Zinc modulation of drug binding, cocaine affinity states, and dopamine uptake on the dopamine uptake complex

EK Richfield

Department of Neurology, University of Rochester School of Medicine and Dentistry, New York 14642.

Zinc plays an important role in synaptic function in the brain. Zinc is present in synaptic vesicles, is released with neuronal activity, and provides modulation of different neurotransmitter systems. Zinc altered characteristics of the dopamine uptake complex in rat caudate-putamen. The density of the dopamine uptake complex labeled with [3H]GBR 12935 (0.25 nM) was increased by up to 215% in the presence of zinc (10 microM), compared with control. Augmentation of binding occurred with concentrations of zinc from 0.5 to 100 microM. This effect on the dopamine uptake complex was due to a 65% decrease in the equilibrium dissociation constant for [3H]GBR 12935 without a significant change in the total number of binding sites. The presence of exogenous zinc (50 microM) increased the percentage of high affinity sites for cocaine from 73 +/- 4% to 90 +/- 1% and decreased the high affinity constant from 2250 +/- 880 nM to 890 +/- 150 nM. Similar effects of zinc occurred with the cocaine congener 2 beta-carbomethoxy-3 beta- (fluorophenyl)tropane. Zinc inhibited dopamine uptake into synaptosomes at concentrations from 0.5 to 100 microM. Zinc (0.5 and 1 microM) augmented cocaine inhibition of uptake by 58-79%. Modulation of drug binding to the dopamine uptake complex is another role for zinc in the central nervous system. Sulfhydryl oxidation of the dopamine uptake complex by certain metal cations (Cu2+, Hg2+, and Cd2+) or N- methylmaleimide reduced binding of [3H]GBR 12935 to the dopamine uptake complex. The sulfhydryl oxidation by N-methylmaleimide was blocked by coincubation with dithiothreitol and dopamine uptake blockers. These data support the existence of a sulfhydryl group involved in binding of uptake blockers to the dopamine uptake complex.

Volume 43, Issue 1, pp. 100-108, 01/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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