3,4-dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid in the mouse striatum: a reflection of intra- and extra-neuronal metabolism of dopamine?

1. The administration of probenecid to mice increased the concentration of 4-hydroxy-3-methoxyphenylacetic acid (HVA) in the striatum, but did not raise the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC).2. After drug treatments which normally increase the concentration of HVA several-fold, inhibition of catechol-O-methyltransferase (COMT) by tropolone greatly reduced the concentration of HVA but resulted in only a small increase in the concentration of DOPAC in the striatum of the mouse.3. These results indicate that HVA and DOPAC do not occur at the same location in the tissue of the striatum and that DOPAC is not normally metabolized to HVA to any great extent in this tissue.4. When mice were treated with reserpine, which is thought to prevent the intraneuronal storage of dopamine, there was an increase in the striatal concentration of DOPAC which preceded an increase in the concentration of HVA. Since non-cholinergic nerve endings of rat brain contain mitochondria and show monoamine oxidase activity, this result suggests that DOPAC is formed intraneuronally.5. It is concluded that the DOPAC in the striatum represents intraneuronal metabolism of dopamine and that only the HVA which is sensitive to the action of probenecid represents entirely extraneuronal metabolism of this amine. Some of the HVA is not sensitive to the action of probenecid. This suggests that part of the metabolism of dopamine involved both locations.6. A group of drugs which are chemically related to amphetamine were tested for their effects on the concentrations of DOPAC and HVA in the striatum. It is suggested that D-amphetamine, 2-aminotetralin and 1,2,3,4-tetrahydroisoquinoline reduced the intraneuronal metabolism of dopamine whereas adamantanamine did not.