Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons - PubMed (original) (raw)
. 2005 Mar;312(3):1195-205.
doi: 10.1124/jpet.104.077172. Epub 2004 Nov 2.
Affiliations
- PMID: 15522999
- DOI: 10.1124/jpet.104.077172
Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons
Yasco Aracava et al. J Pharmacol Exp Ther. 2005 Mar.
Abstract
The N-methyl-d-aspartate (NMDA) receptor antagonist memantine is an approved drug for treatment of Alzheimer's disease (AD). Other such treatments are cholinesterase inhibitors and nicotinic acetylcholine receptor (nAChR)-sensitizing agents such as galantamine. The present study was designed to test whether memantine exerts any effect on the cholinergic system, in particular the Ca(2+)-conducting alpha7(*) nAChR, in cultured hippocampal neurons. Memantine caused a concentration-dependent reduction of the amplitudes of whole-cell currents evoked by the alpha7(*) nAChR-selective agonist choline (10 mM) or by N-methyl-d-aspartate (NMDA) (50 muM) plus glycine (10 muM). It also inhibited tonically activated NMDA receptors. Memantine was more potent in inhibiting alpha7(*) nAChRs than NMDA receptors; at -60 mV, the IC(50) values for memantine were 0.34 and 5.1 muM, respectively. Consistent with an open-channel blocking mechanism, memantine-induced NMDA receptor inhibition was voltage and use-dependent; the Hill coefficient (n(H)) was approximately 1. Memantine-induced alpha7(*) nAChR inhibition had an n(H) < 1 and showed a variable voltage dependence; the effect was voltage-independent at 0.1 muM, becoming voltage-dependent at >/=1 muM. Thus, memantine interacts with more than one class of sites on the alpha7(*) nAChRs. One is voltage-sensitive and therefore likely to be within the receptor channel. The other is voltage-insensitive and therefore likely to be in the extracellular domain of the receptor. It is suggested that blockade of alpha7(*) nAChRs by memantine could decrease its effectiveness for treatment of AD, particularly at early stages when the degrees of nAChR dysfunction and of cognitive decline correlate well.
Comment in
- Comments on "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons".
Banerjee P, Samoriski G, Gupta S. Banerjee P, et al. J Pharmacol Exp Ther. 2005 May;313(2):928-9; author reply 930-3. doi: 10.1124/jpet.104.081976. J Pharmacol Exp Ther. 2005. PMID: 15831445 No abstract available.
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