George; Johnson, Helena Louise; O'Callaghan, Matthew; Seo, Sangwon; Choi, Deog-Young; Riedel, Gernot; Platt, Bettina.

In: Journal of Alzheimer's Disease, Vol. 12, No. 4, 12.2007, p. 319-333.

Research output: Contribution to journalArticle

Drever, BD, Anderson, WG, Johnson, HL, O'Callaghan, M, Seo, S, Choi, D-Y, Riedel, G & Platt, B 2007, 'Memantine acts as a cholinergic stimulant in the mouse hippocampus', Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 319-333.
Drever BD, Anderson WG, Johnson HL, O'Callaghan M, Seo S, Choi D-Y et al. Memantine acts as a cholinergic stimulant in the mouse hippocampus. Journal of Alzheimer's Disease. 2007 Dec;12(4):319-333.
Drever, Benjamin D. ; Anderson, William George ; Johnson, Helena Louise ; O'Callaghan, Matthew ; Seo, Sangwon ; Choi, Deog-Young ; Riedel, Gernot ; Platt, Bettina. / Memantine acts as a cholinergic stimulant in the mouse hippocampus. In: Journal of Alzheimer's Disease. 2007 ; Vol. 12, No. 4. pp. 319-333.
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AB - 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 mu M, and a corresponding downward shift in latency, indicative of overall enhanced synaptic transmission. This action was blocked by the muscarinic antagonist scopolamine (10 mu M) but not by the NMDA antagonist MK-801 (10 mu M) or the GABA antagonist bicuculline (20 mu M). Further, memantine occluded potentiation induced by 50 nM carbachol (CCh), while enhancing inhibitory actions of CCh at 1 mu M, suggesting additive actions. As anticipated for an NMDA antagonist, 100 mu M (but not 10 mu M) memantine also inhibited tetanus-induced long-term potentiation (LTP), and NMDA-induced Ca2+ signals were blocked in cultured hippocampal neurones at 10 mu M (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.

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