Abstract

The effect of amantadine on neuromuscular transmission was studied in frog sartorius and rat soleus and diaphragm muscle preparations. Amantadine blocked transmission reversibly, while having negligible presynaptic effects and inducing 10-20 mV depolarization of the muscle membrane that was tetrodotoxin insensitive. Its most pronounced effect was on the acetylcholine receptor-mediated postsynaptic conductances. Amantadine caused voltage-dependent attenuation of the peak endplate current amplitude and marked departure from linearity in the current voltage relationship. The drug altered the voltage-dependence of the falling phase of the endplate current, and reduced the slope of the relationship between endplate current half decay time and membrane potential with subsequent reversal of the slope such that the endplate current became faster with hyperpolarization. In addition, amantadine was found to inhibit the carbamylcholine-induced ²²Na efflux from microsacs formed from Torpedo electric organ membranes, suggesting that amantadine had postsynaptic action. Amantadine did not inhibit binding of [³H]acetylcholine or [¹²⁵I]α-bungarotoxin to the acetylcholine receptor but inhibited competitively the binding of [³H]perhydrohistrionicotoxin to the ionic channel of the acetylcholine receptor with K_i of 60 µM. These effects of amantadine on postsynaptic ionic current, coupled with its inability to protect against blockade of transmission by α-bungarotoxin and its inhibition of [³H]perhydrohistrionicotoxin binding suggest that amantadine blocks neuromuscular transmission by reacting with the ionic channel of the acetylcholine receptor.