Abstract

The action of cocaine on neuromuscular transmission of the frog has been studied to unveil the molecular site upon which this agent acts to block synaptic function. Indirectly elicited twitches of the sciatic nerve-sartorius muscle were reduced at greater than or equal to 50 microM cocaine. The electrically evoked action potentials of muscle membrane were inhibited at 200 microM cocaine, in a manner consistent with a local anesthetic effect. At the synaptic region, the quantal release of transmitter from the nerve terminal was not affected by cocaine at concentrations up to 100 microM. The most potent action of cocaine was the blockade of the ion channel of the nicotinic acetylcholine receptor. Transient membrane depolarization induced by microiontophoresis of acetylcholine was reduced to 7% of control at 50 microM cocaine in a dose-related manner; receptor desensitization was affected to a lesser extent by cocaine at all concentrations tested. The decay time constants of endplate currents were reduced at concentrations greater than or equal to 10 microM. The single channel conductances remained unchanged whereas the channel lifetimes were greatly reduced at 25 and 50 microM of the drug. Unblocking could not be discerned from the observed kinetics of either endplate current decay or single channel closed durations. However, with a combination of 10 microM cocaine and 0.4 M ethanol the endplate currents became biphasic. This suggested a blocking of open ion channels of the nicotinic receptor by cocaine followed by dissociation of acetylcholine from the blocked channel (in the absence of ethanol).