Dopamine/dopaminergic system synthesis

Schizophrenia appears to be caused by an overactivity of dopamine pathways in certain parts of the brain such as the limbic system.2,23 This idea is based primarily on the fact that most antipsychotics block dopamine receptors, thereby reducing dopaminergic hyperactivity in mesolimbic pathways and other limbic structures (see the next section of this chapter). The increased dopamine influence underlying psychosis could be caused by excessive dopamine synthesis and release by the presynaptic neuron, decreased dopamine breakdown at the synapse, increased postsy-naptic dopamine receptor sensitivity, or a combination of these and other factors. 

Muscle-derived differentiation factor (MDF) induces tyrosine hydroxylase expression in a variety of central nervous system neurons, including those of striatum, cerebellum, and cortex. Normally, i.e., without MDF, these neurons do not express this enzyme of catecholamine synthesis. Further in vitro studies revealed that MDF enhances TH-mRNA 40-fold in fetal mesencephalic neurons. In vivo studies, employing infusion of partially isolated MDF, reported this molecule to enhance tyrosine hydroxylase activity in dopamine-depleted striata of 6-OHDA-lesioned animals. Furthermore, an increase of striatal dopamine concentrations and a partial compensation of rotational asymmetry were observed. In contrast, dopaminergic parameters were not affected by administration of MDF in control animals, suggesting that adult dopaminergic neurons may regain sensitivity toward differentiation factors after lesion. 

Adrenergic neurons (Figure 6-4) also transport a precursor molecule into the nerve ending, then synthesize the catecholamine transmitter, and finally store it in membrane-bound vesicles, but—as indicated in Figure 6-5—the synthesis of the catecholamine transmitters is more complex than that of acetylcholine. In most sympathetic postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, norepinephrine is further converted to epinephrine. Conversely, synthesis terminates with dopamine in the dopaminergic neurons of the central nervous system. Several important processes in these nerve terminals are potential sites of... 

L-dopa is a chemical intermediate produced in the synthesis of dopamine (see Figure below). It is formed from the actions of tyrosine hydroxylase on tyrosine, and is subsequently converted into dopamine by aromatic-L-amino acid decarboxylase (LAAD, or dopa decarboxylase). This molecule is taken up into the dopaminergic nerve terminal and converted to dopamine, which is then released into the synaptic cleft. Unlike dopamine, dopa is in nonionized form at physiologic pH and thus will cross into the central nervous system (CNS). 

---