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 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 (n_H) was ∼1. Memantine-induced α7^* nAChR inhibition had an n_H < 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.