H. Matsubayashi et al., AMANTADINE INHIBITS NICOTINIC ACETYLCHOLINE-RECEPTOR FUNCTION IN HIPPOCAMPAL-NEURONS, The Journal of pharmacology and experimental therapeutics, 281(2), 1997, pp. 834-844
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.