Subcellular distribution of dopamine metabolites and their elimination from the rat brain

Abstract

A compartmentation of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) was found in the rat brain when its synthesis was inhibited by the monoamine oxidase inhibitor pargyline. Homovanillic acid (HVA) did not show such compartmentation after pargyline administration, but similar compartmentation was observed for HVA after treatment with tropolone which is an inhibitor of catechol- o-methyl transferase. The most rapid HVA compartment was eliminated after inhibition of the active transport with probenecid. No anatomical substrate could be found for these compartments. A relatively larger portion of DOPAC than of HVA was found to be associated with the crude mitochondrial/synaptosomal fraction when the subcellular distribution of these two compounds was investigated. Intraventricular injection of DOPAC in conjunction with either probenecid or tropolone resulted in increased DOPAC levels compared to intraventricular DOPAC alone, but no potentiating effect was observed when probenecid and tropolone were given in combination. It is concluded that the compartmentation of DOPAC is related to the HVA/DOPAC ratio in the various brain regions and the different metabolic pathways involved. The compartmentation of HVA shows that the acid is transported between different structures prior to removal from the brain. These results indicate that great care must be taken in estimating dopamine metabolic turnover on the basis of the elimination of metabolites subsequent to the inhibition of dopamine synthesis.