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PubMed2000

Central serotonin system in Dystonia musculorum mutant mice: biochemical, autoradiographic and immunocytochemical data.

The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways that lead to ataxia. To investigate possible changes in the central serotonin system of these mice, HPLC measurements of 5-hydroxytryptophan, 5-hydroxy-tryptamine (serotonin; 5-HT), and 5-HT metabolites were obtained from 22 brain regions and the spinal cord of wild type and dt(J)/dt(J) mutant mice. Also, 5-HT transporters were quantified by [(3)H]citalopram autoradiography in 72 brain regions, subregions, and nuclei, and the 5-HT innervation visualized by immunocytochemistry throughout the brain and spinal cord. In all brain regions measured for indoleamine content, there were no significant differences between the two genotypes. In the spinal cord, an increased tissue concentration of 5-HT (+34%), 5-hydroxyindole-3-acetic acid (+33%), 5-hydroxytryptophol (+21%), and 5-hydroxytryptophan (+45%) in dt(J)/dt(J) actually corresponded to the same total amount of each of these indoleamines in the entire spinal cord, when taking into account its reduced size in the mutants. Quantification of the binding to 5-HT transporters showed increases in the medial geniculate nucleus (+14%), medial (+24%) and lateral (+18%) hypothalamus, interpeduncular (+13%), vestibular (+22%), and deep cerebellar nuclei (+37%) of dt(J)/dt mice, and decreases in the ventral tegmental area (-13%), median and linear raphe nuclei (-20%), as well as in the solitary complex (-35%). There were no apparent differences in the distribution of 5-HT-immunostained fibers in these and other regions of brain and in the spinal cord of dt(J)/dt(J) compared to wild type mice. The bulk of these results indicates a relative sparing of the central 5-HT system in the dt(J)/dt(J) mice, even though alterations in 5-HT transporters could justify attempts at improving the sensorimotor dysfunction by administration of serotoninergic agents in these mice.

5-Hydroxytryptophan↗

PubMed1995

Fusaric acid in Fusarium moniliforme cultures, corn, and feeds toxic to livestock and the neurochemical effects in the brain and pineal gland of rats.

Fusaric acid is produced by several species of Fusarium, which commonly infect corn and other agricultural commodities. Since this mycotoxin may augment the effects of other Fusarium toxins, a gas chromatography/mass spectrometry method of analysis in feeds was developed. Fusaric acid was analyzed as the trimethylsilyl-ester from F. moniliforme-cultures, -contaminated corn screenings, and feeds toxic to livestock. The mycotoxin was found in all samples and ranged from 0.43 to 12.39 micrograms/g sample. Also, fusaric acid was tested for its neurochemical effects in the brain and pineal gland of rats. Animals were dosed intraperitoneally (100 mg/kg body weight) 30 min prior to the onset of the dark phase (lights out) and the effects were studied at 1.5, 3.5, and 5.5 h after treatment. Brain serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), tyrosine (TYRO), and dopamine (DA) were increased (P < 0.05) by fusaric acid, and norepinephrine (NEpi) was decreased (P < 0.05). Analogously, DA in the pineal gland increased and NEpi decreased (P < 0.05). Pineal N-acetylserotonin (NAc5HT) was increased (P < 0.05), whereas pineal 5HT and its two major metabolites 5HIAA and 5-hydroxytryptophol (5HTOL) decreased (P < 0.05). Elevated brain TYRO and brain and pineal DA, with decreased NEpi, may be consistent with fusaric acid's partial inhibitory effect on tyrosine-hydroxylase and its inhibitory effect on dopamine-beta-hydroxylase, respectively. Elevated pineal Nac5HT is consistent with decreased pineal 5HT and the increased pineal DA, and support the dopaminergic stimulatory activity of the enzyme responsible for the conversion of 5HT to NAc5HT. This is the first report of fusaric acid's in vivo effect on pineal DA, NEpi, 5HT, and NAc5HT in rats, and a relation for the effects on TYRO, 5HT, and 5HIAA in brain tissue. The results indicate fusaric acid alters brain and pineal neurotransmitters and may contribute to the toxic effects of Fusarium-contaminated feeds.

