Decrease In 5-hydroxyindoleacetic Acid Research Articles

Maternal Inflammation Results in Altered Tryptophan Metabolism in Rabbit Placenta and Fetal Brain

Maternal inflammation has been linked to neurodevelopmental and neuropsychiatric disorders such as cerebral palsy, schizophrenia, and autism. We had previously shown that intrauterine inflammation resulted in a decrease in serotonin, one of the tryptophan metabolites, and a decrease in serotonin fibers in the sensory cortex of newborns in a rabbit model of cerebral palsy. In this study, we hypothesized that maternal inflammation results in alterations in tryptophan pathway enzymes and metabolites in the placenta and fetal brain. We found that intrauterine endotoxin administration at gestational day 28 (G28) resulted in a significant upregulation of indoleamine 2,3-dioxygenase (IDO) in both the placenta and fetal brain at G29 (24 h after treatment). This endotoxin-mediated IDO induction was also associated with intense microglial activation, an increase in interferon gamma expression, and increases in kynurenine and the kynurenine pathway metabolites kynurenine acid and quinolinic acid, as well as a significant decrease in 5-hydroxyindole acetic acid (a precursor of serotonin) levels in the periventricular region of the fetal brain. These results indicate that maternal inflammation shunts tryptophan metabolism away from the serotonin to the kynurenine pathway, which may lead to excitotoxic injury along with impaired development of serotonin-mediated thalamocortical fibers in the newborn brain. These findings provide new targets for prevention and treatment of maternal inflammation-induced fetal and neonatal brain injury leading to neurodevelopmental disorders such as cerebral palsy and autism.

Developmental origins of neurotransmitter and transcriptome alterations in adult female zebrafish exposed to atrazine during embryogenesis

Atrazine is an herbicide applied to agricultural crops and is indicated to be an endocrine disruptor. Atrazine is frequently found to contaminate potable water supplies above the maximum contaminant level of 3μg/L as defined by the U.S. Environmental Protection Agency. The developmental origin of adult disease hypothesis suggests that toxicant exposure during development can increase the risk of certain diseases during adulthood. However, the molecular mechanisms underlying disease progression are still unknown. In this study, zebrafish embryos were exposed to 0, 0.3, 3, or 30μg/L atrazine throughout embryogenesis. Larvae were then allowed to mature under normal laboratory conditions with no further chemical treatment until 7 days post fertilization (dpf) or adulthood and neurotransmitter analysis completed. No significant alterations in neurotransmitter levels was observed at 7dpf or in adult males, but a significant decrease in 5-hydroxyindoleacetic acid (5-HIAA) and serotonin turnover was seen in adult female brain tissue. Transcriptomic analysis was completed on adult female brain tissue to identify molecular pathways underlying the observed neurological alterations. Altered expression of 1928, 89, and 435 genes in the females exposed to 0.3, 3, or 30μg/L atrazine during embryogenesis were identified, respectively. There was a high level of overlap between the biological processes and molecular pathways in which the altered genes were associated. Moreover, a subset of genes was down regulated throughout the serotonergic pathway. These results provide support of the developmental origins of neurological alterations observed in adult female zebrafish exposed to atrazine during embryogenesis.

Prolonged Changes in Neurochemistry of Dopamine Neurones After Chronic Ethanol Consumption

The effects of 3 weeks of chronic ethanol consumption in mice on brain concentrations and turnover of monamine transmitters was examined. The measurements were made at 24 h, 6 days and 2 months after cessation of the ethanol intake to examine changes that might be relevant to relapse drinking. Increases in noradrenaline and dopamine concentrations, and decreases in the ratios of dopamine metabolites to dopamine, were seen in ventral tegmental tissue at 24 h after alcohol consumption. Increased noradrenaline was also evident at the 6-day interval, but no other changes were seen at this time. At the 2-month interval, the ventral tegmentum from ethanol-treated animals showed decreases in metabolite/dopamine ratios. No changes were seen in 5-hydroxytryptamine or its metabolite. In striatal tissue, none of these changes were seen, but at 24 h decreases occurred in the content of dopamine and its metabolites and a decrease in 5-hydroxyindoleacetic acid. The results indicate changes occur in monoamine turnover in the VTA as long as 2 months after cessation of chronic ethanol consumption; such changes may be related to the prolonged nature of alcohol dependence.

