Dopamine homovanillic acid

Another aspect of catecholaminergic turnover that has been studied is the measurement of the metabolites of dopamine (homovanillic acid, HVA) and noradrenaline (vanillylmandelic acid, VMA). Silbergeld and Chisholm (1976) reported that HVA was increased by 33% in brain and 265% in urine, and VMA was increased by 48% in brain and 216% in urine in mice given 5g Pb/1 (2625 ppm Pb) from birth. It is likely that increased urinary... 

Dopamine. Dopamine (DA) (2) is an intermediate in the synthesis of NE and Epi from tyrosine. DA is localized to the basal ganglia of the brain and is involved in the regulation of motor activity and pituitary hormone release. The actions of DA are terminated by conversion to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase-A and -B (MAO-A and -B) in the neuron following reuptake, or conversion to homovanillic acid (HVA) through the sequential actions of catechol-0-methyl transferase (COMT) and MAO-A and -B in the synaptic cleft. 

MAO converts dopamine to DOPAC (3,4-dihydrox-yphenylacetic acid), which can be further metabolized by COMT to form homovanillic acid (HVA). HVA is the main product of dopamine metabolism and the principal dopamine metabolite in urine. Increased neuronal dopaminergic activity is associated with increases in plasma concentrations of DOPAC and HVA. COMT preferentially methylates dopamine at the 3 -hydroxyl position and utilizes S-adenosyl-L-methio-nine as a methyl group donor. COMT is expressed widely in the periphery and in glial cells. In PD, COMT has been targeted since it can convert l-DOPA to inactive 3-OMD (3-O-methyl-dopa). In the presence of an AADC inhibitor such as carbidopa, 3-OMD is the major metabolite of l-DOPA treatment. 

FIGURE 3-27 Three-dimensional chromatogram for oxidizable biological compounds at a multichannel amperometric detection system, consisting of an array of 16 carbon-paste electrodes held at different potentials. AA = ascorbic acid NE = norepinephrine DOPAC = 3,4-dihydroxyphenylacetic acid 5-HIAA = 5-hydroxyindole-3-acetic acid DA = dopamine HVA = homovanillic acid. (Reproduced with permission from reference 68.)... 

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). 

Court, J., Lloyd, S., Thomas, N. et al. Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use. Neuroscience. 87 63, 1998. 

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

Altered dopaminergic system function has been implicated in major depression. Patients with major depression have been reported to have lower CSF levels of the dopamine metabolite homovanillic acid (HVA) compared to nondepressed controls, with more severely depressed patients having still lower CSF HVA levels (see [42] for a... 

Numerous reports of altered neurotransmitter and hormone functions which have been associated with the affective disorders are reviewed by Levell [142]. It was originally proposed that one or more of the neurotransmitter amines in the brain (norepinephrine, dopamine, serotonin) may be functionally elevated in manic patients and reduced in depressed patients [143]. For instance, an increase in the production of dopamine, observed in a number of case reports, is thought to be the cause of the switch into the manic phase in bipolar patients. For example, Bunney et al. reported an increase in the level of homovanillic acid (HVA), a... 

Cassel GE, Koch M, Tiger G. 1995. The effects of cyanide on the extracellular levels of dopamine, 3,4,-dihydroxyphenylacetic acid, homovanillic acid, 5-hydroxyindoleacetic acid and inositaol phospholipid breakdown in the brain. Neurotoxicology 16(l) 73-82. 

The antischizophrenic actions of these drugs may not consist simply of postsynaptic blockade of hyperactive dopamine systems. Such a blockade occurs within hours, while most symptoms improve over weeks. This discrepancy in the latency to therapeutic effect has been hypothesized to be linked to drug-induced changes in dopaminergic activity after initiation of therapy, dopamine turnover increases, but after continued antipsychotic treatment, tolerance develops and dopamine metabolism returns to normal. This downward adjustment of dopaminergic activity is consistent with the decreased plasma concentrations of the dopamine metabolite homovanillic acid, an observation that correlates temporally with the clinical response to drug treatment. 

Dopaminergic activity. Smoke was administered intranasally to mice for 20 minutes twice daily for 3 days before methamphet-amine treatment. The treatment significantly attenuated the neurotoxicity as judged by a lesser depletion of dopamine, dihydrophenylacetic acid, and homovanillic acid. The lesser effect of methamphetamine on the content of serotonin level was unaltered by prior inhalation of smoke h Tobacco glycoside, administered to mice, increased behavior via dopamine 2 neuronal activity but not dopamine 1 activity in a dose-dependent manner. The results indicated that smoking can affect the human brain function via not only the nicotinic cholinergic neuron but also the dopamine 2 neuron . 

