5-Hydroxyindoleacetic acid 5- HIAA

HT is metabolised primarily by MAO to 5-hydroxyindoleacetic acid (5-HIAA) (Fig. 9.4). In vitro, 5-HT is the preferred substrate for the MAOa, rather than the MAOb isoenzyme (see Chapter 8) and this appears to be the case in vivo since MAOa, but not MAOb, knock-out mice have increased concentrations of 5-HT in the brain. Obviously, because of its indole nucleus, 5-HT is not a substrate for the enzyme COMT which metabolises the catechol derivatives, dopamine and noradrenaline. However, other metabolic products of 5-HT are theoretically possible and one, 5-hydroxytryptophol,... 

When administered in doses higher than 12 mg/kg/day, depletions of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) last up to 6 months after cessation of drug treatment (Harvey and McMaster 1975 Harvey et al. 1977 Clineschmidt et al. 1978 Steranka and Sanders-Bush 1979 Schuster et al. 1986 Kleven et al. 1988). Other long-lasting effects of fenfluramine include a decrease in 5-HT uptake sites (Schuster et al. 1986) and tryptophan hydroxylase activity (Steranka and Sanders-Bush 1979). 

This chapter will review some recently completed studies on the long-term effects of MDMA in nonhuman primates. The goals of these studies were to (1) determine if the neurotoxic effects of MDMA, which have been well documented in the rodent (see below), generalize to the primate (2) compare the relative sensitivity of primates and rodents to the neurotoxic effects of MDMA (3) ascertain if the toxic effects of MDMA in the monkey are restricted to nerve fibers (as they are in the rat), or if they involve cell bodies as well (4) evaluate how closely toxic doses of MDMA in the monkey approximate those used by humans and (5) examine whether 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) can be used to detect MDMA-induced serotonergic damage in the CNS of primates. Before presenting the results of these studies, previous results in the... 

Serotonergic function has been investigated by using multiple methods. Assaying the major metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) has been widely used (Ch. 13). This method assumes that CSF 5-HIAA is related to brain serotonin activity. This premise is supported by the rostral-caudal concentration gradient of CSF 5-HIAA and the observation in postmortem studies that CSF 5-HIAA correlates with levels of 5-HIAA in prefrontal cortex [16], both of which suggest that CSF 5-HIAA is a reasonable index of prefrontal serotonin turnover. ... 

A puzzling finding regarding the 5-HT syndrome is the report that the deam-inated indoles 5-hydroxyindoleacetic acid (5-HIAA the primary metabolite of 5-HT) and indoleacetic acid (IAA) are effective in producing the syndrome... 

Serotonin is an indolamine neurotransmitter, derived from the amino acid L-tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. 5-HTP is converted to 5-hydroxytryptamine (serotonin, 5-HT) by aromatic amino acid decarboxylase. In the pineal gland, 5-HT may be further converted to /V-acetyl serotonin by 5-HT /V-acetyltransferase and then to melatonin by 5-hyroxyindole-O-methyltransferase. 5-HT is catabolized by monoamine oxidase, and the primary end metabolite is 5-hydroxyindoleacetic acid (5-HIAA). 

HT is metabolized by the action of monoamine oxidase by a process of oxidative deamination to yield 5-hydroxyindoleacetic acid (5-HIAA). In the pineal gland, 5-HT is o-methylated to form melatonin. While the physiological importance of this transmitter in the regulation of the oestrus cycle in ferrets would appear to be established, its precise role in man is unknown. Nevertheless, it has been speculated that melatonin plays some... 

Colorimetric assays used in endocrinological procedures are also often subject to drug interference. We have observed an interesting interference in a patient with carcinoid. The patient excreted 400 mg of 5-hydroxyindoleacetic acid (5-HIAA) and when a vanillylmandclic acid (VMA) determination was performed by a nonspecific diazo method, the value was reported to be 375 mg. The catecholamines were just above normal. There was an immediate suggestion that the patient also had a pheochromocytoma. However, when a specific chromatographic VMA method was used, the value was found to be within normal limits. Subse-... 

In essentially all species of animals, including humans, serotonin is important in aggression (Kravitz, 2000). Relationships between CSF concentrations of a serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and human aggression were described in As-berg et al. s landmark study (1976), which showed a bimodal distribution among depressed patients. A meta-analysis of 27 studies, involving 1202 psychiatric patients, showed an association between attempted suicide and low levels of CSF 5-HIAA (Lester, 1995). 

Lithium has numerous pharmacologic effects. It is able to cross through sodium channels, competing with monovalent and divalent cations in cell membranes (AHFS, 2000). Animal studies have shown that lithium at a serum level of 0.66 + — 0.08 mEq/L can increase the amphetamine-induced release of serotonin (5-hydroxytryptamine [5-HT]) and the concentrations of a serotonin metabolite (e.g., 5-hydroxyindoleacetic acid [5-HIAA]) in the perifornical hypothalamus (PFH) of rats before and after chronic lithium chloride administration (Baptista et ah, 1990), a mechanism possibly involved in lithium s antidepressant effect. The precise neurobiological mechanisms through which lithium reduces acute mania and protects against recurrence of illness remain uncertain (Lenox and Hahn,... 