Animal Feed↗

PubMed2000

Volitional ethanol consumption affects overall serotonin metabolism in Syrian golden hamsters (Mesocricetus auratus).

Methods were established for the determination of serotonin (5-HT)(1) metabolites 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL) in the urine of Syrian golden hamsters (Mesocricetus auratus) and used to study the effect of volitional ethanol consumption on overall 5-HT metabolism in this ethanol-preferring rodent. The basal levels of 5-HIAA and 5-HTOL in 24-h urine of ethanol-naive hamsters were 300 +/- 101 and 4.96 +/- 1. 06 nmol (n = 8), respectively. Given free choice between water and a 15% ethanol solution, these hamsters chose to consume increasing amounts of ethanol. The increase was accompanied by a concomitant decrease in urine 5-HIAA and increase in urine 5-HTOL, indicating that volitional ethanol intake diverted part of the 5-HT metabolic flux from an oxidative into a reductive pathway. In a separate experiment, the amounts of ethanol consumed by and blood ethanol concentrations attained in ethanol-drinking golden hamsters were determined at 5 different time intervals between 6 PM and 7 AM when most feeding activities occurred. Except in the first hour after lights were turned off, ethanol was consumed at a relatively even pace throughout the night (2-3 g/kg/3 h) and blood ethanol levels were maintained at the low mM range which rarely exceeded 2 mM. These results suggest that the biochemical pathway that catalyzes 5-HT metabolism is extremely sensitive to ethanol and can play an important role in mediating the reported clinically beneficial action of a low concentration of ethanol during alcohol detoxification.

Animals↗

PubMed1982

Alterations in the spontaneous activity of cells in the guinea pig pineal gland and visual system produced by pineal indoles.

The indoles serotonin (SER), melatonin (MEL), 5-methoxytryptophol (5-MTL) and 5-hydroxytryptophol (5-HTL) were administered during daytime microelectrophoretically to 240 cells in the pineal gland of the guniea-pig. The action of SER and 5-HTL was predominantly depressant on the electrical activity, MEL and 5-MTL caused an excitation in most of the units. Although MEL and 5-MTL caused fairly similar reactions on average, they appear to act on different cells. The effects of microelectrophoretically applied MEL and 5-MTL on the spontaneous or evoked activity in the visual system (retinal ganglion cells, optic tract, lateral lateral geniculate body, superior colliculus) of the guinea-pig were also investigated. Of the 76 cells tested in the visual system 25 of the ON- and OFF-cells increased the rate of discharge when the two indoles were applied. Cells in the optic layer of the superior colliculus showed no measurable response to the application of the two substances. 5-HTL caused no effect on cells in the visual system.

Animals↗

PubMed1978

Differential changes of blood and urinary indoleamines following intravenous ethanol administration in alcoholic and non-drinker women.

Total blood serotonin (5-HT) and the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL) were measured before and after intravenous administration of 0.65 g/kg ethanol to nine chronic alcoholic female patients. Changes were compared to those obtained in twelve age-matched non-drinker neurotic or hysteric women. The two groups showed different pattern of indoleamine response to ethanol: alcoholics reacted by a reduction of 5-HIAA ouput in the urine, while controls showed no change in the 5-HIAA excretion but a marked fall of blood serotonin. Urinary 5-HTOL excretion increased equally in both groups. Despite these biochemical variations, behavioral responses to ethanol were indistinguishable in the two groups. The results indicate that chronic alcoholism leads to permanent changes of the biogenic amine metabolism.

Adult↗

PubMed1989

N-acetyltransferase activity and indole contents of the male Syrian hamster Harderian gland: changes during the light:dark cycle.

