Dopamine synthesis and metabolism

Schmidt RH, Bjorklund A, Stenevi U, Dunnett SB, Gage FH (1983) Intracerebral grafting of neuronal cell suspensions. III. Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism. Acta Physiol Scand Suppl 522 19-28. 

The synthesis and metabolism of trace amines and monoamine neurotransmitters largely overlap [1]. The trace amines PEA, TYR and TRP are synthesized in neurons by decarboxylation of precursor amino acids through the enzyme aromatic amino acid decarboxylase (AADC). OCT is derived from TYR. by involvement of the enzyme dopamine (3-hydroxylase (Fig. 1 DBH). The catabolism of trace amines occurs in both glia and neurons and is predominantly mediated by monoamine oxidases (MAO-A and -B). While TYR., TRP and OCT show approximately equal affinities toward MAO-A and MAO-B, PEA serves as preferred substrate for MAO-B. The metabolites phenylacetic acid (PEA), hydroxyphenylacetic acid (TYR.), hydroxymandelic acid (OCT), and indole-3-acetic (TRP) are believed to be pharmacologically inactive. 

The biochemical pathways in the synthesis and metabolism of dopamine are shown in Fig. 7.2 and their position in the context of the dopamine synapse in Fig. 7.3. 

Figure 7.2 Biochemical pathways for the synthesis and metabolism of dopamine. (—) indicates drug inhibition of enzyme activity...

FIGURE 46-3 Synthesis and metabolism of dopamine. MAO, monoamine oxidase COMT, catechol-O-methyltransferase HVA, homovanillic acid DOPAC, 3,4-dihydroxyphenylacetic acid. 

Figure 2.16. Pathways for the synthesis and metabolism of the catecholamines. A=phenylalanine hydroxylase+pteridine cofactor+Oj B tyrosine hydroxylase+ tetrahydropteridme+Fe+ +Oj C=dopa decarboxylase+pyridoxal phosphate D= dopamine beta-oxidase+ascorbate phosphate+Cu+ +Oj E=phenylethanolamine N-methyltransferase+S-adenosylmethionine l=monoamine oxidase and aldehyde dehydrogenase 2=catechol-0-methyltransferase+S-adenosylmethionine.

The major routes for the synthesis and metabolism of noradrenaline in adrenergic nerves [375], together with the names of the enzymes concerned, are shown in Figure 3.1. Under normal conditions the rate controlling step in noradrenaline synthesis is the first, and the tissue noradrenaline content can be markedly lowered by inhibition of tyrosine hydroxylase [376]. Tissue noradrenaline levels can also be lowered, but to a lesser extent, by inhibition of dopamine-(3-oxidase [377, 378]. However, the noradrenaline depletion produced by guanethidine is unlikely to result from inhibition of synthesis, since intra-cisternal injection of guanethidine does not prevent the accumulation of noradrenaline which follows brain monoamine oxidase inhibition, even though it does cause depletion of brain noradrenaline [323]. 

Elsworth JD, Roth RH (1997) Dopamine synthesis, uptake, metabolism, and receptors relevance to gene therapy of Parkinson s disease. Exp Neurol 144 4-9. 

Fig. 1. A. Chemical structure of key molecules involved in the key steps in intracerebral synthesis and metabolism of dopamine. The successive steps are regulated by the enzymes tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and dopamine-p-hydroxylase (DBH). B. Structure of key toxins and other drugs acting on dopamine neurones, including 6-hydroxydopamine (6-OHDA), a-methyl tyrosine, and amphetamine. For further details see Iversen and Iversen (1981) or Cooper et al. (1996).

Familial dysautonomia, dopamine [i-liydroxylase deficiency, norepinephrine transporter deficiency, and congenital adrenal hyperplasia include dysautonomias or conditions associated with adrenal medullary dysfunction in which the specific genetic abnormalities have been identified. There are also other disorders involving mutations of genes coding for proteins involved in catecholamine synthesis and metabolism in which the clinical manifestations do not clearly involve the sympathoadrenal systems or may be so globally severe that abnormalities of autonomic or adrenal medullary function are obscured (Table 29-5). 

