A COMPARISON BETWEEN FLUOROMETRIC AND MASS FRAGMENTOGRAPHIC DETERMINATIONS OF HOMOVANILLIC ACID AND 5-HYDROXYINDOLEACETIC ACID IN HUMAN CEREBROSPINAL FLUID

HVA and 5-HIAA in human cerebrospinal fluid were quantitatively determined by both fluorometry and mass fragmentography. The homovanillic acid values obtained by fluorometry were significantly lower than those obtained by mass fragmentography (P < 0.05). The correlation coefficient between values for HVA obtained by the two methods was high, r= 0.90. For 5-HIAA the concentrations obtained by the two methods were not significantly different while the correlation coefficient was lower, r= 0.55.     

Single-step,rapid separation of acidic and basic isoenzymes from commercial horseradish peroxidase

A simple and sensitive high-performance liquid chromatography method with electrochemical detector is described for the determination of free 3-methoxy-4-hydroxyphenylacetic acid (HVA) in human plasma. The method does not involve any extraction, is specific and reproducible, and has the potential to measure serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) simultaneously. The plasma concentration of free HVA in eight normal, healthy adult volunteers was 10.9 ± 4.6 (mean ± SD). In a preliminary study, in one schizophrenic patient the plasma HVA increased twofold after neuroleptic treatment.     

The P300 event-related potentials in dementia of the Alzheimer type. Correlations between P300 and monoamine metabolites

We studied auditory event-related potentials (ERPs) in 40 patients with dementia of the Alzheimer type (DAT). Peak latencies and amplitudes of N100, P200 and P300 components were measured. To study the possible relationships between the ERPs and monoaminergic neurotransmitter functions, CSF neurotransmitter metabolites were also analyzed. In patients with DAT, the P300 amplitude was significantly reduced and the P300 latency was prolonged. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were decreased. The P300 amplitude was significantly correlated with the 5-HIAA concentration. There were no correlations between the P300 components and the HVA concentration. These findings suggest that the serotonergic system modulates the P300 component of ERPs in patients with DAT.     

Amino Acids in Plasma and CSF and Monoamine Metabolites in CSF: Interrelationship in Healthy Subjects

Plasma and cerebrospinal fluid (CSF) concentrations of amino acids were measured in 65 healthy volunteers (50 men and 15 women). The CSF levels of the monoamine metabolites homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) were also determined. Sex differences were observed in both plasma and CSF amino acid levels as well as in the relationship between these concentrations. No significant correlations were observed between the CSF levels of HVA and 5-HIAA, and the concentrations of their precursor amino acids in either plasma or CSF. The MOPEG level in CSF correlated positively with the plasma concentrations of several amino acids.     

Measurement of acid monoamine metabolites in human and animal cerebrospinal fluid

Techniques for measuring 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) have been modified to permit the use of smaller samples for measuring these acid monoamine metabolites in human and animal CSF. Levels of both HVA and 5-HIAA were approximately three times as high in human ventricular CSF as in human lumbar CSF. Lumbar CSF levels of 5-HIAA in neurologic patients were significantly higher than those in psychiatric patients. Values were obtained for HVA in dog cisternal CSF and for 5-HIAA in dog, rabbit, and cat cisternal CSF.     

Amine Metabolites in the Lumbar Cerebrospinal Fluid of Humans with Restricted Flow of Cerebrospinal Fluid

