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PubMed1983

Natural and synthetic analogues of melatonin and related compounds. II. Effects on plasma thyroid hormones and cholesterol levels in male Syrian hamsters.

Synthetic or natural analogues of the pineal indole, melatonin, were injected separately every evening (1700 hours) for 7 (Exp. 1) or 10 (Exp. 2) weeks into adult male Syrian hamsters maintained in 14 hours of light and 10 hours of darkness each day. Plasma thyroxine (T4) levels were significantly depressed by 25 micrograms/day of melatonin (aMT) in both experiments. Injecting 25 micrograms/day either of acetyl methoxytryptophol or of synthetic analogues (hexanoyl methoxytryptamine, propionyl methoxytryptophol, or 6-chloro-melatonin) in Exp. 1 or of a natural analogue (N-acetylserotonin, 6-hydroxy-melatonin, hydroxytryptophol, or methoxytryptophol) in Exp. 2 had no effect on the circulating T4 levels. Plasma levels of triiodothyronine (T3) and thyrotropin (TSH) were unaffected in either experiment. Since none of the tested melatonin analogues is capable of suppressing circulating T4 concentration when given in a dose at which melatonin is reproducibly effective, the pineal-induced suppression of T4 is most likely mediated by melatonin. Plasma cholesterol levels were elevated only in hamsters receiving 6-chloromelatonin injections. However, plasma triglyceride levels were significantly higher than the diluent treated controls in Exp. 1 after injections of melatonin, acetyl methoxytryptophol, propionyl methoxytryptophol and 6-chloromelatonin. Interscapular brown adipose tissue was significantly heavier in melatonin treated animals.

Animals↗
PubMed1980

A survey of the location, isolation and identification of indoles, pteridines and some unknown active substances in sheep pineals. The possible significance of pteridines for the neuroendocrine control of neoplastic growth.

Several indoles with mass spectra identical to those of synthetic melatonin, 5-hydroxyindole-3-acetic acid (5-HIAA), 5-methoxyindole-3-acetic acid (5-MIAA), 5-hydroxytryptophol (5-HTL) and 5-methoxytryptophol (5-MTL) could be located, isolated and identified in sheep pineal extracts using rather simple and mild extraction and separation methods. An antigonadotropin, which differs from melatonin, was isolated and partially purified from sheep pineals, using compensatory ovarian hypertrophy after unilateral ovariectomy as a bioassay. Antigonadotropic and gonadotropic compounds which differ from the indoles above mentioned could be located with the same methods. In vitro, these fractions act either on the hypothalamus or on the anterior pituitary. From the paper chromatography fraction, acting on the anterior pituitary in vitro, a compound could be isolated which is most probably identical with biopterin. In our opinion, however, this compound is not responsible for the antigonadotropic activity of the fraction, observed in vitro. Some pineal fractions showing an effect on the activity of the hypothalamus or anterior pituitary of male rats and mice in vitro, may be also active in some experimental tumour models. A possible relationship between disorders in pteridine metabolism and neoplastic growth is discussed.

Animals↗
PubMed1989

Probable mechanism of catalysis of pineal gland hydroxyindole-O-methyltransferase (HIOMT) from rainbow trout (Salmo gairdneri).

Activity of trout pineal HIOMT was found to increase with increase in incubation temperature from 5 to 40 degrees C although the activation energy remained constant over this range. From examination of the effects of the products of HIOMT catalysis on the enzyme it was apparent that the catalytic mechanism was ordered Bi-Bi with S-adenosylmethionine as the obligatory first substrate. Trout HIOMT was found to methylate all the common pineal hydroxyindoles with hydroxytryptophol having the greatest affinity for the enzyme. The pH optimum for trout HIOMT was found to be about pH 9.0 although routine use of a pH of 7.9 is recommended to limit potentially deliterious effects caused by degradation of S-adenosylmethionine at elevated pHs.

