5-hydroxyindole-3-acetic acid 5-HIAA

Metabolites of biogeiuc amines have also been analyzed by GC-ECD. For the simultaneous analysis of 5-hydroxyindole-3-acetic acid (5-HIAA), homovanillic acid (HVA) and m- and p-hydroxyphenylacetic acid (m-, p-HPAA), (metabolites of 5-HT, DA, and m- and p-tyramine acid respectively) in urine, a simple acidic extraction followed by derivatization with PFPA (derivatizes phenols) and hexafluoroisopropanol (deriva-tizes carboxylic acid groups) has been used (Davis et al., 1982 Baker et al., 1987). 

Numerous assays are also available in the literature for analysis of biogenic amines and their acid metabolites in brain tissue. For example, Chi and colleagues (1999) developed a rapid and sensitive assay for analyzing NE, DA, 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA), and homovanilHc acid (HVA) in rat brain. The assay used a C18 column (150 x 4.6 mm) coupled to an amperometric electrochemical detector. The mobile phase consisted of a phosphate buffer (pH 4.75) and octane sulphonic acid as an ion-pair reagent in acetonitrile. The sensitivity of the analytes reported was 3-8 pg on column. 

Disposition - It is possible that one mechanism for the disposition of the endogenously produced amine is by diffusion, which could be followed by re-uptake by nerve endings (or by other material in tissues) as has been shown with norepinephrine. But as yet there is no evidence for such a cycle for HT, although, as noted above, brain and its particulate fractions have the capacity for uptake. A main catabolic pathway for HT is oxidative deamination by monoamine oxidase to form 5-hy-droxyindoleacetaldehyde, most of which is converted to 5-hydroxyindole-acetic acid (HIAA) by aldehyde dehydrogenase and NAD S, 56 relatively small portion is reduced to 5-hydroxytryptophol by alcohol dehydrogenase and NADH " Monoamine oxidase, which, like... 

The possible effects of hallucinogens on central monoaminergic neurons were first explored by Freedman (34), who discovered that a single injection of LSD increases 5-HT levels in the rat brain, whereas its inactive congener BOL fails to affect brain 5-HT. Since this change is associated with a decrease in the concentration of the main metabolite of 5-HT, 5-hydroxyindole acetic acid (5-HIAA) (Fig. 1), Rosecrans et al. (98) postulated that LSD administration in... 

Also, harmala alkaloids create effects on monoamine turnover. Postnatal rats administered harmaline (shortly before birth) have elevations in brain levels of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG), but decreases in the dopamine and serotonin metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) (Okonmah et al. 

Table 1. Significant increase (P<0.05, t-test) in dihydroxyphenyl acetic acid (DOPAC) and 5-hydroxyindol acetic acid (5-HIAA) in the mouse hypothalamus following treatment of mice with Agaricus muscarius 12 through the oral route. No significant change in the level of dopamine (DA) and serotonin (5 HT) was observed. Data from Sc Cult 56 134-135 (1990) reproduced with author s permission.

The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in depressed patients. Whereas the overall psycho-physiological effects of noradrenaline in the CNS appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood. It is not surprising therefore to find that the serotonergic system is abnormal in depression. This is indicated by a reduction in the main 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), in the cerebrospinal fluid of severely depressed patients and a reduction in 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims. The 5-HT receptor function also appears to be abnormal in depression. This is indicated by an increase in the density of cortical 5-HT2A receptors in the brains of suicide victims and also on the platelet membrane of depressed patients. Platelets may be considered as accessible models of the nerve terminal. 

List of Abbreviations Ach, acetylcholine AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid CNS, central nervous system COMT, catechol-O-methyltransferase DA, dopamine DRP-2, dihy-dropyrimidinase-related protein 2 DSM, diagnostic and statistical manual of mental disorders GNAS1, guanine nucleotide-binding protein (G-protein) alpha stimulating activity polypeptide 1 5-HIAA, 5-hydroxyindole acetic acid 5-FIT, serotonin (5-hydroxytryptamine) MAO, monoamine oxidase MHPG, 3-methoxy-4-hydroxyphenylglycol NE, norepinephrine NMDA, N-methyl-D-aspartate PCP, phencyclidine SSRI, selective serotonin reuptake inhibitor SDS, schedule for the deficit syndrome... 

Serotonin (5-hydroxytryptamine, 5-HT) is synthesized from the essential amino acid tryptophan. It is a biogenic amine belonging to the indole family. 5-HT is broken-down by MAO and ultimately metabolized to 5-hydroxyindole acetic acid (5-HIAA). In the brain, the 5-HT afferents originate in the raphe nuclei and project to the striatum, thalamus, hippocampus, amygdala, and cortex. 