DETERMINATION of homovanillic acid (HVA) and 5-hydroxy-indole acetic acid (5HIAA) in human lumbar cerebrospinal fluid (CSF) is becoming an important tool in the study of the metabolism in the brain of their respective precursors, dopamine and 5-hydroxytryptamine and in the interpretation of the effects of drugs on these substances. The assumption that the concentration of the acidic metabolites HVA and 5HIAA in the lumbar CSF gives a measure of the amount of turnover of the parent amines in the brain is supported by several findings. (1) Amine metabolite concentrations in the lateral ventricular CSF of the dog correlate with their concentrations in adjacent brain areas¹. (2) Peripherally administered HVA only penetrates slightly or not at all to lateral ventricular CSF in the cat² or dog³, similar results being obtained for 5HIAA in the dog⁴. (3) Drugs which alter brain amine turnover in laboratory animals also alter the concentrations of the acidic metabolites in dog³, rabbit⁵ and human⁶ CSF in the appropriate direction. (4) In Parkinsonism and in senile and presenile dementia, conditions in which there is evidence of defective turnover of amines in the brain, low concentrations of HVA and 5HIAA are found in the CSF⁷.     

Decreased level of beta-endorphin-like immunoreactivity in cerebrospinal fluid of patients with senile dementia of Alzheimer type

beta-Endorphin-like immunoreactivity in cerebrospinal fluid(CSF) was observed to decrease in patients with Huntington's disease and dementia due to brain vascular disease. The greatest decrease was seen in patients with presenile and senile dementia of Alzheimer type(SDAT). The immunoreactivity significantly correlated with psychological functions when examined using a dementia rating scale (r=0.51, p less than 0.01, for all dementia, r=0.65, p less than 0.02, for only SDAT). These results suggest that a B-endorphin-like substance may be related in the pathophysiology of dementia.     

Effects of kainic acid,quisqualic acid,and their antagonist,pCB-PzDA,on rat electrocorticograms and monoamine metabolite levels in rat striatum

The action of kainic acid (KA), quisqualic acid (QA), and 1-(4-chlorobenzoyl)-piperazine-2,3-dicarboxylic acid (pCB-PzDA) was investigated in the central nervous system of male Sprague Dawley rats. Intracerebroventricularly injected KA and QA (100 nmol) induced spike discharges, and pCB-PzDA (100 nmol) suppressed electrocorticograms for one hour. pCB-PzDA enhanced the KA-induced spike discharges and inhibited those induced by QA. 2,3-Di-hydroxyphenylacetic acid(DOPAC) and homovanillic acid (HVA) levels were increased transiently by 10 nmol and continuously by 100 nmol of KA. KA dose-dependently increased 5-hydroxyindoleacetic acid (5-HIAA) levels 2 hours after administration. While 10 nmol of QA slightly increased the HVA level, 100 nmol of QA significantly increased DOPAC, HVA, and 5-HIAA levels. DOPAC and HVA levels were increased by 100 nmol of pCB-PzDA, although this agent inhibited KA-induced increases in DOPAC, HVA, and 5-HIAA levels. On the other hand, while pCB-PzDA first inhibited QA-induced increases in DOPAC, HVA and 5-HIAA levels for one hour, DOPAC and HVA levels thereafter increased additively. These findings suggest that pCB-PzDA may act not only as a NMDA antagonist, but that it may also act directly on dopaminergic neurons.     

Correlations between aminergic metabolites simultaneously obtained from human CSF and brain

Brain and cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were simultaneously measured in 48 individuals at autopsy. Concentrations of 5-HIAA and HVA in the cerebral cortex were positively correlated with their levels in the CSF for the same individual. Additionally a positive correlation was observed between postmortem CSF levels of 5-HIAA and HVA and a significant concentration gradient for both metabolites was observed in serial fractions of CSF. These findings suggest that determinations of 5-HIAA and HVA in CSF from living individuals may reflect brain metabolite levels as well as the functional activity of these specific neuronal systems.     

