Figure 2. Monoamine neurotransmitter synthesis and regulation in neurons.

L-tyrosine () and L-tryptophan () are the substrates for dopamine () and serotonin synthesis respectively. Both cross the blood brain barrier and enter neurons via diffusion facilitated by the LAT1 neutral amino acid transporter in competition with L-phenylalanine () and other large neutral amino acids. Tyr is converted to L-DOPA by tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. TH activity is stimulated by Tyr, but inhibited through Phe-mediated competition, DA or L-DOPA-mediated feedback inhibition, and via a DA-activated, G-protein coupled, synthesis-modulating autoreceptor. TH activity is also regulated through reversible phosphorylation triggered by a variety of stimuli (not shown). DA is synthesized from L-DOPA by aromatic amino acid decarboxylase (AADC), taken up into secretory vesicles via a monoamine specific transporter (VMAT) and secreted into the synapse following Ca⁺² influx in response to a nerve stimulus. Neurotransmission terminates through DA reuptake via a specific transporter (DAT) or through degradation of dopamine to homovanillic acid (HVA). Extracellular DA can also act via another G protein-coupled autoreceptor to suppress further synaptic dopamine release. The production of HVA from DA requires both oxidation via the activity of monoamine oxidase (MAO) and methylation by catechol-O-methyl-transferase (COMT), but these sequential reactions can occur in either order. DA oxidation occurring first produces 3,4- dihydroxyphenylacetic acid (DOPAC) followed by methylation to HVA; initial DA methylation yields 3-methoxytyramine (3-MT) that is subsequently oxidized to HVA. The brain content of DOPAC and 3-MT are indicators of neuronal and synaptic DA turnover. Analogous mechanisms regulate the synthesis and secretion of serotonin from Trp followed by degradation to 5-hydroxyindoleacetic acid (5-HIAA) (not shown).