Reversals of the neostigmine-induced tetanic fade and endplate potential run-down with respect to the autoregulation of transmitter release.

1. In order to shed more light on the role of presynaptic cholinoceptors in the modulation of transmitter release, the effects of tubocurarine, choline and hexamethonium on neostigmine-induced tetanic fade and run-down of endplate potentials (e.p.ps) in response to indirect stimulation with trains of pulses were studied in the intact and cut isolated phrenic nerve-diaphragm preparation of the mouse, respectively. 2. Tubocurarine, choline and hexamethonium reduced both the tetanic fade and e.p.p. run-down caused by neostigmine, despite the fact that they themselves also induced these two effects. 3. At a given degree of postsynaptic inhibition, choline and hexamethonium caused less e.p.p. run-down and reversed the neostigmine-induced tetanic fade and e.p.p. run-down better than tubocurarine. Moreover, the e.p.p. run-down caused by choline or hexamethonium, but not that induced by tubocurarine, was reciprocally reversed by neostigmine. 4. Tubocurarine, choline and hexamethonium significantly decreased the endplate depolarization induced by repetitive nerve stimulation in the presence of neostigmine. The remaining depolarization continued to grow during repetitive stimulation in the presence of choline or hexamethonium, but not, however, in the presence of tubocurarine; a finding which suggests that choline and hexamethonium but not tubocurarine may be displaced from the receptor by the accumulated acetylcholine. 5. The mutual reversal by neostigmine and cholinoceptor antagonists of e.p.p. run-down may implicate the presence of a positive (physiological) and a negative (pharmacological) feedback regulation for evoked transmitter release via nicotinic cholinoceptors in the mammalian motor nerve, depending on the concentration of acetylcholine within the synaptic cleft.