Changes of Biogenic Amines and Their Metabolites in Postmortem Brains from Patients with Alzheimer-Type Dementia

Noradrenaline (NA), 3,4-dihydroxyphenylethylamine (dopamine, DA), 5-hydroxytryptamine (serotonin, 5-HT), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in 22 regions of postmortem brains from four histologically verified cases with Alzheimer-type dementia (ATD) and nine histologically normal controls. Compared with the controls, concentrations of 5-HT and 5-HIAA in the ATD brains were significantly reduced in nine regions (superior frontal gyrus, insula, cingulate gyrus, amygdala, putamen, medial and lateral segments of globus pallidus, substantia nigra, lateral nucleus of thalamus) and in eight regions (amygdala, substantia innominata, caudate, putamen, medial and lateral segments of globus pallidus, medial and lateral nuclei of thalamus), respectively. NA concentrations of the ATD brains were significantly reduced in six regions (cingulate gyrus, substantia innominata, putamen, hypothalamus, medial nucleus of thalamus, raphe area). In contrast, significant reductions of DA and HVA concentrations in the ATD brains were found only in putamen and amygdala, respectively. The 5-HIAA/5-HT ratio in the ATD brains decreased significantly in locus coeruleus, while the HVA/DA ratio increased significantly in putamen and medial segment of globus pallidus. These findings suggest that the serotonergic and noradrenergic systems are affected, while the dopaminergic system is relatively unaffected in ATD brains.     

The relationship of the electrical reactions of the brain to lipid peroxidation processes in pathological aging

The content of breathing air pentane as in vivo index of lipid peroxidation and electrophysiological parameters (visual evoked potentials and direct current (DC) potential level) of healthy volunteers and patients with senile dementia and Alzheimer's disease following weak stress sound influence were investigated. Unlike healthy subjects correlation between stress-induced changes of pentane level and electrophysiological parameters for patients with psychopathology was shown.     

5-Hydroxyindoleacetic acid and homovanillic acid concentrations in cerebrospinal fluid in patients with Alzheimer's disease, depression and mild cognitive impairment

In this study we investigated the cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in Alzheimer (AD) patients (n=75), patients with mild cognitive impairment (MCI, n=9) and patients with depression (n=7). CSF HVA was significantly elevated in AD with depression (Geriatric Depression Scale, 15 point version GDS>5) in comparison to AD without depression (p<0.05, ANOVA) and CSF HVA showed a significant positive correlation with the GDS score of AD-patients (p=0.03, Spearman Rho: 0.38, Spearman Rank Correlation). In the group of AD patients CSF 5-HIAA was positively correlated with cerebrospinal fluid beta-amyloid 1-42 (Abeta42), p<0.05, Spearman Rho: 0.3, Spearman Rank Correlation, but not with CSF tau. Additionally, there was a significant positive correlation between cerebrospinal fluid 5-HIAA and HVA in the group of AD patients (p<0.0001, Rho: 0.47, Spearman Rank correlation). Neither 5-HIAA nor HVA in CSF could differentiate between mild cognitive impairment, depression and AD. The results of this study support the hypothesis that the serotonergic system plays a role in the course of AD. They further suggest an important role of dopamine metabolism in depression within AD patients.     

Increased Cerebrospinal Fluid Dopamine and 3,4-Dihydroxyphenylacetic Acid Levels in Huntington''s Disease: Evidence for an Overactive Dopaminergic Brain Transmission

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of patients with Huntington's disease (HD) were measured by HPLC. CSF DA, DOPAC, and MHPG levels were found to be increased in HD patients. Levels of HVA, 5-HIAA, and NA in the CSF of HD patients did not differ from those of controls. Changes in CSF DA and DOPAC levels were consistent with previous findings of increased DA tissue content in some brain areas of patients with HD. These results suggest that CSF DOPAC levels could be a more reliable index of overactive dopaminergic brain systems in HD than CSF HVA levels.     