The activities of N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) and the indole contents of the Harderian glands of male Syrian hamsters were studied throughout a 24-h period. NAT activity exhibited a sharp rise 1 h after lights on, decreasing to basal levels 1 h later. Neither a HIOMT activity nor a melatonin concentration rhythm was detected throughout the 24 h. The 5-hydroxytryptamine (serotonin) concentration was highest during the dark phase reaching a peak at 0300 h; with light onset serotonin levels exhibited a rapid short-term drop. The 5-hydroxytryptophol concentration was highest during the mid- to late photophase; the lowest values to this constituent were measured late in the dark phase and at 1 h after lights on. The 5-hydroxyindole acetic acid concentration of the Harderian glands was rather stable throughout the 24-h period but levels did show a short-lived drop 1 h after light onset. Only a few animals contained detectable amounts of N-acetyl-5-hydroxytryptamine (N-acetylserotonin) in their Harderian glands. In agreement with previous work on the Harderian glands of female Syrian hamsters, the present results in males suggest that light onset is associated with marked changes in Harderian indoleamine metabolism.

Acetylserotonin O-Methyltransferase↗

PubMed1988

Changes in biogenic amines in rat hippocampus during development and aging.

The effects of postnatal development and aging on the concentration of dopamine, noradrenaline, serotonin and their principle metabolites have been studied in the hippocampus of the rat. During development the concentration of dopamine increases 1.5 fold during the first 90 days. 3-methoxytyramine was found in low concentrations. The homovanillic acid and DOPAC concentrations showed no changes apart from a decrease at day 15 and an increase at day 8, respectively. From birth up to 30 months, the noradrenaline concentration increased by a factor of about 10. Their metabolites each showed a different profile. The concentration of tryptophan was always the highest among the compounds studied. It decreased from birth to day 15, while the concentration of serotonin and 5-hydroxyindolacetic acid increased 3 and 5 fold respectively during this time. However, 5-hydroxytryptophan and 5-hydroxytryptophol concentrations were very low and unchanged at all stages. These findings led to the conclusion that the neurotransmitters: noradrenaline and serotonin, are developed in the hippocampus during the first three months. During aging, the serotonin concentration is increased without significant change in the other compounds studied.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Time course of ethanol-induced changes in serotonin metabolism.

The effect of acute ethanol consumption on serotonin metabolism was examined in healthy volunteers in the fasted and fed state by determination of plasma and urinary levels of the serotonin metabolites 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL). The plasma and urinary levels of 5-HIAA were reduced by about 40% and 25%, while the 5-HTOL levels were increased on an average 7-fold and 50-fold, respectively, after oral intake of ethanol (0.8 g/kg) over 30 min in a fasted state. The maximal effect on both 5-HIAA and 5-HTOL levels was found 4-6 h after starting drinking. Urinary 5-HTOL and the 5-HTOL/5-HIAA ratio did not return to baseline until 19 h after the start of the administration (i.e., about 10 h after ethanol reached zero level). The mean 24-h excretion of 5-HTOL was increased 15-fold by the ethanol intake, while the 5-HIAA excretion was not significantly different. A clear dose dependent effect was observed in one individual who also ingested a lower amount of ethanol (0.5 g/kg). When ethanol (0.8 g/kg) was ingested over 3 h together with food, the urinary level of 5-HTOL and the 5-HTOL/5-HIAA ratio did not return to baseline until after 20-22 h. In other subjects who had unlimited access to ethanol and ingested between 1.3-2.3 g/kg together with food, the time to reach baseline 5-HTOL/5-HIAA ratio in urine ranged from 20 h to over 26 h.

Adult↗

PubMed1993

Rapid postmortem changes of rat striatum dopamine, serotonin, and their metabolites as monitored by brain microdialysis.

Brain microdialysis was used to monitor changes in extracellular dopamine (DA), serotonin (5-HT), and their metabolite levels in the rat striatum at death by cervical dislocation. Maximum respective 450-fold and 150-fold increases in the extracellular output of DA and 5-HT were observed within the first 30 min of death. DA and 5-HT outputs remained elevated over the following 2 h at levels about 100-fold and 50-fold above pre-death values, respectively. In contrast with monoamine outputs, the outputs of the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), and the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), rapidly decreased by 10% and 20%, respectively 1 h after death. 5-Hydroxytryptophol (5-HTOL) gradually decreased after death. Before death both the extracellular DOPAC/DA and 5-HIAA/5-HT ratios were about 400; after death these ratios dropped to 0.56 and 4.0, respectively at 30 min. These observations suggested that regulation of neurotransmitter releases through the neuronal membrane and metabolisms in the rat striatum were seriously disrupted at death. This finding may be helpful in the determination of death in the field of forensic medicine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

Accurate assignment of ethanol origin in postmortem urine: liquid chromatographic-mass spectrometric determination of serotonin metabolites.

