AMANTADINE INHIBITS NICOTINIC ACETYLCHOLINE-RECEPTOR FUNCTION IN HIPPOCAMPAL-NEURONS

The effects of amantadine on nicotinic acetylcholine receptors (nAChRs ) of hippocampal neurons were studied by recording three types of acet ylcholine (ACh)-evoked currents, using the whole-cell patch-clamp tech nique. The rapidly desensitizing type IA nicotinic current, which is a lpha-bungarotoxin-sensitive and is mediated by nAChRs bearing alpha 7 subunits, was inhibited by application of amantadine to neurons for 10 min (IC50 = 6.5 mu M), but the potency of ACh (EC50 = 0.27 mM) was no t affected by the drug. Amantadine (30-50 mu M) attenuated the peak cu rrent 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. W hen amantadine was coapplied briefly with ACh, the drug was markedly l ess potent (IC50 = 130 mu M). Thus, the noncompetitive effects of aman tadine on the type IA nicotinic current are complex, involving actions on the closed and desensitized states of the alpha 7 nAChR. The slowl y desensitizing, alpha-bungarotoxin-insensitive nicotinic currents of type II, which is inhibited by dihydro-beta-erythroidine and is mediat ed by alpha 4 beta 2 nAChRs, and of type III, which is inhibited by me camylamine and is mediated by alpha 3 beta 4 nAChRs, were also sensiti ve to inhibition by amantadine. The peak amplitude of type ii current was reduced only slightly by 10 mu M amantadine coapplied with ACh, bu t 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 nicotini c currents, amantadine at 10 mu M did not affect currents evoked by N- methyl-D-aspartate plus glycine, gamma-aminobutyric acid, glycine or k ainate, Thus, on cultured hippocampal neurons, amantadine preferential ly inhibits nicotinic currents.