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Journal of Pharmacology And Experimental Therapeutics, Vol. 190, Issue 1, 123-130, 1974
Copyright © 1974 by American Society for Pharmacology and Experimental Therapeutics

THE NERVE IMPULSE-BLOCKING ACTIONS OF TRANQUILIZERS AND THE BINDING OF NEUROLEPTICS TO SYNAPTOSOME MEMBRANES

P. Seeman 1, A. Staiman 1, and M. Chau-Wong 1

1 Pharmacology Department, University of Toronto, Toronto, Canada

In order to test the presynaptic coupling-blockade hypothesis of neuroleptic drug action'. we measured the conduction-blocking concentrations for phenothiazines and butyrophenones using rat phrenic nerve. The threshold concentration for blockade of the phrenic nerve was 6 x 10-6 M for promethazine, 3.8 x 10-6 M for promazine, 1.1 x 10-6 M for imipramine, 2.5 x 10-7 M for chlorpromazine, 8.6 x 10-8 M for thioridazine, 5 x 10-8 M for haloperidol, 2.9 x 10-8 M for trifluperidol, 2.5 x 10-8 M for fluphenazine. 2 x 10-8 M for moperone and 2 x 10-8 M for reserpine phosphate. The concentrations required to block the rat sciatic nerve were about 10-fold higher than those for rat phrenic nerve. The synaptosome membrane/buffer partition coefficients were 18.8 for promethazine, 30 for promazine, 295 for imipramine, 1700 for chlorprornazine, 8500 for thioridazine, sim200 for haloperidol and sim80 for trifluperidol. Ca++ displaced the neuroleptics from the synaptosome membranes. The blocking potencies correlated with the daily dosage used to control acute schizophrenia and with the octanol/water partition coefficients. Since the threshold blocking concentrations are in the same range as those found in the patient's plasma water, it is suggested that presynaptic blockade of coupling (between impulse and dopamine release) may play a role in the antipsychotic and extrapyramidal actions of neuroleptics.

Submitted on July 26, 1973
Accepted on February 7, 1974




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