Acetylserotonin O-Methyltransferase↗
PubMed1982

The effect of melatonin and other indole derivatives in maintaining ovulation in rats kept in continuous light and the influence of these indoles on HIOMT activity in the pineal gland.

The aim of the present study was to investigate whether the ovulation-maintaining effect of melatonin in rats, exposed to continuous light (LL), was also exerted by other pineal indoles which have been reported to influence the reproductive processes of mammals. The effect of 10 micrograms melatonin was compared with that of similar amounts of either N-acetylserotonin, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid, 5-hydroxytryptophol, 5-methoxytryptamine or 5-methoxytryptophan. All these compounds appeared to be significantly less effective than melatonin in preventing the effect of LL, ovulation being preserved in only 20--33% of the rats investigated, with melatonin this percentage being 60--75%. Investigations were also carried out to assess the effect of these indole derivatives on HIOMT (hydroxyindole-O-methyl transferase) activity in synthesizing different 5-methoxyindoles in the abnormally influenced pineal gland due to LL. Melatonin, the compound the effect of which on ovarian cyclicity is strongest, stimulates 5-methoxytryptophol synthesis; while other less active compounds stimulate the synthesis of melatonin and inhibit that of O-acetyl-5-methoxytryptophol. The possibility that the effect of other indoles than melatonin on ovarian cyclicity might be due to stimulation of melatonin synthesis was considered. A possible functional relationship of the different indoles cannot be excluded.

Acetylserotonin O-Methyltransferase↗
PubMed1983

An automated method for the determination of biogenic amines and their metabolites by high-performance liquid chromatography.

An automated high-performance liquid chromatographic method has been developed that allows for the determination of a number of compounds related to catechol- and indoleamine metabolism. The compounds that can be measured include L-DOPA, dopamine, dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, norepinephrine, 3-methoxy-4-hydroxyphenylglycol, dihydroxyphenylglycol, vanilmandelic acid, epinephrine, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophol. Dihydroxybenzylamine is used as an internal standard. Although dihydroxyphenylglycol and vanilmandelic acid could be detected and quantified, they could not be separated from each other. The method is completely automated and is sensitive enough to detect amounts as low as 500 fmol. Up to 200 samples a week can be analyzed in the automated mode. Using this method, analyses of brain tissue can be accomplished with no need for a cleanup procedure. The value of this procedure lies in its ability to simultaneously determine various amines and metabolites from small tissue samples in the same animals and with automation to analyze a relatively large number of samples a day with little attention by a technician.

Animals↗
PubMed1994

Characteristics, day-night changes, subcellular distribution and localization of melatonin binding sites in the goldfish brain.

Melatonin binding sites in the goldfish brain were characterized by radioreceptor assay using 2-[125I]iodomelatonin as the radioligand. Specific binding of 2-[125I]iodomelatonin was rapid, stable, saturable and reversible. Saturation experiments demonstrated that 2-[125I]iodomelatonin binds to a single class of receptor site with an affinity constant (Kd) of 29.8 +/- 0.7 pM and a total binding capacity (Bmax) of 11.47 +/- 0.33 fmol/mg protein at mid-light. At mid-dark, the Bmax value decreased significantly to 7.90 +/- 0.23 fmol/mg protein (P < 0.01) with no significant variation in the Kd value (33.8 +/- 1.5 pM). Competition experiments revealed the following order of pharmacological affinities: 2-iodomelatonin > melatonin > 6-hydroxymelatonin > N-acetyl-5-hydroxytryptamine > 5-methoxytryptamine > 5-methoxytryptophol > 5-methoxyindole-3-acetic acid. 5-Hydroxytryptamine, 5-hydroxytryptophol, 5-hydroxyindole-3-acetic acid, norepinephrine and acetylcholine exhibited no inhibition. Subcellular distribution of melatonin binding sites was demonstrated to be greatest in the P2 and P3 fractions as compared with the P1 fraction. Localization of melatonin binding sites in discrete brain areas was determined to be highest in the optic tectum-thalamus and hypothalamus, intermediate in the telencephalon, cerebellum and medulla oblongata, and lowest in the olfactory bulbs and pituitary gland. These results suggest that characteristics of melatonin receptors are highly conserved during evolution and that in this species melatonin plays neuromodulatory roles in the central nervous system through specific receptors.