Alterations in monoamines and GABA in the ventromedial and paraventricular nuclei of the hypothalamus following cold exposure: a reduction in noradrenaline induces hyperphagia

A microdialysis technique for the in vivo assessment of the monoaminergic and GABAergic levels in the ventromedial (VMN) and paraventricular nuclei (PVN) of the hypothalamus was used in order to examine the activities of neurons that project to the hypothalamic regions and are implicated in the regulation of ingestive behavior and energy balance. Cold exposure increased food intake, as well as the circulating levels of glucose, noradrenaline (NA), 3,5,3′-triiodothyronine, and corticosterone. The dialysate concentrations of NA, dopamine (DA), serotonin (5-HT), and γ-aminobutyric acid (GABA) in the VMN all decreased after exposure to cold. The changes in extracellular NA, DA, and GABA in the PVN under cold conditions were similar to those in the VMN. NA release in the VMN or PVN was decreased after local electrolytic lesions, which significantly increased food intake. Thus, low activities of noradrenergic axons of neurons terminating in the VMN and PVN may be a good mechanism to induce feeding behavior. Extracellular 5-HT in the PVN was significantly increased, along with a significant decrease in 5-hydroxyindoleacetic acid, in cold-exposed rats, suggesting that serotonergic fibers terminating in the PVM are more closely related to the increases in adrenocortical and thyroid hormone secretion than to food intake. The neuronal activities, indicating that a sympathetic tone is activated on stimulation of the VMN and/or PVN, may be changes in GABAergic and/or serotonergic neurons.

Monoamine Oxidase Inhibitory Properties of Some Methoxylated and Alkylthio Amphetamine Derivatives: Structure–Activity Relationships

The monoamine oxidase (MAO) inhibitory properties of a series of amphetamine derivatives with different substituents at or around the para position of the aromatic ring were evaluated. In in vitro studies in which a crude rat brain mitochondrial suspension was used as the source of MAO, several compounds showed a strong ( ic 50 in the submicromolar range), selective, reversible, time-independent, and concentration-related inhibition of MAO-A. After i.p. injection, the compounds induced an increase of serotonin and a decrease of 5-hydroxyindoleacetic acid in the raphe nuclei and hippocampus, confirming the in vitro results. The analysis of structure–activity relationships indicates that: molecules with amphetamine-like structure and different substitutions on the aromatic ring are potentially MAO-A inhibitors; substituents at different positions of the aromatic ring modify the potency but have little influence on the selectivity; substituents at the para position such as amino, alkoxyl, halogens, or alkylthio produce a significant increase in the activity; the para-substituent must be an electron donor; bulky groups next to the para substituent lead to a decrease in the activity; substituents located at positions more distant on the aromatic ring have less influence and, even when the substituent is a halogen (Cl, Br), an increase in the activity of the compound is obtained. Finally, the MAO-A inhibitory properties of some of the compounds evaluated are discussed in relation to: (a) potential antidepressant activity, and (b) their reported hallucinogenic, neurotoxic, or anxiolytic effects.

Low-level cadmium exposure of lactating rats causes alterations in brain serotonin levels in the offspring.

Effects on monoaminergic and cholinergic transmitter systems as well as neurotrophins were characterized in developing Sprague-Dawley rats directly exposed to 5 ppm cadmium in the drinking water or indirectly via exposed dams. Cadmium was given to dams during the lactation period, from parturition to postnatal day 17, and/or to the offspring until postnatal day 42. Cresyl violet staining and glial fibrillary acidic protein immunohistochemistry did not reveal any obvious neuropathology after cadmium exposure. Following high-power microwave fixation, concentrations of acetylcholine (ACh) and monoamines were determined in cerebral cortex, striatum, and hippocampus using HPLC with electro-chemical detection. ACh, dopamine, and noradrenaline levels were not significantly affected after the different cadmium exposures. Cortical levels of serotonin were significantly reduced in rats exposed to cadmium during lactation as well as in rats exposed to cadmium during both lactation and postweaning. A major decrease in 5-hydroxyindoleacetic acid was found in cortex and hippocampus in rats exposed to cadmium during lactation. The regional characteristics of cadmium toxicity as reflected in changes of neurotrophins were studied using in situ hybridization histochemistry with oligonucleotide probes and phosphoimaging evaluation. No significant changes in the mRNA expression of brain-derived neurotrophic factor (BDNF), neurotrophin-3, and the high-affinity tyrosine kinase receptor of BDNF, trkB, were detected. The present results demonstrate that exposure to levels of cadmium as low as 5 ppm in the drinking water leads to neurochemical disturbances of the serotonergic system in the offspring during the lactational period.