Differential abnormalities in plasma 5-HIAA and platelet serotonin concentrations in violent suicide attempters: relationships with impulsivity and depression

Brain serotonergic systems may participate in the regulation of mood, impulsivity and aggressive behavior. Because some monoaminergic mechanisms seem to be similar in the central nervous system and peripheral tissues, we tested whether serotonergic or dopaminergic biochemical parameters in peripheral venous blood are related or not to violent suicide behavior.We simultaneously studied plasma serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and platelet 5-HT content in patients within 3 days following a violent suicide attempt and in matched healthy controls. We examined their relationship with depression and impulsivity. Twenty seven drug-free suicide attempters and controls were included. Plasma 5-HIAA and platelet 5-HT concentrations were lower in suicide attempters than in controls. Fifteen patients were classified as impulsive (I), including all patients suffering from personality disorder and alcohol abuse, and 12 as non impulsive (NI), mostly melancholics. MADRS scores were similar in both I and NI suicide attempters.When controlling for age, plasma 5-HIAA was lower in I than in NI suicide attempters or controls; these findings are similar to those we observed recently with CSF 5-HIAA in I and NI violent suicide attempters. Contrarily, platelet 5-HT levels were lower in NI than in I patients or controls. Plasma HVA was not associated with suicide behavior. Plasma 5-HIAA concentration was inversely associated with the degree of impulsivity and platelet 5-HT with the intensity of depression. This study indicates that each peripheral serotonergic index is specifically related to a distinct clinical feature and shows differential alteration according to the impulsivity group. In I and NI drug-free violent suicide attempters an inverse figure between plasma 5-HIAA and platelet 5-HT data was observed indicating a non parallelism between these two peripheral variables. Further prospective studies are needed to investigate whether these peripheral serotonergic parameters may be used as helpful early predictors of violent suicide behavior.     

Neurochemical investigation of an endogenous model of the "hyperkinetic syndrome" in a hybrid dog.

A telomian-beagle hybrid has been recently proposed as a possible model for the hyperkinetic syndrome. They resemble hyperkinetic children in their poor ability to respond with the appropriate behavior in an inhibitory training test. Two groups of hybrids could be differentiated, the behavior of one of which improved with amphetamine (“Responders”) and of the other did not (“Non responders”). In the present study, the levels of HVA, 5-HIAA, MOPEG-SO were measured in CSF and the levels of NA, DA, HVA, DOPAC⁴, 5-HIAA were assayed in brain tissues from different regions, taken under basal conditions from beagles and telomian-beagle hybrids. Responder hybrids had lower levels of NA, DA, HVA in brain and low HVA in CSF. Therefore, they can be distinguished biochemically as well as behaviorally from non-responder hybrids and beagles and may prove to be useful as models for study of the mechanism and the therapy of this syndrome.     

Intra- and inter-individual relationships between central and peripheral serotonergic activity in humans: a serial cerebrospinal fluid sampling study

Data are lacking concerning the longitudinal covariability and cross-sectional balance between central and peripheral 5-HIAA concentrations in humans and on the possible associations between tobacco smoking or post-traumatic stress disorder (PTSD) and CSF and plasma 5-HIAA concentrations. Using serial cerebrospinal fluid (CSF) and blood sampling, we determined the concentrations of 5-HIAA in CSF and plasma over 6 h, and examined their relationships in healthy volunteers and patients with PTSD-both smokers and nonsmokers. Patients with PTSD and healthy volunteers had very similar CSF 5-HIAA concentrations. Significant and positive correlations between CSF and plasma 5-HIAA levels were observed within individuals, but this CNS-peripheral 5-HIAA relationship was significantly reduced in smokers (nonsmokers: mean r = 0.559 +/- 0.072; smokers: mean r = 0.329 +/- 0.064 p < 0.038). No significant cross-sectional, interindividual correlation of mean CSF and mean plasma 5-HIAA was seen (r = 0.094). These data show that changes in CSF 5-HIAA levels within an individual over time are largely reflected in plasma 5-HIAA, albeit significantly less so in smokers. The present results therefore suggest that clinically, longitudinal determination of plasma 5-HIAA concentrations within an individual patient can be used to make inferences about relative changes in integrated CSF 5-HIAA concentrations. However, plasma 5-HIAA concentrations provide no significant information about absolute levels of the serotonin metabolite in the CSF.     

