Figure 2.

Metabolic pathways of catecholaminergic neurons. This drawing represents terminals of the dopamine (DA) neuron (left) and noradrenaline (NA) (right), a capillary, and a post-synaptic cell. L-3,4-dihydroxyphenylalanine (L-DOPA), normally synthesized from the amino acid tyrosine through hydroxylation by the enzyme tyrosine hydroxylase (the rate-limiting enzyme of catecholamine biosynthesis), can virtually reach all cells upon its exogenous administration. Neurons expressing the L-aromatic acid decarboxylase (AADC) can convert L-DOPA into DA. In monoaminergic cells, vesicular monoamine transporter VMAT2 allows for the penetration of newly synthesized DA inside the vesicles of exocytosis. In NA terminals, DA is converted by dopamine ß-hydroxylase (DBH) to NA, mainly in vesicles. DA undergoes deamination, by monoamine oxidase (MAO), to form 3,4-dihydrophenylacetaldehyde (DOPAL), which is subsequently oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (AD). DOPAC leaves the dopaminergic cells and is then taken up by the postsynaptic cells. DOPAC is O-methylated by catechol-O-methyltransferase (COMT, not present in catecholaminergic neurons), generating homovanillic acid (HVA), the final metabolite. A similar circuit occurs with NA catabolism. NA can be converted into 3,4-methoxyphenylacetaldehyde (DOPEGAL) as a result of the action of MAO. DOPEGAL, which is reduced by aldehyde reductase (AR) to 3,4-dihydroxyphenylglycol (DHPG), is released out from the NA terminals. The final product of the NA metabolism is VMA, produced by post-synaptic cells. The post-synaptic pathways can be directly alimented by the nonspecific uptake of DA and NA or, upon L-DOPA administration, by the production of DA directly in the post-synaptic cells.