Chronic Hyperprolactinemia and Changes in Dopamine Neurons

The tuberoinfundibular dopaminergic (TIDA) system is known to inhibit prolactin (PRL) secretion. In young animals this system responds to acute elevations in serum PRL by increasing its activity. However, this responsiveness is lost in aging rats with chronically high serum PRL levels. The purpose of this study was to induce hyperprolactinemia in rats for extended periods of time and examine its effects on dopaminergic systems in the brain. Hyperprolactinemia was induced by treatment with haloperidol, a dopamine receptor antagonist, and Palkovits' microdissection technique in combination with high-performance liquid chromatography was used to measure neurotransmitter concentrations in several areas of the brain. After 6 months of hyperprolactinemia, dopamine (DA) concentrations in the median eminence (ME) increased by 84% over the control group. Nine months of hyperprolactinemia produced a 50% increase in DA concentrations in the ME over the control group. However, DA response was lost if a 9-month long haloperidol-induced hyperprolactinemia was followed by a 11 12 month-long extremely high increase in serum PRL levels produced by implantation of MMQ cells under the kidney capsule. There was no change in the levels of DA, norepinephrine (NE), serotonin (5-HT), or their metabolites in the arcuate nucleus (AN), medial preoptic area (MPA), caudate putamen (CP), substantia nigra (SN), and zona incerta (ZI), except for a decrease in 5-hydroxyindoleacetic acid (5-HIAA) in the AN after 6-months of hyperprolactinemia and an increase in DA concentrations in the AN after 9-months of hyperprolactinemia. These results demonstrate that hyperprolactinemia specifically affects TIDA neurons and these effects vary, depending on the duration and intensity of hyperprolactinemia. The age-related decrease in hypothalamic dopamine function may be associated with increases in PRL secretion.

Sex difference for tolerance of 5-HT 1A receptor-mediated temperature and corticosterone responses in mice

Repeated treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) resulted in significant attenuation of 8-OH-DPAT-induced hypothermia and adrenocorticol effect in mice of both sexes, while it did not affect the 8-OH-DPAT-induced decrease in 5-hydroxyindoleacetic acid in the hypothalamus in either sex. The attenuated responses developed more rapidly in female than in male mice, indicating sex differences in the adaptive regulation of the 5-HT 1A receptor-mediated responses.

Determination of 5-hydroxytryptophan, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid in 20 rat brain nuclei using liquid chromatography with electrochemical detection.

High-performance liquid chromatography with electrochemical detection is utilized for the simultaneous determination of serotonin, its precursor 5-hydroxytryptophan, and its major metabolite 5-hydroxyindoleacetic acid in nervous tissue samples. Tissue preparation required only homogenization in acidic solution and centrifugation prior to application to the chromatograph. Detection limits in the low picogram range were obtained for those indoles separated. This assay was used in combination with a micropunch dissection technique of 20 discrete rat brain nuclei to measure serotonin, its precursor, and major metabolite. The specificity of the assay was checked with pharmacological experiments aimed to increase or decrease serotonin levels. Pargyline, a monoamine oxidase inhibitor, led to a marked increase in serotonin and a decrease of 5-hydroxyindoleacetic acid while p-chlorophenylalanine, by blocking the conversion of tryptophan to 5-hydroxytryptophan, selectively depleted 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid.

Disposition and pharmacological effects of m-Chlorophenylpiperazine in rats

1-( m-Chlorophenyl)piperazine (CPP) was a potent inhibitor of [ 3H]-serotonin binding to membrane receptors from rat brain in vitro, its K i being 138 nM. It had less effect on [ 3H]-lysergic acid diethylamide binding ( K i = 300 nM), the relative K i , values indicating CPP to be a serotonin receptor agonist. A dose-related decrease in 5-hydroxyindoleacetic acid (5-HIAA) concentration in rat brain in vivo, was caused by CPP, with no effect on serotonin concentration, and CPP reduced the rate of 5-HIAA accumulation after probenecid. Also, CPP caused a dose-related increase in corticosterone concentration in rat serum, as did'fluoxetine (an inhibitor of serotonin uptake). Milk-drinking was suppressed by CPP in non-fasted rats, whereas fluoxetine had no effect; the effect of CPP was doserelated and was antagonized by metergoline. These results are consistent with the idea that CPP acts principally as a direct serotonin agonist rather than as a serotonin uptake inhibitor in vivo. The half-life of CPP in brain was just over 1 hr in control rats and about 3hr in rats pretreated with iprindole, an inhibitor of aromatic ring hydroxylation. In iprindole-treated rats, the dose-response curve for lowering the concentration of 5-HIAA CPP at 4hr was shifted to the left, and the duration of 5-HIAA concentration lowering by a 10 mg/kg dose of CPP was prolonged. 1-( p-Chlorophenyl)piperazine had a longer half-life in rat brain than did CPP and caused almost as much serotonin receptor stimulation in vivo as did CPP due to the higher drug levels, despite its lower affinity for serotonin receptors in vitro. In iprindole-treated rats, CPP was more potent than in control rats in elevating serum corticosterone and prolactin. 1-( m-Chlorophenyl)piperazine is a known metabolite of the antidepressant drug trazodone and may contribute to or account for some of the in vivo effects of trazodone.