Synthesis and metabolism of catecholamines. Arrows indicate molecular conversions catalyzed by specific enzymes. Bold arrows indicate major (preferred) pathways. Enzymes (I) tyrosine hydroxylase (2) aromatic L-amino acid decarboxylase (3) dopamine-jSymonooxygenase (4) PNMT (5) cateckel-o-methyltransferase (6) monoamine oxidase. 

Autacoids are endogenous molecules with powerful pharmacologic effects but poorly defined physiologic roles. Histamine and serotonin (5-hydroxytryptamine 5-HT) are two of the most important autacoids. Both are synthesized in the body from amino acid precursors and then eliminated by amine oxidation the pathways of synthesis and metabolism are very similar to those used for catecholamine synthesis and metabolism. The ergot alkaloids are a heterogeneous group of drugs that interact with serotonin receptors, dopamine receptors, and alpha receptors. They are included in this chapter because of their effects on serotonin receptors and on smooth muscle. 

The sites of action of drugs affecting the dopamine synapse are indicated in Fig. 7.3. Those modifying the synthesis, storage, release, uptake and metabolism of DA have been covered above in the appropriate sections on neurochemistry. The actions and uses of agonists and antagonists are outlined in Table 7.4 and covered in detail in appropriate chapters. Their structures are given in Fig. 7.6. 

Figure 7.1 Schematic of the prototypical dopaminergic synapse. Pre- and post-synaptic components of a dopaminergic synapse summarizing molecular pathways for dopamine synthesis, metabolism, and second messenger effects following Dl-like or D2-like receptor activation. (See also Plate 6.)...

These results led to the suggestion that the functional unit of reward is a population of individual neurons ( hedonistic neurons ) scattered around reward areas of the brain which are specifically responsive to certain transmitters and are presumably connected to pathways controlling motivated behaviour. Phillips and Fibiger (1989) demonstrated an increase in dopamine metabolism, synthesis and release in the ventral tegmental area and nucleus accumbens during ICSS in rats, an increase proportional to the stimulation rate and intensity. 

All the pharmacological and behavioural effects elicited by dopamine agonists and antagonists in the brain can only be explained if such an interaction occurs at the level of the dopamine receptor (D2 receptor site) the site still remains in search of a function. Bovine parathyroid cells were reported to possess dopamine sites which should be involved in the control of parathormone secretion. However, the very poor pharmacological characterization and the lack of in vivo evidence do not allow to assess the dopaminergic nature of this hormone secretion. Dopamine-sensitive adenylate cyclase is thus not a receptor directly implicated in the dopaminergic neurotransmission it is an enzyme which could have an important role in the control of long term metabolic effects such as the synthesis of neuronal constituents. 

Fig. 3. Schematic representation of the neurochemical events associated with neurotransmitter synthesis, release, re-uptake and metabolism in axons of diencephalic DA neurons terminating in classical synapses (Top Panel), and TIDA neurosecretory neurons terminating in close proximity to the hypophysial portal system (Botton Panel). Arrows with dashed lines represent end-product inhibition of TH activiy by DA (Top + Bottom Panels) or DA presynaptic autoreceptor-mediated inhibition of DA synthesis and release (Top Panel). Abbreviations COMT, Catechol-O-methyltransferase D, dopamine DDC, DOPA decarboxylase DOPA, 3,4-dihydrophenylalanine DOPAC, 3,4-dihydroxyphenylacetic acid HVA, homovanillic acid MAO, monoamine oxidase 3MT, 3-methoxytyramine TH, tyrosine hydroxylase.

Smith AD, Justice JB (1994) The effect of inhibition of synthesis, release, metabolism and uptake on the microdialysis extraction fraction of dopamine. J Neurosci Methods 54 75-82. 

Figure 29-3 Schematic diagram illustrating the dynamics of synthesis, exocytotic release (R), neuronal reuptake (NU), extraneurona uptake (EU), vesicular leakage (VL), vesicular sequestration (VS), and metabolism of norepinephrine (NE) in sympathetic nerve endings in relation to extraneuronal tissue and the bloodstream. Relative magnitudes of the various processes are reflected by the relative sizes of arrows. TH, Tyrosine hydroxylase MAO, monoamine oxidase COMT catechol-O-methyitransferase T R, tyrosine L-dopa, 3,4-dihydroxyphenyialanine DA, dopamine DHPG, 3,4-dihydroxyphenylglycol NMN, normetanephrine MHPG, 3-methoxy-4-hydroxypheny [glycol.

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