Dopamine catabolism

Once returned to the presynaptic terminal, dopamine is repackaged into synaptic vesicles via the vesicular monoamine transporter (VMAT) or metabolized to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO). Two alternative pathways are available for dopamine catabolism in the synapse, depending on whether the first step is catalyzed by MAO or catechol-O-methyltransferase (COMT). Thus, dopamine can be either deaminated to 3,4-dihydroxyphenylacetic acid (DOPAC) or methylated to 3-methoxytyramine (3-MT). In turn, deamination of 3-MT and methylation of DOPAC leads to homovanillic acid (HVA). In humans, cerebrospinal fluid levels of HVA have been used as a proxy for levels of dopaminergic activity within the brain (Stanley et al. 1985). 

Inhibitors of MAO (A). The enzyme is located predominantly on mitochondria, and serves to scavenge axoplasmic free NE. Inhibition of the enzyme causes free NE concentrations to rise. Likewise, dopamine catabolism is impaired, making more of it available for NE synthesis. 

Inhibitors of MAO (A) block enzyme located in mitochondria, which serves to scavenge axoplasmic free norepinephrine (NE). Inhibition of the enzyme causes free NE concentrations to rise. Likewise, dopamine catabolism is impaired, making more of it available for NE synthesis. In the CNS, inhibition of MAO affects neuronal storage not only of NE but also of dopamine and serotonin. The functional sequelae of these changes include a general increase in psychomotor drive (thymeretic effect) and mood elevation (A). Moclobemide reversibly inhibits MAOa and is used as an antidepressant. The MAOB inhibitor selegiline (deprenyl) retards the catabolism of dopamine, an effect used in the treatment of Parkinsonism (p. 188). 

Ethyl benzene is an inducer of the cytochrome P450 and cytochrome c reductase enzyme systems. Ethyl benzene acts as a mitochondrial-uncoupling agent. It is believed that ethyl benzene metabolites are capable of interfering with dopamine catabolism in the brain. The tuberoinfundibular dopaminergic system may be a target for these metabolites. 

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. 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

The mechanism of action of valproate is complex and still the subject of uncertainty. The drug appears to act by enhancing GABAergic function. Thus it increases GABA release, inhibits catabolism and increases the density of GABA-B receptors in the brain. There is also evidence that it increases the sensitivity of GABA receptors to the action of the inhibitory transmitter. Other actions that may contribute to its therapeutic effects include a decrease in dopamine turnover, a decrease in the activity of the NMDA-glutamate receptors and also a decrease in the concentration of... 

In addition to impairing norepinephrine storage and thereby enhancing its catabolism, reserpine impairs the vesicular uptake of dopamine, the immediate precursor of norepinephrine. Since dopamine must be taken up into the adrenergic vesicles to undergo hydroxylation and form norepinephrine, reserpine administration impairs norepinephrine synthesis. The combined effects of the blockade of dopamine and norepinephrine vesicular uptake lead to transmitter depletion. 

Monoamine oxidase exists in the human body in two molecular forms, known as type A and type B. Each of these isozymes has selective substrate and inhibitor characteristics. Neurotransmitter amines, such as norepinephrine and serotonin, are preferentially metabolized by MAO-A in the brain. MAO-B is more likely to be involved in the catabolism of human brain dopamine, although dopamine is also a substrate for MAO-A. 

Monoamine oxidases (MAOs) are mitochondrial membrane enzymes. These flavin-dependent enzymes are responsible for the oxidative deamination of numerous endogenic and exogenic amines (norepinephrine, serotonin, dopamine, etc.). MAO A and B take part in the regulation of these amines in many organs, such as the brain. The essential physiological role of these amines, especially in the central nervous system, has motivated the search for inhibitors of their catabolism in order to enhance the synaptic concentration of neuroamines. 

Monoamine oxidase inhibitors. The monoamine oxidase inhibitors (MAOIs) inhibit the intracellular catabolic enzyme monoamine oxidase. There are two types of monoamine oxidase MAO-A and MAO-B, both of which metabolize tyramine and dopamine. In addition, MAO-A preferentially metabolizes norepinephrine, epinephrine, and serotonin, and MAO-B preferentially metabolizes phenylethylamine (an endogenous amphetamine-like substance) and N-methylhistamine (Ernst, 1996). Some MAOIs are selective for A or B and some are nonselective (mixed). In addition, irreversible MAOIs (e.g., phenelzine, tranylcypromine) are more susceptible to the cheese effect than are the reversible agents (e.g., moclobemide). 

In addition to the aforementioned inborn errors of metabolism, deficiencies in the catabolism of dopamine and serotonin would also be expected to result in decreased concentrations of HVA and 5HIAA (e.g. MAO deficiency and COMT deficiency). 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

The discovery that dopamine was depleted in the basal ganglia of patients who suffered from Parkinsonism at the time of death led to the rational development of the therapeutic treatment, namely the use of L-dopa. Since dopamine does not cross the blood-brain barrier, and is rapidly catabolized... 

Released dopamine can be reutilized by neuronal reuptake and re-storage in vesicles or can be catabolized like other endogenous catecholamines by the enzymes MAO and COMT (p. 86). 

Catechol O-methyltransferase plays an important role in the catabolism of catecholamine neurotransmitters such as dopamine, norepinephrine, and epinephrine, and inactivation of catechol estrogens and catechol xenobiotics. Several different methods have been developed. 

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