Most tryptamine molecules are metabolized by the enzyme monoamine oxidase (MAO). MAO actually occurs in two different forms, MAO-A and MAO-B, which have preferences for different neurotransmitter molecules. MAO-A oxidizes the terminal amine of the tryptamines to an imine. This imine then undergoes nonenzymatic hydrolysis to an aldehyde that is subsequently converted to a carboxylic acid by a second enzyme, aldehyde dehydrogenase. The result is the conversion of the tryptamine into an acidic molecule, called an indole-3-acetic acid, which lacks psychoactivity. DMT is converted into indole acetic acid, whereas serotonin is converted into 5-hydroxyindole acetic acid (5-HIAA), and psilocin is converted into 4-hydroxy indole acetic acid. 

Org 6582 (12) was found to be a strong, long lasting blocker of 5-HT uptake, five times chlorimipramine, with no apparent effect on NE uptake systems.13 Compound L2 also caused a decrease in 5-HT turnover and lowered brain 5-HIAA (5-hydroxyindole acetic acid). 

Not only is methamphetamine administration toxic to the dopaminergic system, but the serotonergic system in the various brain areas is also altered. Hotchkiss and Gibb (1980) reported that methamphetamine, administered as described above, decreased tryptophan hydroxylase (TPH) activity in the serotonergic nerve terminal of rat brain and spinal cord. Similarly, the content of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were also severely depressed. In contrast to the effects in the dopaminergic system, these serotonergic parameters were decreased by methamphetamine within 15 minutes after a single dose... 

AgRP Agouti-related gene product 5-HIAA 5-Hydroxyindole acetic acid... 

Hydroxy"5-methoxytryptamine produces an increase in exploratory behavior in animals, but not significant from controls. No effect on serotonin norepinephrine brief decrease in 5-hydroxyindole acetic acid (5-HIAA). (Maickei 1978)... 

The indoleamines The indole of greatest significance in human metabolism is serotonin (5-hydro-xytryptamine (5-HT)) which is synthesized from tryptophan and metabolized by the monoamine oxidase system to 5-hydroxyindole acetic acid (5-HIAA). Serotonin is believed to play a significant role in maintenance of mood and many antidepressant drugs act via the serotoninergic receptor system. 

In another study, adult Wistar rats were injected intravenously with 33-600 ULg of Cd + as cadmium chloride and the 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels were measured in various brain regions including the hypothalamus, thalamus, mesencephalon, and cortex. The concentration of 5-HIAA increased in all tissues as a function of the cadmium dose. Serotonin levels were reduced by the lowest cadmium dose, but were increased in all regions by the other doses of cadmium. ... 

Another technique O for measuring turnover time of 5-HT makes use of a blockade of monoamine oxidase with a number of inhibitors (including pargyline and tranylcypromine) and calculation of the rate of synthesis from the product of the rate constant of 5-hydroxyindole acetic acid (5-HlAA) decline and the normal 5-HIAA level. On the other hand, because of variation seen in the rate of Increase in NE after inhibition of MAO in different species, it has been inferred that the rate of increase in NE after blockade of MAO is not a good measure of rate of synthesis of this... 

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.)... 

Figure 2 Selective electrochemical detection of a mixture on multielectrode amper-ometry. AA = Ascorbic acid, NE = norepinephrine, DOPAC = 3-4-dihydroxy-phenylacetic acid, E = epinephrine bitartrate, 5-HIAA = 5-hydroxyindole-3-acetic acid, HVA = homovanillic acid, TRP = tryptophan, 5-HT = 5-hydroxytryptamine, and 3-MT = 3-methoxytyramine (separated by RPLC). Detection was with a 4-electrode glassy carbon array, with electrode 1 at 500 m V) electrode 2 at 700 mV, electrode 3 at 900 mV, and electrode 4 at 1100 mV. Note that at electrode 1, HVA, TRP, and 3-MT are not seen. At electrode 2, only TRP is not seen. A standard calomel electrode was used as reference. (Reprinted with permission from Hoogvliet, J. C., Reijn, J. M., and van Bennekom, W. P., Anal. Chem., 63, 2418, 1991. 1991 Analytical Chemistry.)...

Fig. 4.4.12. Separation of a mixture of acidic and basic catecholamines on a LiChrosorb RP-8 column (0.28x25 cm). Eluent Water containing 0.02 M citrate (pH 2.5)/l% propanol/NaCIQ4 (0.08 M)/0.3% sodium dodecyl sulphate. Peaks DHMA, 3,4-dihydroxymandelic acid VMA, vanilmandelic acid HGA, 2,5-dihydroxyphenylacetic acid DOPAC, 3,4-dihydroxyphenylacetic acid 5-HIAA, 5-hydroxyindole-3-acetic acid HVA, homovanillylmandelic acid E, epinephrine NE, norepinephrine N-Syn, norsyneph-rine Syn, synephrine Dopa, 3,4-dihydroxyphenylalanine NM, normetanephrine MN, metanephrine Isopren, isoprenaline 3-H-Tyrm, dopamine Tyrm, tyramine 3-M-Tyrm, 3-methoxytyramine. Reprinted from Ref. 21 with permission.

HIAA, 5-hydroxyindole-3-acetic acid DOPAC, 3,4-dihydroxyphenylacetic add HVA, homovanillic acid AA, ascorbic add and UA, uric acid. 

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