Animals↗
PubMed1992

2[125I]iodomelatonin binding sites in spleens of guinea pigs.

2-[125I]Iodomelatonin was found to bind specifically to the membrane preparations of the spleens of guinea pigs with high affinity. The binding was rapid, stable, saturable and reversible. Scatchard analysis of the binding assays revealed an equilibrium dissociation constant (Kd) of 49.8 +/- 4.12 pmol/l and binding site density (Bmax) of 0.69 +/- 0.082 fmol/mg protein at mid-light (n = 10). There was no significant change in the Kd (41.8 +/- 3.16 pmol/l) or the Bmax (0.58 +/- 0.070 fmol/mg protein) at mid-dark (n = 10). Kinetic analysis showed a Kd of 23.13 +/- 4.81 pmol/l (mean +/- SE, n = 4), in agreement to that derived from the saturation studies. The 2-[125I]iodomelatonin binding sites have the following order of potency: 2-iodomelatonin greater than melatonin greater than 6-chloromelatonin much greater than N-acetylserotonin, 6-hydroxymelatonin greater than 5-methoxytryptamine, 5 methoxytryptophol greater than serotonin, 5-methoxyindole-3-acetic acid greater than 5-hydroxytryptophol, 3-acetylindole, 1-acetylindole-3-carboxyaldehyde, L-tryptophan greater than tryptamine, 5-hydroxyindole-3-acetic acid. Differential centrifugation studies showed that the binding sites are localized mainly in the nuclear fraction (65.5%), the rest are distributed in the microsomal fraction (17.4%), mitochondrial fraction (14.7%) and cytosolic fraction (0.3%). The demonstration of 2-[125I]iodomelatonin binding sites in the spleen suggests the presence of melatonin receptors and a direct mechanism of action of melatonin on the immune system.

Animals↗
PubMed1994

Influence of genetic variation in alcohol and aldehyde dehydrogenase on serotonin metabolism.

The influence of genetic variation in alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase (ALDH; EC 1.2.1.3) on the metabolic pattern of serotonin (5-hydroxytryptamine, 5-HT) in humans was examined from the relative urinary concentrations of the end products 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL). Healthy Caucasian (Swedish) and Oriental (Chinese) subjects were genotyped for ADH2, ADH3 and ALDH2 by a PCR/SSCP technique. The 5-HTOL/5-HIAA ratios ranged between 0.9-9.4 pmol/nmol (4.4 +/- 1.8, mean +/- SD, n = 143). No significant difference in the 5-HT metabolic pattern was observed between Caucasians and Orientals (4.3 +/- 1.8 and 4.4 +/- 1.8 pmol/nmol, respectively), nor between any of the ADH2, ADH3 and ALDH2 genotypes. Despite the modulatory effects of genetic variation of these enzymes on ethanol metabolism, the present results indicate that the individual isozyme composition of ADH2, ADH3 and ALDH2 is not important for the metabolic pattern of 5-HT.

Alcohol Dehydrogenase↗
PubMed1986

Pineal indoles: significance and measurement.

Despite intensive investigation, particularly over the past fifteen years, many aspects of pineal function with respect to mammalian physiology remain obscure. Much of this work is reviewed and particular attention focussed on indole metabolism within the pineal gland. Emphasis is placed on the development of new analytical techniques with special reference to high performance liquid chromatography coupled with electrochemical detection. The growth in knowledge regarding pineal indole synthesis which can be attributed to the use of this technique is discussed. The possibility that pineal indoles other than melatonin may function as hormones or neuromodulators is considered. A functional role for 5-hydroxytryptophol as a neuromodulator, possibly associated with diffuse neuroendocrine function (amine precursor, uptake and decarboxylation, APUD) is suggested.