Effect of progesterone on regional 5-hydroxytryptamine metabolism in the rat brain

The influence of progesterone upon 5-hydroxytryptamine (5-HT) metabolism in the rat brain was investigated in view of a possible connection with premenstrual tension and postpartum depression. A progesterone dose, resulting in a plasma level which was still in a physiological range, increased 5-HT turnover in septum, hypothalamus and raphe. A higher unphysiological dose, besides producing a further increase of 5-HT turnover, also resulted in a decrease of 5-hydroxyindoleacetic acid (5-HIAA) levels which was most pronounced in the septum. Neither of the two doses showed a clearcut influence on 5-HT concentrations in any of the investigated brain areas.

Brain concentrations and synthesis rates of biogenic amines during chronic cobalt experimental epilepsy in the rat

Both the absolute levels and the turnover rates of the monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT) were measured in the brains of rats rendered epileptic by the application of cobalt powder to the surface of the cerebral cortex. Throughout the entire 21-day time course studied after cobalt treatment, during which a sustained reduction in the pentylenetetrazol (Metrazol) seizure threshold developed gradually within the first four days, whole brain levels of NE, DA, and 5-HT remained similar to their respective control values. Whereas the turnover rate of NE as well as that of DA in the brains of the cobalt-epileptic rats likewise remained within normal limits, both the rise of brain 5-HT after blockade of its metabolism and its decline from the brain after synthesis blockade followed time courses of change which differed significantly from those of the control groups. The decrease in 5-hydroxyindole acetic acid (5-HIAA) content of the brain caused by blockade of 5-HT catabolism, however, was found to be similar in cobalt-treated and control rats. These results suggest that the involvement of brain biogenic amines in the development and the maintenance of a chronic epileptic state differs markedly from the established role of these potential neurotransmitters in the production of acute seizure activity.

Psychotomimetic drugs and brain 5-hydroxytryptamine metabolism

The effects of indolealkylamine and phenylethylamine psychotomimetic drugs on brain 5-hydroxytryptamine (5-HT) metabolism have been studied. Indolealkylamines (psilocybin, psilocin, N, N-dimethyltryptamine or DMT) have a lysergic acid diethylamide (LSD)-like effect (increased 5-HT with concomitant decrease in 5-hydroxyindoleacetic acid. 5-HIAA). A degree of inhibition of monoamine oxidase can be demonstrated with psilocybin and psilocin, but not with LSD. The data suggest that other factors are operative in producing decreased levels of 5-HIAA. Phenylethylamines (mescaline, 2,5-dimethoxy-α,4-dimethylphenylethylamine or DOM) not only increase 5-HT but also, at higher doses, 5-HIAA; at lower doses, there is some indication of an LSD-like effect on 5-HIAA. Both categories of drug influence 5-HT metabolism, and the noted differences with respect to 5-HIAA cannot as yet be accounted for.

Biochemical Basis of the Sulfonylurea-induced Antabuse Syndrome

The antabuse reaction, seen in patients imbibing alcohol while being treated with an antidiabetic sulfonylurea, is thought to be due to either an increase in acetaldehyde levels or an alteration in the metabolism of serotonin. Both can occur through an inhibition of aldehyde dehydrogenase. The oral antidiabetic sulfonylureas, chlorpropamide and tolbutamide, were found to be noncompetitive inhibitors of this enzyme. Acetaldehyde, a metabolite of ethanol, can competitively inhibit aldehyde dehydrogenase. Moreover, the oxidation of ethanol reverses the DPN/DPNH ratio so that the favored pathway of serotonin metabolism is altered, resulting in a decrease of 5-hydroxyindoleacetic acid (5-HIAA) and an increase of 5-hydroxytryptophol. Thus, ethanol augments the action of the sulfonylureas. Whether the syndrome results from an accumulation of acetaldehyde due to a block in ethanol metabolism, or whether it is a result of an alteration in the metabolism of serotonin, the noncompetitive inhibition of aldehyde dehydrogenase by the sulfonylureas, coupled with the actions of ethanol, may be considered as a potential cause.

DECREASE OF 5-HYDROXYINDOLEACETIC ACID (5-HIAA) EXCRETION IN OLD AGE.

DECREASE OF 5-HYDROXYINDOLEACETIC ACID (5-HIAA) EXCRETION IN OLD AGE.