Brain 5-hydroxyindoles

Fuller, R.W., and Snoddy, H.D. Long-term effects of 4-chloroamphetamine on brain 5-hydroxyindole metabolism in rats. Neuropharmacology 13 85-90, 1974. 

Yokogoshi, H., Kato, Y, Sagesaka, Y. M., Matsuura, T. T., Kakuda, T., and Takeuchi, N. 1995. Reduction effect of theanine on blood pressure and brain 5-hydroxyindoles in spontaneously hypertensive rats. Biosci. Biotechnol. Biochem. 59 615-18. 

Brain 5-hydroxyindole acetic acid ifiglg brain tissue) Forebrain 0 37 Oil- 0-34... 

Sanders-Bush, E. Bushing, J.A. and Sulser, F. Long-term effects of p-chloroamphetamine on tryptophan hydroxylase activity and on levels of 5-hydroxytryptamine and 5-hydroxyindole aeetie acid in brain. 

Houdouin, F., Cespuglio, R. 8r Jouvet, M. (1991). Effects induced by the electrical stimulation of the nucleus raphe dorsalis upon hypothalamic release of 5-hydroxyindole compounds and sleep parameters in the rat. Brain Res. 565, 48-56. 

FIG. 1. Reversal by a 5-HT antagonist (methiothepin) of changes induced by LSD administration on indole levels in the whole brain of adult rats. LSD alone (2X1 mg/kg i.p. 120 and 100 min before death) induced a significant reduction of the 5-HIAA/5-HT ratio, indicating a marked decrease in 5-HT turnover. This effect was almost entirely suppressed by the combined treatment with the potent 5-HT antagonist methiothepin (20 mg/kg i.p. 110 min before death). Therefore, 5-hydroxyindole alterations due to LSD involve the direct stimulation of 5-HT receptors by the hallucinogen. Bar, mean SEM of six determinations. p < 0.05 when compared with saline-treated rats p < 0.05 when compared with rats treated with LSD alone. 

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. 

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. 

The blood-brain barrier foils most efforts to use the blood to measure the brain s chemistry, but researchers can get aroimd this obstacle by sampling cerebrospinal fluid (CSF). CSF is the fluid that circulates in the meninges of the brain and spinal cord and keeps the delicate tissues from getting rattled around and damaged in their hard, bony container. The brain makes CSF from blood, and certain metabolites get mixed in. One of these metabolites is 5-hydroxyindole acetaldehyde (5-FIIAA), a major metabolite of serotonin. Researchers who carefully puncture the meninges and extract a sample are rewarded with information concerning serotonin levels in the person s brain, as described below. 

Morier-Teissier et al. [156] determined that administration of EGb altos the levels of catecholamines, indolamines and their metabolites in some brain areas of young rats and mice. Marked changes in the EGb-treated brain were found for norepinephrine, 5-HT, and its metabolite, 5-hydroxyindole-3-acetic add, whereas it was less effective for dopamine and its metabolite 3,4-dihydroxy-phenylaoetic add. EGb-induced changes depend on the route of administration (p.o. or L p.), dose and duration of treatment (acute or chronic). 

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. 

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. 

Both these 5-hydroxyindoles are natural compounds, playing an important role in the brain. 5-hydroxytryptophan (5-HTP) 315 is the metabolic precursor for the neurotransmitter serotonin melatonin 316 is a neurohormone involved in the regulation of chronobiological rhythms such as sleep and fertility306. They have been labelled with F-18, for in vivo metabolic imaging with PET, in reaction of dilute [18F]fluorine gas with melatonin or with 5-hydroxytryptophan in hydrogen fluoride307 at — 70 °C (equation 134). 

The sedative effect of palmatine on locomotor activity and concentration of monoamine in rats was studied via behavioral and biochemical methods. Palmatine was shown to enhance the hypomotility induced by a-methyl-p-tyrosine, reserpine, and 5-hydroxytryptophan, but reduced the hypermotility produced by L-dopa plus benserazide and p-chlorophenylalanine. In addition, the alkaloid significantly decreased the concentration of dopamine and homovanillic acid in the cortex and the concentration of serotonin in the brain stem, but increased the concentration of 5-HT in the cortex and 5-hydroxyindole acetic acid in the brain stem. These results suggest that the sedative action associated with palmatine may be related to the decrease in catecholamine concentration in the cortex and serotonin in the brain stem, and the increase in the concentration of 5-HT in the cortex [309],... 