CEREBROSPINAL FLUID HOMOVANILLIC ACID AND ISO-HOMOVANILLIC ACID: A GAS–LIQUID CHROMATOGRAPHIC METHOD

Abstract— The hexafluoroisopropyl esters of trifluoroacetylated homovanillic acid (HVA) and 3-hydroxy-4-methoxyphenylacetic acid (iso-HVA) were the derivatives chosen for assay of these phenolic acids in lumbar cerebrospinal fluid (CSF) specimens from 65 control subjects. The mean value obtained in these specimens was 40.0 ± 23.5 ng/ml. Recovery of added HVA and iso-HVA was 94 ± 2 per cent and reproducibility was ±5 per cent. CSF from Parkinson's disease patients undergoing treatment with l -DOPA showed significant increases in HVA. Iso-HVA was detected in those CSF samples obtained during l -DOPA therapy.     

Effects of transient, global, cerebral ischemia on striatal extracellular dopamine, serotonin and their metabolites

Rat striatal extracellular fluid levels of dopamine, serotonin, 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured before, during and after transient, global cerebral ischemia in awake rats using in vivo brain microdialysis. Before ischemia, extracellular levels of dopamine, DOPAC, HVA and 5-HIAA were detectable and consistent from sample to sample. During cerebral ischemia, there was a large increase in extracellular dopamine levels and a decrease in the extracellular levels of DOPAC, HVA, and 5-HIAA. During reperfusion, dopamine levels returned to normal as did those of DOPAC, HVA and 5-HIAA. Dialysate serotonin and 3-methoxytyramine concentrations were below detection limits except for samples collected during ischemia and early reperfusion.     

Determination of Picomole Amounts of Dopamine, Noradrenaline, 3,4-Dihydroxyphenylalanine, 3,4-Dihydroxyphenylacetic Acid, Homovanillic Acid, and 5-Hydroxyindolacetic Acid in Nervous Tissue After One-Step Purification on Sephadex G-10, Using High-Performance Liquid Chromatography with a Novel Type of Electrochemical Detection

A determination of dopamine (DA), noradrenaline (NA), 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5-HIAA) in nervous tissue is described. The method is based on a rapidly performed isolation of DA, NA, DOPA, DOPAC, HVA, and 5-HIAA from one single nervous tissue sample on small columns of Sephadex G-10, followed by reverse-phase high-performance liquid chromatography with electrochemical detection. A new type of electrochemical detector based on a rotating disk electrode (RDE) was used. The rotating disc electrode was found to be a reliable and sensitive amperometric detector with several advantages over the currently used thin-layer cells. The detector appeared very useful for routine analysis. Practical details are given for the routine use of the RDE. Brain samples containing no more than 75-150 pg (DA, DOPA, DOPAC, HVA, and 5-HIAA) or 500 pg (NA) could be reproducibly assayed with high recovery (approx. 85%) and precision (approx. 5%), without the use of internal standards. Endogenous concentrations of DA, NA, DOPA, DOPAC, HVA, and 5-HIAA were determined in eight brain structures.     

Circadian periodicity of urinary volume, creatinine and 5-hydroxyindole acetic acid excretion in healthy Indians

The circadian periodicity of urinary output, creatinine (Cr) and 5-hydroxyindole acetic acid (5-HIAA) excretion was studied under near-tropical conditions in 130 healthy volunteers (65 men and 65 women, 16-75 years of age) with a diurnal activity from about 06:30 to about 22:00 and nocturnal rest. These volunteers were divided into 4 groups, 16-30, 31-45, 46-60 and 61-75 years of age, comprising 20, 20, 15 and 10 participants of each gender, respectively. A marked circadian rhythm was recorded for urine volume, Cr and 5-HIAA excretion in healthy Indians of different ages. The acrophase tended to be delayed in the older age group. The relative amplitude decreased with advancing age, notably in women. Overall, men produced a larger urine volume as compared to women. Excretions of Cr and 5-HIAA in healthy Indian volunteers of different ages may be influenced by diet, societal relations, climate and/or geographic location. The contribution of such factors in metabolism and degradation warrants further study.