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.     

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.     

Significant correlation between cerebrospinal fluid and brain levels of norepinephrine, serotonin and acetylcholine in anesthetized rats

The present study was undertaken to determine cerebrospinal fluid (CSF) and brain levels of norepinephrine (NE), serotonin (5-HT) and their metabolites--3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA)--in rats pretreated with 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT). In the 6-OHDA pretreated rats, both CSF and brain concentrations of NE, DOPAC and HVA sustained significant decreases as compared with those in non-treated rats. Positive and significant correlations between CSF and brain levels were observed in respect to NE, DOPAC and HVA. In 5,7-DHT pretreated rats, both CSF and brain concentrations of 5-HT and 5-HIAA were significantly decreased. A positive and significant correlation between CSF and brain levels in respect to 5-HT and 5-HIAA was observed. Further studies were carried out to determine ACh levels of both the CSF and the brain in microspheres (MS)-treated rats, which are used as a model of microembolization. The CSF ACh concentrations in MS-treated groups were significantly decreased as compared with those in non-treated rats. The brain ACh contents also tended to decrease in this group. A positive and significant correlation was observed between CSF and brain levels of ACh. These findings suggest that NE, 5-HT and ACh concentrations in the CSF are direct indications of central noradrenergic, serotonergic and cholinergic nerve activity, respectively.     

Simultaneous determination of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high-performance liquid chromatography using electrochemical detection

An improved high-performance liquid chromatographic method with electrochemical detection (HPLC-EC) for the simultaneous determination of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) in cerebrospinal fluid (CSF) of humans and nonhuman primates is described. Quantitation is based on the use of an internal standard, 5-fluoro-HVA. Sample preparation consists of mixing an aliquot of CSF with a solution of the internal standard followed by ultrafiltration. The precision of the method is high, with within-run and between-run coefficients of variation of 2-6% and less than 10%, respectively, in the concentration ranges of the metabolites encountered in human lumbar CSF. Accuracy was tested by comparing the present HPLC method with specific gas chromatographic-mass spectrometric (GS-MS) assays for MHPG and HVA and a GC-MS-validated HPLC assay for 5-HIAA: the correlations obtained were 0.968 for MHPG, 0.989 for 5-HIAA, and 0.999 for HVA, with no systematic bias between the methods. The use of ascorbate as a preserving agent for monoamine metabolites in CSF was not found to be necessary when proper care was exercised in sample handling and storage. The analysis of samples with up to 2% ascorbic acid was possible as well, but MHPG had to be assayed separately using an extraction procedure and an alternative internal standard, 3-ethoxy-4-hydroxyphenylglycol.     

Higher Orexin A levels in lumbar compared to ventricular CSF: A study in idiopathic normal pressure hydrocephalus

Orexin A (ORX-A) is implicated in the regulation of various physiological processes, including sleep/wake cycles and reward/motivation. The hypothalamic ORX-A neurons project throughout the brain and spinal cord. In the present study we established and compared ORX-A levels in lumbar and ventricular cerebrospinal fluid (CSF) samples, drawn from idiopathic normal pressure hydrocephalus (INPH) patients, during respectively, lumbar puncture and shunt placement. Ventricular and lumbar CSF levels of total protein and of the dopamine, serotonin and norepinephrine metabolites HVA, 5-HIAA and MHPG respectively, were also estimated. ORX-A was quantified using a commercially available radioimmunoassay kit. Neurotransmitter metabolites were quantified by high performance liquid chromatography. Expectedly, HVA and 5-HIAA levels were significantly higher and total protein levels lower in ventricular compared to lumbar CSF while there were no differences in MHPG levels. However, in contrast to HVA and 5-HIAA and similar to total protein, lumbar ORX-A levels were significantly higher than ventricular levels. The higher lumbar compared to ventricular ORX-A levels may reflect elevated contributions from the spinal cord. The finding of a ventriculo-lumbar difference for ORX-A should be considered in studies utilizing its CSF levels in assessing Orexin system status.     

