RT Journal Article
SR Electronic
T1 Memantine Blocks α7<sup>*</sup> Nicotinic Acetylcholine Receptors More Potently Than <em>N</em>-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1195
OP 1205
DO 10.1124/jpet.104.077172
VO 312
IS 3
A1 Yasco Aracava
A1 Edna F. R. Pereira
A1 Alfred Maelicke
A1 Edson X. Albuquerque
YR 2005
UL http://jpet.aspetjournals.org/content/312/3/1195.abstract
AB 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 &lt; 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. The American Society for Pharmacology and Experimental Therapeutics