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... 

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... 

HT is also metabolised by MAO to form 5-hydroxyindole aeetie acid (5-HIAA), which is actively transported across the blood-brain barrier out of the brain, in common with other low molecular weight organic acids (e.g. HVA uric acid). 

Gessa et al.1 were the first to demonstrate that the acute administration of an amino acid mixture containing all of the essential amino acids, except tryptophan, caused a rapid fall in plasma free and total tryptophan in rats. Furthermore, this effect was associated with a parallel depletion in brain tryptophan, serotonin, and 5-hydroxyindole acetic acid in rats.2 These early studies opened the way for subsequent studies, using acute tryptophan depletion by feeding a tryptophan-free amino acid mixture, a simple, specific, and nontoxic method, to delete brain serotonin and thus provide a tool for clarifying the physiological role of serotonin in the central nervous system. 

The hydroxylation of tryptophan produces 5-hydroxytryptophan, which can then be decarboxylated, catalyzed by tryptophan decarboxylase, a PALP-requiring enzyme, to 5-hydroxy tryptamine, also known as serotonin. Serotonin is an important compound in normal brain function and tranquility. Therefore, any disturbance of tryptophan metabolism via this pathway can lead to mental disturbances. Serotonin can be destroyed by the enzyme monoamine oxidase (a flavo protein), which catalyzes the formation of ammonia and 5-hydroxyindole acetaldehyde in an irreversible reaction. The aldehyde is rapidly oxidized enzymatically, utilizing NAD+ to form 5-hydroxy indoleacetate, which is then usually excreted. The formation and turnover of serotonin can be estimated by 5-hydroxy indoleacetate output in the urine. 

Norepinephrine reduction can be due to a severe cell loss in LC of AD brains. Serotonin, its metabolite 5-hydroxyindole-3-acetic acid and norepinephrine are measured to be decreased in hippocampal formation. The substantia innominata may be unaffected (Baker and Reynolds, 1989). The loss of serotonin correlates to many neuropathological findings in serotonergic cells of the nuclei raphe (Quirion et al., 1986). 

Tyramine methyltransferase from barley roots Norbelladine-O-mediyltransferase from amarylis bulbs ImidazoIe-N-methyltransferase from guinea pig brain (2.1.1.8) Hydroxyindole-O-methyltransferase from pineal (2.1.1.4) Homocysteine-S-methyltransferase from yeast (2.1.1.10 ) S-Adenosylmethionine cyclotransfeiase from yeast (2.5.1.4) S-Adenosylmethionine decarboxylase from E. coli... 

Urinary estimations of dopamine and its metabolites are of limited value as L-dopa occurs in a wide variety of dietary sources, particularly cereals [570]. Urinary 3,4-dimethoxyphenylethylamine, postulated as a circulating Parkinsonian toxin [304], probably arises from such sources. Estimations of 5-hydroxyindole-3-acetic acid in cerebrospinal fluid reflect metabolic changes of serotonin in the spinal tissue but not in the brain [571]. Cerebral ventricular fluid may yield more reliable results [572]. Measurements of... 

A massive phytochemical survey by the U.S. Department of Agriculture [610] has identified a number of useful sources of L-dopa, the most promising being cultivated velvet beans. However, the microbiological hydroxylation of A-formyl-L-tyrosine esters [436] can be duplicated chemically in excellent yield by the use of benzoyl peroxide in chloroform [611]. Reports state that L-dopa from Japanese sources is superior to that from the U.S.A. [612]. Suitability of patients for L-dopa therapy can be assessed by determination of homovanillic acid and 5-hydroxyindole-3-acetic acid levels before and after treatment with probenecid [613, 614]. This drug reduces the outflow of brain monoamine metabolites into the blood and provides an index of the degree of... 

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. ... 

Sheard M. H. (1969) The effect of p-chlorophenylalanine on behavior in ratS relation to brain serotonin and 5-hydroxyindole acetic acid Brain Res. 15, 524-528. 

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