The dopaminergic neurotransmitter system is associated with aggression and agitation in frontotemporal dementia

To identify neurochemical correlates of behavioral and psychological signs and symptoms of dementia (BPSD), we set up a prospective study. Patients with probable Alzheimer's disease (AD) (n=181), mixed dementia (MXD) (n=28), frontotemporal dementia (FTD) (n=25) and dementia with Lewy bodies (DLB) (n=24) were included. At inclusion, all patients underwent lumbar puncture, neuropsychological examination and behavioral assessment (battery of behavioral assessment scales). Cerebrospinal fluid (CSF) levels of norepinephrine and of (nor)epinephrine (MHPG), serotonin (5HIAA) and dopamine (DOPAC, HVA) metabolites were determined by HPLC and electrochemical detection. Spearman Rank-Order followed by Bonferroni correction was used for calculating correlations. In FTD patients, CSF norepinephrine levels were positively correlated with dementia severity (r=0.539; p=0.021). CSF DOPAC levels were correlated with BPSD in general (r=0.537; p=0.007), associated caregiver burden (r=0.567; p=0.004) and agitated and aggressive behavior (r=0.568; p=0.004). In a subgroup of FTD patients who did not receive psychotropic pharmacological treatment, a strong correlation between CSF HVA/5HIAA ratios (reflecting serotonergic modulation of dopaminergic neurotransmission) and aggressive behavior (r=0.758; p=0.009) was found. In MXD patients, (verbally) agitated behavior was positively associated with the turnover of norepinephrine (r=0.633; p=0.002). No significant correlations were found in AD and DLB groups. In FTD, increased activity of dopaminergic neurotransmission and altered serotonergic modulation of dopaminergic neurotransmission is associated with agitated and aggressive behavior respectively. This study demonstrated that neurochemical mechanisms underlying the pathophysiology of BPSD are both BPSD-specific and disease-specific which might have implications for future development of new and more selective pharmacological treatments of BPSD.     

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.     

Neuropsychological and behavioural correlates of CSF biomarkers in dementia

To improve clinical, neuropsychological and behavioural characterisation of the cerebrospinal fluid (CSF) biomarkers beta-amyloid((1-42)) protein (Abeta42), protein tau (tau) and tau phosphorylated at threonine 181 (P-tau181) across diagnostic dementia categories, a prospective study was set up. Patients with probable Alzheimer's disease (AD) (n=201), AD with cerebrovascular disease (CVD) (AD+CVD) (n=33), frontotemporal dementia (FTD) (n=27), dementia with Lewy bodies (DLB) (n=22) and healthy controls (n=148) were included. All patients underwent neuropsychological examination and behavioural assessment by means of a battery of behavioural assessment scales. CSF was obtained by lumbar puncture and levels of Abeta42, tau and P-tau181 were determined with commercially available ELISA kits. Negative correlations between CSF Abeta42 levels and aggressiveness (Spearman: r=-0.223; p=0.002) and positive correlations with age at inclusion (r=0.195; p=0.006), age at onset (r=0.205; p=0.003) and MMSE scores (r=0.198; p=0.005) were found in AD. In AD+CVD, CSF Abeta42 levels were correlated with MMSE (r=0.482; p=0.006), Hierarchic Dementia Scale (r=0.503; p=0.017) and Boston Naming Test (r=0.516; p=0.012) scores. In controls, age was positively correlated with CSF tau (r=0.465; p<0.001) and P-tau181 levels (r=0.312; p<0.001). CSF tau and P-tau181 levels correlated significantly in all groups, whereas CSF Abeta42 correlated with tau and P-tau181 levels in healthy controls only. Negative correlations between CSF Abeta42 levels and aggressiveness were found in AD patients. CSF Abeta42 seems to be a stage marker for AD (+/-CVD) given the positive correlations with neuropsychological test results suggesting that CSF Abeta42 might be of help for monitoring disease progression. Different correlations between age and CSF biomarker levels were obtained in healthy controls compared to AD patients, indicating that AD-induced pathophysiological processes change age-dependent regulation of CSF biomarker levels.     

