Effect of chlorpromazine and some of its metabolites on synthesis and turnover of catecholamines formed from 14C-tyrosine in mouse brain

Rates of accumulation and disappearance of labelled catecholamines formed from ¹⁴C-tyrosine in mouse brain in vivo were determined. The effects of chlorpromazine (CPZ) and the following metabolites were studied: desmethyl-CPZ, didesmethyl-CPZ, 7-hydroxy-CPZ, CPZ-sulphoxide and CPZ-N-oxide. As we have found previously CPZ accelerated both accumulation and disappearance of ¹⁴C-dopamine indicating that synthesis and turnover of brain dopamine are accelerated. All the metabolites, with the exception of CPZ-sulphoxide, accelerated accumulation and disappearance of ¹⁴C-dopamine to about the same extent as did the parent compound. Neither CPZ nor the metabolites significantly affected the accumulation and disappearance of ¹⁴C-noradrenaline. The accelerated turnover of brain dopamine is probably a consequence of a central receptor blockade, which by a compensatory feed-back mechanism activates the presynaptic neurons. The results indicate that sulphoxidation of CPZ interferes with the action of CPZ on brain dopamine receptors, and that the clinical effects of CPZ may be mediated at least partly by its metabolites.