Low cerebrospinal fluid (CSF) concentrations of homovanillic acid, a dopamine metabolite, were associated with suicide attempts in two pediatric studies (Kruesi et al., 1992 L. Greenhill, personal communication). 

None of the TCAs seem to have an effect on dopaminergic neurotransmission in the central nervous system (CNS). This has been supported by the lack of alterations in dopamine receptor sensitivity in chronically treated patients who have shown response to treatment (Sugrue, 1983). More recent investigations have also shown that administration of DMI to depressed subjects had no effect on levels of homovanillic acid, the principal metabolite of dopamine, in a measure of brain neurotransmitter production. In this investigation, DMI administration did increase norepinephrine production and overall cerebral metabolism (Lambert, 2000). 

The effect of lithium on dopamine [DA] synthesis and transmission has been investigated extensively in preclinical studies by directly determining changes in DA or homovanillic acid and indirectly examining lithium-induced changes in DA-linked behaviors [Bunney and Garland 1984 Bunney and Garland-... 

Dopamine metabolism was covered in the discussion of general catecholamine biochemistry. Dopamine is stored in synaptic vesicles, and this storage can be manipulated. Although the reuptake of released DA is the major deactivating mechanism, MAO and COMT act enzymatically on DA in the same way as on NE. However, following the degradative pathway of NE, DA will finally be metabolized to homovanillic acid (3-methoxy-4-hydroxy-phenylacetic acid), since it lacks the P-hydroxyl group. 

Randrup et al. (55) first postulated a role for dopamine in depressive disorders. More recently, a reanalysis of the data from several groups has found evidence for a bimodal distribution of CSF homovanillic acid (HVA) levels in depressed patients, with one group comparable with normal control subjects and the other with decreased levels (56). Roy and colleagues (57) also reported on the potential predictive value of lower urinary HVA output in depressed patients who attempted suicide versus those who did not. Both reports indicate a decreased turnover in dopamine. 

If schizophrenia results from an elevated dopamine content of the brain, the fault may lie with either an oversupply or a reduced rate of metabolism of dopamine. The possibilities of reduced activity of monoamine oxidase or of dopamine (i-hydroxylase have both been suggested. The plasma level of the dopamine metabolite homovanillic acid (Fig. 30-26) is elevated in schizophrenia and is correlated with the... 

Since dopamine is present in sympathetic nervous tissue as a precursor of norepinephrine, and it has a separate metabolic pathway that yields homovanillic acid (HVA), tumors such as neuroblastomas may cause elevations of the urinary dopamine and its metabolite HVA. In some cases these elevations have been observed with normal VMA, total catecholamine, and metanephrine. Urinary HVA is usually normal in patients with phenochromocytoma. Increased HVA is found in special fluids of patients with Parkinson s disease treated with L-dopa. 

Electrochemical binding assays have also been applied for testing computational predictions which render the highest stabilization energy for the pre-polymerization mixture of several formulations traditionally used in non-covalent MIPs [119]. The batch binding assays and voltammetric detection confirm the theoretically best monomer-porogen solvent mixture for preparation of a recognition material for the dopamine metabolite homovanillic acid. 

Both clinical and experimental studies have provided evidence that 5-HT can also regulate dopamine turnover. Thus several investigators have shown that a positive correlation exists in depressed patients between the homovanillic acid (HVA), a major metabolite of dopamine, and 5-HIAA concentrations in the CSF. In experimental studies, stimulation of the 5-HT cell bodies in the median raphe causes reduced firing of the substantia nigra where dopamine is the main neurotransmitter. There is thus convincing evidence that 5-HT plays an important role in modulating dopaminergic... 

Homovanillic acid, one of the main metabolites of dopamine formed by the actions of monoamine oxidase and catechol-O-methyltransferase. 

On-chip chiral separation of enantiomers of adrenaline, noradrenaline, and dopamine was achieved using a mixture of carboxymethyl-p-cyclodextrin (CMCD) and a polyamidoamine dendrimer (Starburst) [120], On-chip chiral separation of enantiomers of homovanillic acid, DOPA, cDOPA, methoxy-tyramine (MT), metanephrine, and normetanephrine was achieved using a mixture of 18-crown-6-ether and carboxymethyl-P-cyclodextrin [120],... 

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