Delayed dispersal and elevated monoaminergic activity in free-ranging rhesus monkeys

Male rhesus monkeys typically disperse from their groups of birth when they are between 3 and 5 years of age. Some males, however, delay dispersal from their natal groups until after they are 5 years old. The current study evaluated central monoaminergic neurotransmitter activity as a potential correlate of such “delayed” dispersal among 54 randomly selected adolescent and adult male rhesus monkeys (Macaca mulatta) captured on Cayo Santiago during an annual trapping season. Specifically, cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite), 3-methoxy-4-hydroxyphenylglycol (MHPG, a norepinephrine metabolite), and homovanillic acid (HVA, a dopamine metabolite) were compared in monkeys 60 months of age or more that had either dispersed (n = 33) or were still in their natal groups (n = 5). The monkeys still in their natal groups had higher CSF concentrations of both 5-HIAA and HVA (but not MHPG) than did the animals that had emigrated (Ps < 0.05). Subsequent analysis indicated that only 5-HIAA independently differentiated dispersing monkeys from delayed dispensers. Of monkeys less than 60 months of age (n = 16), only two had dispersed from their natal groups; in this age class, there were no significant differences between dispersing and natal individuals in any CSF monoaminergic metabolite (all Ps = NS). Finally, there was no difference in the CSF 5-HIAA concentrations of the five delayed dispersers and those of younger animals (P = NS), suggesting a failure to experience the frequently reported adolescent decline in serotonergic activity. In contrast, the CSF 5-HIAA concentrations of the dispersing animals were lower than those of the younger animals (P < 0.05), consistent with either an agerelated decline or an effect of dispersal per se. © 1995 Wiley-Liss, Inc.     

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.     

Effect of age on cisternal cerebrospinal fluid concentrations of monoamine metabolites in nonhuman primates

There are conflicting reports of the effects of aging on human neurotransmitter systems as estimated by monoamine metabolite concentrations in cerebrospinal fluid (CSF). These discrepancies may be due to sampling site, age or sex of the subjects or other variables that affect CSF metabolite determinations. Cisternal CSF concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenyl-ethylene glycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), major metabolites of dopamine, norepinephrine and serotonin, respectively, were measured in rhesus monkeys (Macaca mulatta) of two age groups. Concentrations of HVA and MHPG were significantly lower in the older group of monkeys, whereas no changes in 5-HIAA were found. This supports the hypothesis that brain catecholamine concentrations decline with age.     

Motor Activity Increases Tryptophan, 5-Hydroxyindoleacetic Acid, and Homovanillic Acid in Ventricular Cerebrospinal Fluid of the Conscious Rat

An investigation was made into the effects of running (1 h at 20 m/min) on central serotonergic and dopaminergic metabolism in trained rats. Methodology involved continuous withdrawal of cerebrospinal fluid (CSF) from the third ventricle of conscious rats and measurements of tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels during a 2 h post-exercise period. All three compounds were increased during the hour following exercise and returned to their basal values within an hour later. CSF flow rate was stable when metabolite levels were elevated. Brain determinations indicated that CSF metabolite variations only qualitatively paralleled brain changes. Indeed, post-exercise TRP, 5-HIAA, and HVA levels were increased to a greater extent in brain when compared to CSF. It is suggested that increased serotonergic and dopaminergic metabolism, caused by motor activity, may be involved in the behavioral effects of exercise.     

A modified HPLC technique for simultaneous measurement of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in cerebrospinal fluid, platelet and plasma.

A sensitive, reliable and simplified HPLC assay for simultaneous measurement of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in human cerebrospinal fluid (CSF), platelets and plasma is described. Perchloric acid is used for one step precipitation of proteins and extraction of 5-HT and 5-HIAA. Precision of the assay has been increased by calibration of the instrument using serotonin-free plasma spiked with known amount of standards and N-w-methyl-5-hydroxytryptamine as internal standard. Integration of the peaks and calculations are achieved by a preprogrammed data module using ratio method. As little as 20 pg/ml of serotonin in the deproteinated sample can be detected using this procedure. In a group of surgical patients, plasma 5-HT concentration is (Mean +/- S D) 3.4 +/- 2.7 ng/ml and that of platelet 748.3 +/- 448.3 ng/10(9) platelets. In CSF, 5-HT is found to be 3.3 +/- 3.4 ng/ml and 5-HIAA is 15.1 +/- 7.3 ng/ml. A good correlation (r = 0.648, p less than .0001) is observed between 5-HT and 5-HIAA in CSF.     