Toxicological examination of fatal aviation accident victims routinely includes analysis of ethanol levels. However, distinguishing between antemortem ingestion and postmortem microbial formation complicates all positive ethanol results. Development of a single analytical approach to determine concentrations of 5-hydroxytryptophol (5-HTOL) and 5-hydroxyindole-3-acetic acid (5-HIAA), two well-known metabolites of serotonin, has provided a convenient, rapid and reliable solution to this problem. Antemortem ethanol leads to an elevation in the 5-HTOL/5-HIAA ratio for 11-19 h after acute ingestion. The liquid-liquid extracts of postmortem urine samples were subjected to liquid chromatography-mass spectrometry (LC-MS) for the simultaneous quantitation of these two analytes, yielding detection limits of 0.1 ng/ml for each. Examination of the 5-HTOL/5-HIAA ratio was undertaken for 44 urine samples known to be antemortem ethanol-positive or antemortem ethanol-negative. Recent ethanol ingestion was conveniently and accurately separated using a 5-HTOL/5-HIAA ratio of 15 pmol/nmol, a value previously suggested using human volunteers. All 21 ethanol-negative postmortem samples were below this cutoff, while all 23 ethanol-positive postmortem samples were above this cutoff. Thus, we recommend the employment of this cutoff value, established using this straightforward LC-MS procedure, to confirm or deny recent antemortem ethanol ingestion in postmortem urine samples.

Chromatography, High Pressure Liquid↗

PubMed1986

Human alcohol dehydrogenases and serotonin metabolism.

Human liver alcohol dehydrogenases (ADH) may participate in serotonin (5-hydroxytryptamine) metabolism. Class I and II isozymes catalyze the oxidation of 5-hydroxytryptophol (5-HTOL) with kcat/Km values ranging from 10 to 100 mM-1 min-1 compared to 4-66 mM-1 min-1 for that of ethanol at pH 7.40, 25 degrees C. The product, 5-hydroxyindoleacetaldehyde, was purified as its semicarbazone and identified by mass spectrometry. Ethanol competitively inhibits 5-HTOL oxidation by beta 1 gamma 2 ADH with a Ki of 440 microM, a value similar to the Km of ethanol, 210 microM. The inhibition constants for 1,10-phenanthroline and 4-methylpyrazole are 20 microM and 80 nM respectively, essentially identical to those obtained with ethanol as substrate, 22 microM and 70 nM, respectively. The competition between ethanol and 5-HTOL for ADH can explain observations of ethanol induced changes in serotonin metabolism in vivo.

Alcohol Dehydrogenase↗

PubMed2000

Studies on the interaction between ethanol and serotonin metabolism in rat, using deuterated ethanol and 4-methylpyrazole.

The metabolic interaction between ethanol and serotonin (5-hydroxytryptamine) via alcohol dehydrogenase (ADH; EC 1.1.1.1) was studied in tissue homogenates of Sprague-Dawley rats by following the transfer of deuterium from deuterated ethanol over endogenous NADH to 5-hydroxytryptophol (5HTOL). Homogenates of whole brain, lung, spleen, kidney, liver, stomach, jejunum, ileum, colon, and caecum were incubated in the presence of [2H2]ethanol and 5-hydroxyindole-3-acetaldehyde (5HIAL), and the [2H]5HTOL formed was identified and quantified using gas chromatography-mass spectrometry. ADH activity was most abundant in liver, kidney, and within the gastrointestinal tract. The highest incorporation of deuterium was obtained in homogenates of kidney, lung, and colon, whereas in brain, which contains very low ADH activity, no incorporation could be demonstrated. Addition of extra NAD+ (2.4 mM) increased the formation of [2H]5HTOL 2.6-fold in liver homogenates, but only 1.2-fold in kidney homogenates. 4-Methylpyrazole, a potent inhibitor of class I ADH, inhibited the 5HIAL reduction in homogenates of lung, kidney, jejunum, ileum, and colon, and caused a marked drop in 5HTOL oxidation in all tissues except stomach and spleen. These results demonstrate that in the rat a metabolic interaction between ethanol and serotonin via the ADH pathway may take place in several tissues besides the liver, which is the main tissue for ethanol detoxification.