The first neurochemical evidence of a disturbed serotonin function in cognition came from the changes in serotonin and/or 5-hydroxyindoleacetic acid (5-HIAA) levels in a number of forebrain nuclei, the temporal and cingulate cortex, hippocampus, and other areas of the brain taken at autopsy from patients with senile dementia of the Alzheimer s type (Adolfsson et al. 1978 Arai et al. 1984 D. M. Bowen et al. 1979, 1983 A. J. Cross et al. 1983 Winblad et al. 1982). The depletions are regionally selective reductions in se-... 

There is also evidence of low levels of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) of impulsive individuals. We might hypothesize that, in a nonresponsive, impulsive patient, diminished serotonin plays a role in the pathophysiology. This hypothesis could now be tested and simultaneously serve as the foundation for a pathophysiologically based treatment by choosing therapies specific for various components of this system. For example, the 5-HT agonist buspirone might be tried, because there is limited evidence from open trials that it has antiaggressive properties. 

Serotonin is metabolized by MAO, and the intermediate product, 5-hydroxyindoleacetaldehyde, is further oxidized by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA). In humans consuming a normal diet, the excretion of 5-HIAA is a measure of serotonin synthesis. Therefore, the 24-hour excretion of 5-HIAA can be used as a diagnostic test for tumors that synthesize excessive quantities of serotonin, especially carcinoid tumor. A few foods (eg, bananas) contain large amounts of serotonin or its precursors and must be prohibited during such diagnostic tests. 

The hypothesis that SSRIs work in OCD by a serotonergic mechanism is also supported by studies showing a strong positive correlation between improvement in obsessive-compulsive symptoms during clomipramine treatment and drug-induced decreases in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and platelet serotonin concentrations. Thus, peripheral markers of 5HT function link the symptomatic improvement in OCD symptoms produced by SSRIs to changes in 5HT function. However, these markers do not consistently highlight a 5HT abnormality in untreated patients with OCD,... 

Serotonin (5-hydroxytryptamine) is oxidized [via MAO and aldehyde dehydrogenase] to 5-hydroxyindoleacetic acid (5-HIAA). 

Indolealkylamines. GC-MS methods applied in studies of the biochemical pharmacology of indoleamines parallel work on the catecholamines. SIM assays for serotonin (5-hydroxytryptamine), 5-methoxytryptamine, JV-acetylserotonin and melatonin (5-methoxy-N-acetyltryptamine) in rat pineal and brain tissue have been described [453,469]. Pentafluoro-propionyl derivatives and structural homologue standardisation were employed with detection limits in the subpicomole range. Estimation of central indoleamine turnover in man currently depends upon metabolite determination in CSF. Ion monitoring determination of indole-3-acetic acid [454] a metabolite of tryptamine, and isotope dilution assays for 5-hydroxyindoleacetic acid (5-HIAA) [455,458] have been reported. Serotonin is converted by central monoamine oxidase to 5-HIAA and the measurement of this metabolite, formerly by fluorimetry, is of interest in patients with CNS disorders [470]. GC-MS has also contributed to the identification of N,N-dimethyltryptamine in vitro [471] and isotope dilution technique has been applied to the measurement of this metabolite in control subjects and in psychiatric patients [472]. 

One of the most consistent findings in biochemical research dealing with mental disorders is that some patients with low 5-hydroxyindoleacetic acid (5-HIAA)—the metabolite of serotonin—in CSF are prone to commit suicide (Lidberg et al., 2(X)0 Mann and Malone, 1997 Nordstrom et al., 1994). This gives additional evidence for a possible link between the type-1 cytokine IFN-y and the IDO-related reduction of serotonin availability in the CNS of suicidal patients. 

Serotonin is not a substrate for COMT and follows simpler pathways of metabolism than those for catecholamines (Figure 29-6). Deamination of serotonin to the aldehyde intermediate is preferentially followed by oxidation to 5-hydroxyindoleacetic acid (5-HIAA) catalyzed by... 

Knapp et al.21 reported that the levels of forebrain tryptophan, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and hydroxylase cofactor (BH4) were comparable in two experimental mouse strains (A/J and C57B1/6J), despite two- to three-fold differences in vitro in the relative activities of forebrain and midbrain tryptophan-5-monoxygenase. The enzyme activities did not differ with respect to Km for cofactor at saturating levels, but manifested different degrees of cooperativity with respect to cofactor when examined with BH4 concentrations within a physiological range. 

Depressed persons who commit suicide have been found to have low levels of 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in their brain stem (Mann et al., 1990). Low levels of 5-HIAA also have been found in the cerebrospinal fluid of suicide victims. This has been attributed to a decreased release of 5-HT, rather than to lower numbers 5-HT receptors. Depressed persons also have low brain levels of norepinephrine, as well as 5-HT. 

Carbon and ceramic electrodes have been used for quantitative and qualitative recordings of the neurotransmitters dopamine (DA), 5-hydroxytryptamine (5-HT), and their metabolites 3,4-dihydroxyphenyl-acetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and L-glutamate. Nitric oxide can also be recorded. In this case the carbon surface of the electrode is covered with a p-type semiconducting polymeric porphyrin that acts as a catalyst for the oxidation of nitric oxide. Nitric oxide is responsible for the activity of the endothelium-derived relaxing factor associated with hypertension, diabetes, ischemia, and arteriosclerosis. 

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