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NEUROPHARMACOLOGY
7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons
Department of Pharmacology and Experimental Therapeutics (Y.A., E.F.R.P., A.M., E.X.A.), University of Maryland School of Medicine, Baltimore, Maryland; Departamento de Farmacologia Básica e Clínica (E.X.A.), Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; and Institute of Physiological Biochemistry and Pathobiochemistry (A.M.), Johannes Gutenberg-University Medical School, Mainz, Germany
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 
7* nAChR, in cultured hippocampal neurons. Memantine caused a concentration-dependent reduction of the amplitudes of whole-cell currents evoked by the 7* 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 7* 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 7* 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 7* 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 7* 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.
Address correspondence to: Dr. Edson X. Albuquerque, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore St., Baltimore, MD 21201. E-mail: ealbuque{at}umaryland.edu
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P. Banerjee, G. Samoriski, and S. Gupta Comments on "Memantine Blocks {alpha}7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons" J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 928 - 929. [Full Text] [PDF]
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