Predictive Value of the Probenecid Test for the Effect of L-Dopa Therapy in Parkinson's Disease

ALTHOUGH the results of therapy of Parkinson's disease with L-dopa have been encouraging, about 20% of treated patients have responded poorly and for a further 20% results have been only moderate. Since L-dopa therapy can have serious side effects and because treatment should continue for at least 6 months before any final assessment is made, it is useful to be able to predict the results of therapy in advance-the probenecid test offers such an opportunity for this. Probenecid (p-(di-n-propylsulphamyl)-benzoic acid) (‘Benemid’; Merck, Sharp and Dohme) administered, reduces the outflow of acid monoamine metabolites from the human brain and cerebrospinal fluid (CSF) to the blood¹. Determination of homo-vanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) after administration of probenecid provides an index of the degree of turnover of the parent amines, dopamine and 5-hydroxytryptamine (5-HT)². Central dopamine deficiency is considered to be a factor responsible for the pathogenesis of Parkinson's disease. The rate of accumulation of HVA under thé influence of probenecid may reflect the metabolism of dopamine in the brain. We have tested the hypothesis that there is a correlation between the degree of improvement of motor impairment in Parkinson's disease treated with L-dopa and the concentration of HVA in CSF after administration of probenecid³.     

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.     

Immunocytochemical Detection of Anti-Hippocampal Antibodies in Alzheimer's Disease and Normal Cerebrospinal Fluid

Immunocytochemical staining was performed to investigate the presence of anti-hippocampal antibodies in cerebrospinal fluid (CSF) from patients with probable Alzheimer's disease (AD) (n = 19), aged normal controls (n = 9), and young normal controls (n = 10). Marked staining of neurons in the granule cell layer of the dentate gyrus and in pyramidal neurons in CA1-3 of the rat hippocampus was observed in 5 AD CSF samples (26%), 1 aged control sample (11%), and 1 young control sample (10%). These differences were not statistically significant. One of the immunoreactive AD CSF specimens also contained high concentrations of C5b-9, the membrane attack complex. The infrequent occurrence of anti-hippocampal antibodies in AD CSF, and the detection of similar immunoreactivity in control CSF specimens, suggest that these antibodies are unlikely to play a role in the neurodegenerative process in most individuals with AD. However, elevated C5b-9 concentration in an AD CSF specimen with marked immunoreactivity to hippocampal neurons suggests the possibility that anti-neuronal antibodies may contribute to complement activation in some AD patients.     

In-use stability of monoamine metabolites in human cerebrospinal fluid

Cerebrospinal fluid (CSF) concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) are commonly used to provide information about central nervous system (CNS) dopaminergic and serotonergic activity. However, little attention has been given to the effects of sample handling on the concentrations of these compounds in human CSF. Using high-performance liquid chromatography (HPLC) with electrochemical detection, we observed that, in CSF stored at −80°C, concentrations of the serotonin metabolite 5-HIAA and the dopamine metabolite HVA remained unchanged through six 1-h and six 24-h freeze–thaw cycles. Exposure to bright room light (3 h, 1230 lux) resulted in a 5-HIAA concentration that was 96.3±2.0% of the initial and an HVA concentration that was 98.8±1.03% of initial. The pH of the CSF significantly increased during both freeze–thaw series and while maintained on ice (4°C). These results demonstrate the in-use stability of 5-HIAA and HVA in human CSF under commonly-encountered laboratory conditions.     

