Molecular Pharmacology, Vol 16, 877-885, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of High Affinity Synaptosomal Uptake Systems by Verapamil

¹ Department of Pharmacology, Georgetown University Schools of Medicine and Dentistry, Washington, D. C. 20007

Verapamil and its analogue D-600 have been found to inhibit the uptake of serotonin, dopamine, norepinephrine and choline into rat forebrain synaptosomes. The concentrations of verapamil required for 50% inhibition of the four uptake systems were 2.3 µM, 18 µM, 32 µM and 150 µM, respectively. The inhibitory effect of verapamil on serotonin uptake was studied in detail and found to have a very rapid (less than 1 min) time of onset and an almost equally rapid rate of reversal. Inhibition appeared to be non-competitive with respect to substrate concentration. The inhibitory effects of verapamil did not seem to be due to its ability to block Ca⁺⁺ movements since serotonin uptake was not dependent on Ca⁺⁺ but actually inhibited by elevated Ca⁺⁺, and the inhibition of uptake by verapamil could not be reversed by elevation of Ca⁺⁺. However, due to an increased potency of verapamil at lowered Na⁺ concentrations, the Na⁺-dependency of the uptake processes, and verapamil’s known effects on "slow" Na⁺ currents, we propose that verapamil may be interfering with a Na⁺-dependent component of the uptake systems.