Animals↗
PubMed1995

Melatonin synthesis in the retina and pineal gland of Djungarian hamsters at different times of the year.

Daily profiles of melatonin content in the retina of Djungarian hamsters were measured throughout the course of a year. Peak levels of retinal melatonin were found at various times of the day at different seasons. In a subsequent study we determined concurrently daily profiles of nine indole metabolites (tryptophan, 5-hydroxytryptophan, 5-hydroxytryptamin, 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, N-acetylserotonin, melatonin, 5-methoxyindoleacetic acid and 5-methoxytryptophol) in samples of hamster retina and pineal gland at the four different seasons. Measurements were made using HPLC coupled to a coulometric electrode detection system. Large seasonal variations in the levels and daily rhythm amplitudes of the different indole metabolites were found in the pineal glands. Due to technical problems and unknown interfering substances only tryptophan and serotonin could be determined in the retinas at all four seasons. Despite this, the ability to measure levels of several metabolites in the same sample and in different tissues of the same animals permitted more accurate comparisons of the components involved in melatonin synthesis. Our data suggest that the level of retinal melatonin is regulated and controlled locally within the retina itself. However, long-term feedback mechanisms from other sources of melatonin are not excluded but are rather likely.

Animals↗
PubMed1978

Interaction of arginine vasotocin and norepinephrine upon pineal indoleamine synthesis in vitro.

The interaction of arginine vasotocin (AVT) and norepinephrine (NE) upon pineal gland indoleamine synthesis was investigated. Rat pineal glands were incubated for 10 h in Krebs--Ringer bicarbonate plus 2 mg/ml glucose, 1 mg/ml bovine serum albumin, [14C]tryptophan, NE (10(-6) M), and log doses of AVT ranging from 100 ng to 10 microgram. Incubation media were extracted for [14C]serotonin while the other [14C]indoleamines, melatonin, hydroxyindoleacetic acid (HIAA), methoxyindoleacetic acid (MIAA), N-acetylserotonin (NAS), hydroxytryptophol (HTOL), and methoxytryptophol (MTOH) were separated by thin-layer chromatography. Serotonin metabolism was decreased by 0.1 microgram AVT and NAS decreased by 1.0 microgram AVT. Melatonin synthesis was decreased by both 0.1 and 1.0 microgram AVT. AVT also decreased the conversion of [14C]serotonin to MIAA and to HTOL. The data indicates that AVT decreased NE-stimulated pineal indoleamine synthesis in vitro and further suggests that AVT may participate in the intracellular regulation of melatonin synthesis.

Animals↗
PubMed1982

LCEC monitoring of 5-hydroxyindolic compounds in the cerebrospinal fluid of the rat related to sleep and feeding.

A new technique which allows for both the chronic withdrawal of CSF and continuous recording of EEG sleep patterns and food intake in the freely moving rat is described. Liquid chromatography with electrochemical detection (LCEC) was used for the direct assay of tryptophan metabolites in the CSF. Both 5-hydroxyindolacetic acid (5-HIAA) and 5-hydroxytryptophan (5-HTP) were easily detectable. However, serotonin (5-HT) levels were relatively low and 5-hydroxytryptophol (5-HTPhol) and N-methylserotonin (N-Me-5HT) were undetectable in several cases. The continuous monitoring of 5-HIAA and 5-HTP indicated stable values throughout the 3-hr experiments during which no food or small meals were consumed. In the rat which consumed a large meal, both 5-HIAA and 5-HTP significantly increased following that meal. This increase in metabolites may be the result of an increased availability of tryptophan to the brain as a result of the meal. Although this study is preliminary, the described technique can provide further information about the possible relationship between behavioral (sleep and/or feeding) changes and the concomitant neurochemical fluctuations.