Mass fragmentographic determination of homovanillic acid in tissues and body fluids using the deuterium labeled species as internal standard

Mass fragmentographic methods for determination of 4-hydroxy-3-methoxyphenyl acetic acid (HVA) in human cerebrospinal fluid (CSF), urine, blood plasma and mouse brain were developed. After isolation by extraction or by Amberlite XAD-2 chromatography the HVA was converted to the heptafluorobutyryl methyl ester derivative and analyzed using the 2, 2 dideutero-2 (4-hydroxy-3-methoxy-2, 5, 6-trideuterophenyl) acetic acid (HVA-d₅) as an internal standard. The values (mean ± coefficient of variation) obtained on repetitive analyses of the same sample were for human CSF 0.42 nmole/ml ± 1.5% (n = 10), human plasma 48 pmole/ml ± 4.5% (n = 15), human urine 20 nmole/ml ± 5.4% (n = 10) and mouse brain 1.2 nmole/g ± 0.6% (n = 12). The results demonstrate that the use of HVA-d₅ as an internal standard provides high precision and the necessary sensitivity for the mass fragmentographic determination of HVA in small amount of tissue and body fluids.     

Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

An UPLC-MS/MS method was developed for the determination of serotonin (5-HT), dopamine (DA), their phase I metabolites 5-HIAA, DOPAC and HVA, and their sulfate and glucuronide conjugates in human brain microdialysis samples obtained from two patients with acute brain injuries, ventricular cerebrospinal fluid (CSF) samples obtained from four patients with obstructive hydrocephalus, and a lumbar CSF sample pooled mainly from patients undergoing spinal anesthesia in preparation for orthopedic surgery. The method was validated by determining the limits of detection and quantification, linearity, repeatability and specificity. The direct method enabled the analysis of the intact phase II metabolites of 5-HT and DA, without hydrolysis of the conjugates. The method also enabled the analysis of the regioisomers of the conjugates, and several intact glucuronide and sulfate conjugates were identified and quantified for the first time in the human brain microdialysis and CSF samples. We were able to show the presence of 5-HIAA sulfate, and that dopamine-3-O-sulfate predominates over dopamine-4-O-sulfate in the human brain. The quantitative results suggest that sulfonation is a more important phase II metabolism pathway than glucuronidation in the human brain.     

Kinetics of Drug-Induced Changes in Dopamine and Serotonin Metabolite Concentrations in the CSF of the Rat

Cerebrospinal fluid (CSF) was removed at a constant flow rate of 1 microliter/min from the third ventricle of anesthetized rats. Every 15 min, CSF dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined by direct injection of CSF into a liquid chromatographic system coupled with electrochemical detection. Mean CSF concentrations of DOPAC, HVA, and 5-HIAA were 1.29 microM, 0.88 microM, and 2.00 microM, respectively. In order to determine the turnover rates of dopamine (DA) and serotonin, experiments using monoamine oxidase (MAO) inhibition were performed. Tranylcypromine (20 mg/kg i.p.) induced a sharp exponential decrease of CSF DOPAC, HVA, and 5-HIAA, with respective half-lives of 15.60 min, 16.91 min, and 77.23 min. Their respective turnover rates were 3.74, 2.22, and 1.18 nmol X ml-1 X h-1. m-Hydroxybenzylhydrazine (NSD-1015, 100 mg/kg i.p.) and monofluoromethyl-DOPA (100 mg/kg i.p.), two decarboxylase inhibitors, induced a slow exponential decrease of all three CSF metabolites. alpha-Methyl-p-tyrosine (250 mg/kg i.p.) also induced a slow exponential decrease of DOPAC and HVA. These decreases of CSF DOPAC and HVA induced by DA synthesis inhibitors may reflect the turnover of DA in vivo. Haloperidol (0.5 mg/kg i.p.) considerably enhanced CSF DOPAC and HVA without affecting 5-HIAA, confirming that dopaminergic receptors modulate DA neurotransmission in vivo. Haloperidol administered 1.5 h after NSD-1015 did not increase DOPAC and HVA, in contrast to reserpine (5 mg/kg i.p.) injected under the same conditions.(ABSTRACT TRUNCATED AT 250 WORDS)