Dopac distribution and regulation in striatal dopaminergic varicosities and extracellular space

DOPAC, the major intermediate metabolite of dopamine, is found in the cytosolic compartment of dopaminergic terminals/varicosities and in the extracellular space. It has been proposed that extracellular DOPAC is derived from newly synthesized dopamine rather than from dopamine in the signaling pool. On the basis of literature data supporting such a concept, we hypothesize a DOPAC synthesis/secretory complex producing extracellular DOPAC and use a computational simulation model of dopaminergic varicosities to estimate the distribution of DOPAC between cytosolic and extracellular compartments, amount of newly synthesized dopamine entering the DOPAC synthesis/secretory complex, and potential regulatory processes in the complex. Results suggest that about two-thirds of DOPAC is in the extracellular space. Approximately one-third of newly synthesized dopamine is immediately processed to DOPAC, which is then secreted into extracellular space. Extracellular DOPAC concentration is approximately 300 times higher than extracellular dopamine, and cytosolic DOPAC is ∼18-fold higher than cytosolic dopamine. We suggest that the high levels of extracellular DOPAC coupled with evidence for its production from newly synthesized dopamine imply the existence of an as yet undiscovered regulatory/signaling role for DOPAC.