• DOI:10.1124/JPET.104.077172
• Corpus ID: 17585264

Memantine Blocks α7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons

@article{Aracava2005MemantineB,
  title={Memantine Blocks $\alpha$7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons},
  author={Yasco Aracava and Edna F. R. Pereira and Alfred Maelicke and Edson X. Albuquerque},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2005},
  volume={312},
  pages={1195 - 1205}
}

• Y. Aracava, E. Pereira, +1 author E. Albuquerque
• Published 1 March 2005
• Biology
• Journal of Pharmacology and Experimental Therapeutics

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 Ca2+-conducting α7* nAChR, in cultured hippocampal neurons. Memantine caused a concentration-dependent reduction of the amplitudes of whole-cell currents evoked by the α7* nAChR-selective agonist choline (10 mM) or by N-methyl-d-aspartate (NMDA) (50 μM) plus glycine (10 μM). It also inhibited tonically activated NMDA receptors. Memantine was more potent in inhibiting α7* nAChRs than NMDA receptors; at -60 mV, the IC50 values for memantine were 0.34 and 5.1 μM, respectively. Consistent with an open-channel blocking mechanism, memantine-induced NMDA receptor inhibition was voltage and use-dependent; the Hill coefficient (nH) was ∼1. Memantine-induced α7* nAChR inhibition had an nH < 1 and showed a variable voltage dependence; the effect was voltage-independent at 0.1 μM, becoming voltage-dependent at ≥1 μM. Thus, memantine interacts with more than one class of sites on the α7* 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 α7* 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.