Inhibition of human α7 nicotinic acetylcholine receptors by open channel blockers of N-methyl-D-aspartate receptors

1 Human alpha7 nicotinic acetylcholine (ACh) receptors were expressed in Xenopus oocytes and the effects of the N-methyl-D-aspartate (NMDA) receptor open channel blockers memantine and cerestat on this receptor were examined using two-electrode voltage-clamp recordings and I-125-alpha-bungarotoxin (I-125-alpha-bgtx) binding. 2 Memantine and cerestat produced complete inhibition of ACh-induced inward currents with affinities similar to that reported for native NMDA receptors. Cerestat, IC50 1.7 (- 1; + 2) muM, was more potent than memantine, IC50 5 (-3; + 8) muM, and the effects of both drugs were fully and rapidly reversible. 3 Inhibition of alpha7 receptor function was voltage-independent, and it occurred at concentrations far lower than those needed to inhibit (never completely) binding of I-125-alpha-bgtx to alpha7 receptors, suggesting that the effects of memantine or cerestat are noncompetitive. 4 These results provide evidence that human alpha7 receptors are inhibited by memantine and cerestat and suggest that caution should be applied when using these compounds to study systems in which NMDA and nACh receptors co-exist.