EFFECT OF VERATRIDINE ON MINIATURE END-PLATE CURRENT AMPLITUDES AT THE RAT NEUROMUSCULAR-JUNCTION AND ACETYLCHOLINE UPTAKE BY TORPEDO SYNAPTIC VESICLES

Veratridine produces a marked elevation in spontaneous quantal release from nerve endings through its ability to enhance sodium-channel acti vity, leading to sustained membrane depolarization. In the course of a n electrophysiological investigation into the effects of vesamicol, an inhibitor of the synaptic vesicle acetylcholine transporter, on verat ridine-induced acetylcholine release from rat motor nerve terminals we observed that veratridine itself has an effect on miniature endplate current amplitude distributions suggestive of an effect of the compoun d on the filling of cholinergic synaptic vesicles with acetylcholine. This effect of veratridine is release-dependent, being inhibited by ei ther removal of extracellular calcium ions or by the addition of the s odium channel blocking toxin, tetrodotoxin. Biochemical studies using synaptic vesicles isolated from Torpedo electroplaque confirmed the ab ility of veratridine to directly inhibit the vesicular transport of ac etylcholine. This appears to be a consequence of its ability to dissip ate the trans-vesicular membrane proton gradient, which normally drive s the active transport of acetylcholine into synaptic vesicles. We dis cuss how such an action of veratridine could lead to the observed rele ase-dependent effects of the compound on electrophysiologically monito red spontaneous quantal acetylcholine release. The action of veratridi ne on cholinergic synaptic vesicles could be of considerable import wh en using this agent to elicit neurotransmitter release from either per ipheral or central nerve endings.