PT - JOURNAL ARTICLE AU - Matsubayashi, Hiroaki AU - Swanson, Karen L. AU - Albuquerque, Edson X. TI - Amantadine Inhibits Nicotinic Acetylcholine Receptor Function in Hippocampal Neurons DP - 1997 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 834--844 VI - 281 IP - 2 4099 - http://jpet.aspetjournals.org/content/281/2/834.short 4100 - http://jpet.aspetjournals.org/content/281/2/834.full SO - J Pharmacol Exp Ther1997 May 01; 281 AB - The effects of amantadine on nicotinic acetylcholine receptors (nAChRs) of hippocampal neurons were studied by recording three types of acetylcholine (ACh)-evoked currents, using the whole-cell patch-clamp technique. The rapidly desensitizing type IA nicotinic current, which is α-bungarotoxin-sensitive and is mediated by nAChRs bearing α7 subunits, was inhibited by application of amantadine to neurons for 10 min (IC50 = 6.5 μM), but the potency of ACh (EC50 = 0.27 mM) was not affected by the drug. Amantadine (30–50 μM) attenuated the peak current amplitude in a voltage-dependent manner, with greater effect at negative than at positive membrane potentials. In contrast, the decay phase of the currents was shortened in a voltage-independent manner. When amantadine was coapplied briefly with ACh, the drug was markedly less potent (IC50 = 130 μM). Thus, the noncompetitive effects of amantadine on the type IA nicotinic current are complex, involving actions on the closed and desensitized states of the α7 nAChR. The slowly desensitizing, α-bungarotoxin-insensitive nicotinic currents of type II, which is inhibited by dihydro-β-erythroidine and is mediated by α4β2 nAChRs, and of type III, which is inhibited by mecamylamine and is mediated by α3β4 nAChRs, were also sensitive to inhibition by amantadine. The peak amplitude of type II current was reduced only slightly by 10 μM amantadine coapplied with ACh, but the decay-time constant and amplitude of the sustained current were markedly reduced. Type III current was also inhibited when amantadine was briefly coapplied with ACh. In contrast to its effects on nicotinic currents, amantadine at 10 μM did not affect currents evoked byN-methyl-d-aspartate plus glycine, γ-aminobutyric acid, glycine or kainate. Thus, on cultured hippocampal neurons, amantadine preferentially inhibits nicotinic currents. The American Society for Pharmacology and Experimental Therapeutics