Striatal synaptosomal tyrosine hydroxylase activity: A model system for study of presynaptic dopamine receptors

Abstract

Tyrosine hydroxylase activity determined in striatal synaptosomes by the formation of [ 3H]H 2O from [3,5- 3H]tyrosine was used as a system for determining receptor affinities of neuroleptic drugs for the dopamine autoreceptor. Four agonists were tested for their abilities to inhibit tyrosine hydroxylation, and the order of potencies was apomorphine > dopamine > norepinephrine and buspirone was inactive. The abilities of different neuroleptic drugs to shift the IC 50 of apomorphine (500 nM without additional drugs) were used to calculate K B values for each drug. The butyrophenones and +)butaclamol were the most potent of the drugs tested, while (−)sulpiride and thioridazine were very weak inhibitors of apomorphine. Clozapine, promethazine, (-)butaclamol and (+)sulpiride were all inactive. The order of potencies of antipsychotic drugs at the dopamine nerve-ending autoreceptor correlated closely with clinical dose, but it did not correlated with previous reports of displacement of radiolabeled dopamine or apomorphine striatal membrane binding. This observation combined with the fact that the IC 50 of apomorphine at this functional receptor was 100 times the concentration needed to saturates its binding site(s) in radioligand receptor assays suggests that the dopamine autoreceptor is not labeled by nanomolar concentrations of apomorphine or dopamine.