Alcohol Dehydrogenase↗

PubMed2003

Acute effect of simultaneous administration of tryptophan and ethanol on serotonin metabolites in the locus coeruleus in rats.

Using the microdialysis method, we investigated whether the levels of serotonin (5-hydroxytryptamine, 5-HT) and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTPL), in the locus coeruleus are influenced by tryptophan alone or simultaneous administration of tryptophan and ethanol. Tryptophan (50 mg/kg, i.p.) led to a significant increase in the levels of 5-HIAA, but not 5-HT in the locus coeruleus. However, ethanol (1.25 g/kg) had no effect on the levels of 5-HT and its metabolites. Combined administration of tryptophan and ethanol caused very marked increases in 5-HIAA and 5-HTPL levels in the locus coeruleus. A time lag in the increased 5-HIAA levels between tryptophan alone and tryptophan plus ethanol was observed. Moreover, 5-HIAA levels in the locus coeruleus induced by tryptophan were abolished by microinjection of 5,7-dihydroxytryptamine (150 microg/4 microl) into the dorsal raphe nucleus. Judging from the present results, the serotonergic afferents to the locus coeruleus may originate for about 20-30% from cell bodies located in the dorsal raphe nucleus. Teeth-chattering was significantly detected in the tryptophan plus ethanol-treated rats when compared with the tryptophan-treated rats, but not in the saline-treated controls. These results may suggest that the increased levels of 5-HIAA and 5-HTPL in the locus coeruleus induced by tryptophan are potentiated by ethanol, and that these levels are partly responsible for behavioral activation.

5,7-Dihydroxytryptamine↗

PubMed1997

Acute interaction between ethanol and serotonin metabolism in the rat.

The effect of acute ethanol on peripheral serotonin (5HT) metabolism was studied in Sprague-Dawley rats. Four hours after a single dose of ethanol (1.0 g/kg) administered into the stomach, a significant increase in the 5HT level in stomach tissue and a decrease in ileum was observed. The level of 5-hydroxyindole-3-acetic acid (5HIAA) was increased in urine, while increased concentrations of 5-hydroxytryptophol (5HTOL) occurred in jejunum, ileum, spleen and urine. After 7-9 h when the blood ethanol concentration had returned to zero, 5HTOL levels were still higher than control values in jejunum, ileum and urine. At 4 h, an elevated ratio of 5HTOL to 5HIAA was observed in urine and ileum (by approximately 2-fold), liver (approximately 3-fold), and spleen (approximately 5-fold), whereas the ratio was reduced in stomach. In urine and spleen, this metabolic shift persisted after 7-9 h. The 5HTOL level in bile was increased by approximately 3.5-fold after 8 h. 5HIAA was not detectable in bile. The present results indicate that the rat has a much higher proportion of 5HTOL formation than man under normal conditions. The rat does not appear to be an ideal model for studying the interaction between ethanol and 5HT metabolism in man.

Animals↗

PubMed2001

Distribution of serotonin, its metabolites and 5-HT transporters in the neostriatum of Lurcher and weaver mutant mice.

