Dopamine, biosynthesis

Figure 4. DDC (A), serotonin (B), and tyrosine hydroxylase (C) immunore-activity in the posterior region of a wild-type Drosophila ventral ganglion. Tyrosine hydroxylase (TH) encodes the rate-limiting step in dopamine biosynthesis and is a marker for dopamine cells. B and C are the same CNS assayed for both serotonin and TH. M, medial dopamine neurons VL, ventrolateral serotonin neurons DL, dorsolateral dopamine neurons. Short unmarked arrows in C show vacuolated cells that do not contain DDC immunoreactivity. The immunoreactivity in these cells may represent a nonspecific cross-reactivity of the rat TH antibody. The length bar in A is 50 pM. The images are confocal projections generated on a Molecular Dynamics-2000 confocal laser scanning microscope.

Leng A., Mura A., Hengerer B., Feldon J., Ferger B. (2004). Effects of blocking the dopamine biosynthesis and of neurotoxic dopamine depletion with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) on voluntary wheel running in mice. Ilehav. Brain Res. 154, 375-83. 

Borges CR, Geddes T, Watson JT, Kuhn DM. 2002. Dopamine biosynthesis is regulated by S-glutathionylation. Potential mechanism of tyrosine hydroxylast inhibition during oxidative stress. J Biol Chem 277 48295 -8302. 

Dopamine biosynthesis is diminished in Parkinson s disease. L-Dopa, a precursor of dopamine, is given in large doses as a therapeutic agent. 

Andersson et al (1998) show marked inhibition of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis in the striatum and hippocampus after intracranial injections of PAH mixtures. Inhibition of TH can lead to reductions in striatal dopamine (Stephanou et al, 1998 Andersson et al, 1998), which may also contribute to the suppression in motor activity (Saunders et al, 2006). 

The size of the therapeudc transcrip don unit is many dmes employed as an ini dal criterion to focus vector choice. This category also includes a given vector s ability to harbor muldple transcripdon units, thereby potendally affording reconsd-tudon of a complex biochemical pathway (i.e., dopamine biosynthesis for Parkinson s disease). Potendal applicadons for several presently available vector platforms are resdictecl by insert size limitations and are sometimes excluded if muld-gene delivery is a prerequisite for therapy. 

Original evidence for the formation of NADA from arachidonic acid and dopamine or tyrosine (Huang et al. 2002) suggested a biosynthetic pathway common to that of the recently discovered arachidonoyl amino acids (Huang et al. 2001), i.e. from the direct condensation between arachidonic acid and dopamine, or, alternatively, from the condensation between arachidonic acid and tyrosine followed by the transformation of N-arachidonoyl-tyrosine into NADA by the enzymes catalysing dopamine biosynthesis from tyrosine. Preliminary data have shown, however, that NADA cannot be produced from either N-arachidonoyl-tyrosine or N-arachidonoyl-L-DOPA either in vitro, in brain homogenates, or in vivo, and that the lipid formed from tyrosine and arachidonic acid is not NADA (M.J. Walker and V. Di Marzo, unpublished observations). Clearly, further studies are needed to understand the biosynthetic mechanism for this putative endocannabinoid. 

In addition to its other functions BH4 enhances the release of dopamine and serotonin in the rat striatum when administered locally through the dialysis membrane. The enhancement of dopamine release persisted even when dopamine biosynthesis or dopamine reuptake was completely blocked, but it was abolished when hlockers of voltage-dependent Na" " or Ca " " channels were administered with BH4. Further experiments using selective inhibitors of tyrosine, TH, and NOS demonstrated that BH4 stimulates dopamine release directly, independent of its cofactor action on TH and NOS, by acting from the outside of neurons. The exact mechanism is not entirely clear but it has been shown that arginine also induces a concentration-dependent increase of dopamine release in the superfusate of rat striatum slices, and that it is dependent on the presence of BH4. ... 

Following the hypothesis that inhibition of dopamine biosynthesis will deplete pressor catecholamines and thus reduce blood pressure, methyldopa was tested as an antagonist of dopa [66] and found to be active. 

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