5-Hydroxytryptophan↗
PubMed1984

Day/night differences in pineal indoles in the adult pigeon (Columba livia).

Day/night differences in concentrations of 5-hydroxy and 5-methoxy indole metabolites in the pineal gland of the pigeon are described. A simultaneous determination of 5-hydroxytryptamine (serotonin), 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, N-acetyl-5-hydroxytryptamine (N-acetyl serotonin), 5-methoxyindoleacetic acid, 5-methoxytryptophol, tryptophan, indoleacetic acid and melatonin was accomplished using a recently developed procedure employing high-performance liquid chromatography with electrochemical detection. As in mammalian species, an inverse relationship was observed between N-acetylated indoles and serotonin and its acid metabolites. Melatonin and N-acetyl serotonin were increased approximately three-fold at night to concentrations of 0.730 and 1.79 ng/pineal respectively. Daytime serotonin values were 44.9 +/- 13.0 ng/pineal and decreased to 12.3 +/- 6.5 ng/pineal during the dark phase.

Animals↗
PubMed1988

Serotonin (5-hydroxytryptamine) turnover in adult female Ascaris suum tissue.

1. The 5-hydroxytryptamine (5-HT, serotonin) turnover was examined in the tissues of adult female Ascaris suum. The 5-HT turnover was highest in the intestine at 34.7 ng 5-HT produced/mg protein/hr and 13.8 ng 5-HT produced/mg protein/hr in muscle tissue. 2. The levels of 5-HT metabolites namely tryptophan, 5-hydroxytryptophan, 5-hydroxytryptamine, 5-hydroxyindole acetic acid and 5-hydroxytryptophol were measured in muscle and intestinal tissue of adult A. suum. 3. Parachlorophenylalanine inhibited 5-HT production in muscle and intestinal tissue providing in situ evidence for the presence of tryptophan hydroxylase in this tissue. 4. Pargyline increased 5-HT production in muscle and intestinal tissue providing in situ evidence for the presence of monoamine oxidase in this tissue.

Animals↗
PubMedDate not supplied

Effects of acute and short-term administration of tryptophan plus ethanol on noradrenaline and serotonin metabolites in the locus coeruleus.

The effects of acute and short-term administration of tryptophan or tryptophan plus ethanol on serotonin [5-hydroxytryptamine (5-HT)] and two of its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTPL), in the locus coeruleus were investigated in rats by using the microdialysis method. In addition, the acute effects of these drugs on noradrenaline and its metabolite 4-hydroxy-3-methoxymandelic acid (HMMA) were addressed. A single co-administration of tryptophan (50 mg/kg, i.p.) and ethanol (1.25 g/kg, i.p.) did not change the concentrations of either noradrenaline or its metabolite in the locus coeruleus. In contrast, administration of tryptophan (50 mg/kg, i.p.) for three consecutive days caused an increase in the concentration of 5-HIAA, but not that of 5-HT, in the locus coeruleus. Combined administration of tryptophan plus ethanol for 3 days resulted in marked increases in 5-HIAA concentrations in the locus coeruleus, but not in 5-HTPL concentrations. However, administration of ethanol (1.25 g/kg) for 3 days had no effect on the concentrations of 5-HT and its metabolites. The increased 5-HIAA concentration that resulted with combined tryptophan plus ethanol administration was remarkably suppressed by disulfiram. Moreover, in comparison with tryptophan-treated rats, the behavioral sign of teeth-chattering was significantly detected in tryptophan plus ethanol-treated rats, but the enhancement of behavioral signs with combined treatment was markedly suppressed by disulfiram. Results of the current study seem to indicate that the stimulation of 5-HT metabolism in locus coeruleus serotonergic neurons by tryptophan was strengthened by the simultaneous administration of ethanol in short-term experiments, and that the increased 5-HIAA concentrations in the locus coeruleus are responsible for behavioral activation.