Serotonin (5-HT) uptake sites, or transporters, were measured in the neostriatum (caudate putamen) of wild type (+/+) mice and heterozygous (wv/+) and homozygous (wv/wv) weaver, as well as in heterozygous Lurcher (Lc/+) mutants. These topological surveys were carried out by quantitative ligand binding autoradiography using the uptake site antagonist [3H]-citalopram as a probe of innervation densities in four quadrants of the rostral neostriatum and in two halves of the caudal neostriatum. In addition, tissue concentrations of 5-HT, 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol were measured by high-performance liquid chromatography with electrochemical detection in these neostriatal divisions. In +/+ mice and in Lc/+ mutants there was a dorso-ventral gradient of increasing 5-HT levels, and they exhibited a similar heterogeneity of [3H]-citalopram labeling. In contrast, the gradients of 5-HT concentrations and [3H]-citalopram binding disappeared in the weaver mutants, suggesting a rearrangement of the 5-HT innervation. This reorganization of the 5-HT system in the neostriatum was more obvious in the wv/wv and is compatible with the hypothesis that the postnatal dopaminergic deficiencies that characterize weaver mutants lead to a sprouting of fibers and thus constitute a genetic model of dopaminergic denervation that leads to a 5-HT hyperinnervation.

Animals↗

PubMed2001

[Peripheral markers, future perspectives].

Four of the recently described peripheral markers of alcohol abuse have been reviewed. The acetaldehyde adducts allow to detect an alcohol abuse lasting for several weeks, even after a recent alcohol withdrawal. Inversely, 5-hydroxytryptophol (5-HTOL) reflects the alcohol consumption of the last 24 hours. Its detection is possible after the blood alcohol concentration has disappeared. Its measurement is run in urine samples, thus without invasive sampling. The hyaluronic acid and the activity of beta-hexosaminidase are markers of hepatobiliary alcohol induced disorders more than direct markers of alcohol intake. Acetaldehyde adducts could be used as markers of long term alcohol abuse, CDT as a marker of the recent alcohol abuse, and 5-HTOL the detection of alcohol abuse of the past day.

Acetaldehyde↗

PubMed1982

Determination of indoles in human and rat pineal.

Tryptophan, serotonin, N-acetylserotonin, melatonin, 5-hydroxyindoleacetic acid and 5-hydroxytryptophol have been determined in rat and human pineal glands. The compounds were measured by directly injecting centrifuged tissue homogenates into a liquid chromatographic-fluorometric system. Normal ranges are reported for these compounds and upper limits established for several other indoles.

Animals↗

PubMed1998

Changes in the concentrations of ethanol, methanol and metabolites of serotonin in two successive urinary voids from drinking drivers.

The urine-ethanol concentration (UEC), the urine-methanol concentration (UMC) and the ratio of serotonin metabolites, 5-hydroxytryptophol (5HTOL) to 5-hydroxyindoleacetic acid (5HIAA), were determined in two successive voids from apprehended drunk drivers (n = 35). The blood-ethanol concentration (BEC) ranged from 0-3.00 g/l (mean 1.87 g/l, median 2.03 g/l) compared with 0-3.96 g/l (mean 2.48 g/l, median 2.73 g/l) in the first urinary void and 0-3.56 g/l (mean 2.24 g/l, median 2.47 g/l) in the second void. The UEC decreased significantly from 2.48 +/- 0.99 g/l to 2.24 +/- 0.95 g/l (mean +/- S.D.) between first and second voids as did the UEC/BEC ratios, changing from 1.33 +/- 0.15 to 1.20 +/- 0.10. The BEC and UEC were highly correlated; r = 0.97 +/- 0.04 (p < 0.001) for the first void and r = 0.98 +/- 0.03 (p < 0.001) for the second void. The UMC increased from 7.51 +/- 4.95 mg/l to 8.01 +/- 5.04 mg/l between the first and second voids and the mean difference of 0.50 +/- 0.78 mg/l was statistically highly significant (p < 0.001). The ratios of 5HTOL/5HIAA were 771 +/- 363 pmol/nmol and 728 +/- 377 pmol/nmol in first and second voids, respectively and the difference was not statistically significant (p > 0.05). Finding raised concentrations of methanol and a high 5HTOL/5HIAA ratio in urine specimens provides additional evidence to confirm recent drinking. These biochemical markers might prove useful whenever the integrity of blood or urine specimens is questioned, for example, owing to contamination with extraneous ethanol during collection or microbial synthesis of ethanol in vitro after sampling.

Alcoholic Intoxication↗