Background
We present the novel perspective of DOPA as a volume transmitter (Bergersen & Gjedde 2012) that regulates brain activity. Metabolites are volume transmitters of regulatory information when specific criteria are fulfilled in terms of stereoselective interactions with proteins, including unlimited passage across cell membranes by means of facilitated diffusion, unlimited distribution in brain tissue, and interaction with enzymes or receptors. DOPA fulfills these criteria as volume transmitter of information that redistributes monoaminergic activity in brain tissue (Goshima et al. 1986; Ng et al. 1970).
Methods:Synthesis – DOPA is the precursor of dopamine in numerous cells in brain, some of which are not neurons, and some of which do not make DOPA from tyrosine because they lack tyrosine hydroxylase (TH). DOPA is synthesized in catecholaminergic neurons as well as in cells that do not convert DOPA to dopamine because they lack DOPA decarboxylase (DDC) (Ershov et al. 2002). Transmission – DOPA is present in all regions of the brain, with concentrations that vary from 2.5 to 7.5 pmol/g (Thiede & Kehr 1981), with the highest levels in regions of the highest TH activity. The question is how DOPA gets into serotonergic neurons and other cells that do not contain TH. We claim that DOPA enters all cells from the extracellular space by means of the transporter that transports neutral and aromatic amino acids through facilitated diffusion that is affected by the concentrations and occupancies of competitors on both sides of the membranes. By the presence of the transporters in the blood-brain barrier, the circulation is an effective sink for DOPA, depending on the sign and magnitude of the gradient. Remote action – In cells, DOPA interacts with at least two different proteins, including DDC that catalyzes the conversion to dopamine and 3-O-methyltransferase (COMT) that catalyzes the conversion to 3-O-methyl-DOPA. In contradiction of the conventional view, these enzymes actually regulate the DOPA gradient and hence control the supply of DOPA to cells that do not possess TH, as well as the supply of DOPA from cells that possess TH but neither DDC nor COMT. The ubiquitous presence of DOPA and the generally unsaturated state of DDC implies that dopamine is synthesized wherever DDC is present, in more or less direct proportion to its concentration.
Results
This means that all the noradrenergic and serotonergic neurons of the cortex, and the serotonergic and dopaminergic neurons of the striatum, produce dopamine in proportion to the local DOPA concentration, as shown in the Figure.

Figure DOPA diffuses among at least 5 different cell types with TH or DDC activity, or both, in which it is now clear that DOPA is synthesized, metabolized, or both. By this action, DOPA distributes and adjusts the generation of the DA, NA, and 5HT modulators across large volumes of brain tissue.
Conclusions
Treatment of Parkinson's disease with DOPA's provides the most emphatic evidence of volume transmission with additional effects that are independent of DOPA's conventional function as a precursor of dopamine and noradrenaline in the respective neurons. Cells that contain only TH appear in the striatum and elsewhere in parkinsonism where they provide additional DOPA (Darmopil et al. 2008). Endo- and exogenous DOPA supports the synthesis in, and release from, serotonergic and noradrenergic neurons of dopamine, in relation to the appearance of dyskinesia in an animal model of parkinsonism (Nahimi et al. 2012).