Animals↗
PubMed2006

Biomarkers in alcoholism.

Alcoholism ranks as one of the main current threats to the health and safety of people in most Western countries. Therefore, a high priority should be given to aims at reducing its prevalence through more effective diagnosis and early intervention. The need for objective methods for revealing alcohol abuse in its early phase has also been widely acknowledged. It is postulated here that the diagnosis of alcohol use disorders could be markedly improved by a more systematic use of specific questionnaires and laboratory tests, including blood ethanol, serum gamma-glutamyltransferase (GGT), carbohydrate-deficient transferrin (CDT), and mean corpuscular volume of erythrocytes (MCV). Recent research has provided new insights into the relationships between ethanol intake, biomarkers, and factors affecting their diagnostic validation, including gender, age, and the effects of moderate drinking and obesity. It appears that the concept of reference intervals for several ethanol-sensitive parameters in laboratory medicine needs to be revisited. CDT is currently the most specific marker of alcohol abuse, and when combined with GGT using a mathematically formulated equation a high sensitivity is reached without loss of assay specificity. Possible new biomarkers include minor ethanol metabolites (protein-acetaldehyde condensates and associated autoimmune responses, ethylglucuronide, and phosphatidylethanolamine), 5-hydroxytryptophol, and genetic markers although so far their routine applications have been limited.

Alcohol Drinking↗
PubMed1977

Mass fragmentographic determination of 5-hydroxytryptamine and 5-hydroxyindole-3-acetic acid in brain tissue using deuterated internal standards.

A mass fragmentographic method for the determination of 5-hydroxytryptamine (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) in the same extract of rat brain tissue is decribed. Deuterium-labelled analogues were used as internal standards. 5-HT and 5-HIAA were separated by solvent extraction and pentafluoropropionyl derivatives were prepared for the mass fragmentographic analysis. Multiple ion analysis confirmed the identity of 5-HT and 5-HIAA in the rat brain. At the mass numbers used routinely for the determination of 5-HT and 5-HIAA in the rat brain. At the mass numbers used routinely for the determination of 5-HT and 5-HIAA, the experimental error was below 3% (calculated from mean values of 0.05 and 0.24 nmole, respectively). The recovery of the authentic compounds added to brain extracts was more than 95%. The levels of 5-HT and 5-HIAA in the rat brain were 2.95 +/- 0.16 and 0.64 +/- 0.18 nmole/g, respectively. More than 100 samples could be analyzed within 3 days. The presence of 5-hydroxytryptophol in rat brain was also investigated, but none could be detected either as a conjugate or as the free alcohol.

Animals↗
PubMed1977

Direct gas chromatograph-mass spectrometer connection of glass capillary columns for the analysis of serotonin and metabolites by selective ion monitoring.

A direct connection system that requires no modifications to either the gas chromatograph or the mass spectrometer is described for the coupling of glass capillary columns to a commercial mass spectrometer. Vacuum-tight connections can be readily achieved with standard 1/16-in. fittings and septum discs. The system can be operated with column outlet helium flow-rates of 1.5-2 ml/min at ion source pressures of 2-5 - 10(-5) mmHg. Although an injector splitter of our own design has been used, the initial test results obtained with a splitless injection method based on the use of a solids injection syringe together with a packed column injector assembly indicate the feasibility of developing a totally splitless and connection system that is simple to use. The system has been applied to the detection of the pentafluoropropionyl derivatives of serotonin, methoxytryptamine, methoxytryptophol and 5-hydroxytryptophol by selective ion monitoring techniques. Column performances under both sets of conditions (gas-liquid chromatography alone and combined with mass spectrometry) are compared and the evaluation of direct versus indirect coupling showed yields of the order of 50% through the molecular separator.

Chromatography, Gas↗