Cocaine and phencyclidine inhibition of the acetylcholine receptor: analysis of the mechanisms of action based on measurements of ion flux in the millisecond-to-minute time region.

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Abstract
[The commonly abused drugs cocaine (8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-benzoyloxy-8-methyl methyl ester [1R-(exo-exo)]) and phenycyclidine [PCP; 1-(1-phenylcyclohexyl)-piperidine] appear to have effects on multiple neurotransmitter systems.] The effects of cocaine and of PCP and procaine on acetylcholine receptor-controlled ion flux were measured in the millisecond to minute time region. Chemical kinetic measurements of ion flux were made in membrane vesicles prepared from the electric organ of Electrophorus electricus and in PC-12 [rat pheochromocytoma] cells, a sympathetic neuronal cell line. A quench-flow technique was used to measure ion flux in the millisecond to second range in membrane vesicles. Cocaine and PCP both inhibited acetylcholine receptor-controlled ion flux, but by different mechanisms. Both compounds decrease the initial rate of ion flux, an effect observed with the local anesthetic procaine. This inhibition cannot be prevented by saturating concentrations of acetylcholine (1 mM). These results from chemical kinetic experiments are consistent with electrophysiological measurements which indicate that local anesthetics act by interfering with the movement of ions through receptor-formed channels. The chemical kinetic expriments give additional information about the action of PCP. PCP increased the rate of receptor inactivation (desensitization) and changed the equilibrium between active and inactive receptor conformations, effects not observed in the presence of cocaine or procaine.