Molecular Pharmacology, Vol 11, 621-631, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Regulation of Dopamine Synthesis in Rat Brain Striatal Synaptosomes

¹ Laboratory of Behavioral Neurochemistry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305

The properties of dopamine synthesis in rat brain striatal synaptosomes were examined. Addition of catecholamines inhibited the conversion of tyrosine to dopamine, with 50% inhibition occurring at 0.5 µM dopamine. Cocaine antagonized the dopamine-induced inhibition of synthesis to an extent similar to its blockade of dopamine uptake. Stimulation with depolarizing concentrations of veratridine produced a calcium-dependent increase in the conversion of tyrosine to dopamine. Strontium, although less effective, could substitute for calcium in the veratridine-induced stimulation. Veratridine treatment was associated with a significant decline in the specific activity of tyrosine in the tissue, a finding consistent with the concept that the increased rate of dopamine formation is caused by an activation of synthesis rather than by preferential labeling of the precursor. The decrease in tyrosine specific activity was due to a decreased accumulation of tyrosine produced by veratridine. The veratridine-induced inhibition of tyrosine accumulation appears to be related to the ability of the alkaloid to alter sodium permeability, since it was blocked by tetrodotoxin. The tyrosine apparent K_m for synthesis was much lower than the apparent K_m for tyrosine uptake and, along with the apparent V_max for synthesis, was significantly increased by veratridine. In contrast to dopamine synthesis from tyrosine, synthesis from dopa was not inhibited by the addition of dopamine, nor was it activated by veratridine. These studies indicate that isolated synaptosomal preparations respond to depolarizing agents with an activation of tyrosine hydroxylation, a property which suggests their suitability as a useful model for studying synthesis regulation in the central nervous system.

Note:
ACKNOWLEDGMENT The authors gratefully acknowledge the enzyme kinetic computer programs provided by Mr. Glen Elliott.

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