title: Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons.
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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore St., Baltimore, MD 21201, USA.
authors.forename: Yasco
authors.initials: Y
authors.lastname: Aracava
authors.forename: Edna F R
authors.initials: EF
authors.lastname: Pereira
authors.forename: Alfred
authors.initials: A
authors.lastname: Maelicke
authors.forename: Edson X
authors.initials: EX
authors.lastname: Albuquerque
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D008559:Memantine / Q000494:pharmacology*; D008564:Membrane Potentials; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579165:Chrna7 protein, rat; D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D008559:Memantine