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Introduction: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate., Methods: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed., Results: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%., Conclusions: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.

Fluoroquinolones (FQs) are associated with a low incidence of central nervous system (CNS) side effects, possibly leading to convulsions, especially when co-administered with nonsteroidal anti-inflammatory drugs (NSAIDS). Although the in vivo pro-convulsant activity of NSAIDS is essentially unknown, the convulsant potential of FQs is traditionally evaluated by in vitro gamma-aminobutyric acid (GABA) binding experiments in the presence of 4-biphenyl acetic acid (BPAA), the active metabolite of fenbufen. The aim of this study was therefore to investigate the BPAA-norfloxacin convulsant interaction in vivo. Male Sprague-Dawley rats (n = 27) were given BPAA orally, at various doses 1 h before norfloxacin infusion, which was maintained until the onset of maximal seizures, when cerebrospinal fluid (CSF) and plasma samples were collected for analysis. An inhibitory E(max) effect model with a baseline effect parameter was fitted to the norfloxacin versus BPAA concentrations in the CSF, previously shown to be part of the biophase. This model includes three parameters: the concentrations of norfloxacin in the absence of BPAA (C(CSF0, Nor)), and when BPAA concentration tends toward infinity (C(CSFbase, Nor)), and the BPAA concentration for which half of the maximal effect is observed (C(CSF50, BPAA)). The maximal proconvulsant effect of BPAA is given by the C(CSF0, Nor) / C(CSFbase, Nor) ratio, estimated to approximately 6 in this study. Derived models were developed in plasma to account for the non-linear CSF diffusion of norfloxacin and protein binding of BPAA. In conclusion this study has shown that the convulsant interaction between norfloxacin and BPAA in rats, can be adequately characterized by modelling of the CSF concentrations of the two drugs at the onset of activity, following their administration in various proportions.

Cerebrospinal fluid levels of phenylacetic acid (CSF PAA) were obtained from normal controls and from drug-free psychiatric inpatients (schizophrenia, major depression, mania, and schizoaffective disorder). Post-treatment CSF PAA levels were obtained from 16 patients after 4 weeks of neuroleptic treatment. Phenylacetic acid levels were higher in women and were significantly correlated with age. There were no differences in CSF PAA levels between the various diagnostic groups and no difference between the paranoid and the nonparanoid subtypes of schizophrenia. CSF PAA was significantly correlated with several measures of psychopathology, especially the Brief Psychiatric Rating Scale hostility/suspiciousness factor. Neuroleptic treatment did not result in significant PAA changes. These findings are discussed in light of the amphetamine-like role ascribed to phenylethylamine, the precursor of PAA.

Phenylacetate is a naturally occurring plasma component that suppresses the growth of tumor cells and induces differentiation in vitro. To evaluate the in vivo potential and preventive and therapeutic antitumor efficacy of sodium phenylacetate against malignant brain tumors, Fischer 344 rats (n = 50) bearing cerebral 9L gliosarcomas received phenylacetate by continuous s.c. release starting on the day of tumor inoculation (n = 10) using s.c. osmotic minipumps (550 mg/kg/day for 28 days). Rats with established brain tumors (n = 12) received continuous s.c. phenylacetate supplemented with additional daily i.p. dose (300 mg/kg). Control rats (n = 25) were treated in a similar way with saline. Rats were sacrificed during treatment for electron microscopic studies of their tumors, in vivo proliferation assays, and measurement of phenylacetate levels in the serum and cerebrospinal fluid. Treatment with phenylacetate extended survival when started on the day of tumor inoculation (P < 0.01) or 7 days after inoculation (P < 0.03) without any associated adverse effects. In the latter group, phenylacetate levels in pooled serum and cerebrospinal fluid samples after 7 days of treatment were in the therapeutic range as determined in vitro (2.45 mM in serum and 3.1 mM in cerebrospinal fluid). Electron microscopy of treated tumors demonstrated marked hypertrophy and organization of the rough endoplasmic reticulum, indicating cell differentiation, in contrast to the scant and randomly distributed endoplasmic reticulum in tumors from untreated animals. In addition, in vitro studies demonstrated dose-dependent inhibition of the rate of tumor proliferation and restoration of anchorage dependency, a marker of phenotypic reversion. Phenylacetate, used at clinically achievable concentrations, prolongs survival of rats with malignant brain tumors through induction of tumor differentiation. Its role in the treatment of brain tumors and other cancers should be explored further.

1. It has been proposed that an increase in the concentration of the neuromodulator phenylethylamine at the post-synaptic dopamine receptor may be involved in the etiology of schizophrenia. If this increase is the case, a reduction in the CSF and/or serum concentrations of phenylacetic acid, its major metabolite, might be anticipated. 2. The authors have found in hospitalized Indian schizophrenic patients ingesting antipsychotic drugs, that the paranoid subgroup did indeed exhibit lower levels of unconjugated, conjugated and total phenylacetic acid in both serum and CSF.

Four monoamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), were determined in the cerebrospinal fluid (CSF) of cadavers, whose causes of death had been suicidal hanging (SH) or ischemic heart failure (IHF). The concentration of DOPAC increased in parallel with the increment of the postmortem interval (PMI) (r = 0.626), whereas the concentrations of HVA, MHPG and 5-HIAA did not. The correlation coefficient was further increased by considering each cause of death separately: i.e., SH, r = 0.761; IHF, r = 0.705. These findings suggest the possible usefulness of the DOPAC level in CSF for estimating PMI.

Following the hypothesis that attention deficit disorder in adults (attention deficit disorder, residual type; ADD, RT), as well as in children, is associated with decreased central dopaminergic activity, the authors measured lumbar cerebrospinal fluid monoamine metabolites in a group of adults with ADD, RT and matched control subjects. Patients were then entered into a double-blind, placebo-controlled trial of methylphenidate. It was predicted that the patients would have lower levels of homovanillic acid (HVA), the major dopamine metabolite in humans. Patients who had a significant response to methylphenidate showed a trend in this direction. Nonresponding patients had significantly higher levels of HVA than controls.

Twenty-four psychotic patients were studied at two points during continuous neuroleptic treatment. Thirteen patients showed a tolerance pattern with respect to cerebrospinal fluid homovanillic acid following probenecid while 11 showed a nontolerance pattern. Patients who developed tolerance had significantly fewer symptoms and Parkinsonian side effects at approximately the fifth week of treatment.

Adult coeliac patients taking a gluten-free diet for one year showed an increase of 33% in the concentrations in CSF of major monoamine metabolites (5-HIAA, HVA and MOPEG). Tryptophan in CSF rose by 10%. There was concomitant morphological improvement in the jejunal mucosa, and the results would seem to indicate that the reduced central monoamine metabolism in untreated adult coeliacs is not primarily genetically determined but is probably related to the poor intestinal absorption.

Levels of the amine metabolites homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) were measured in the cerebrospinal (CSF) fluid of drug-free patients with Alzheimer's disease and compared to levels in a group of controls. No significant differences were found in CSF HVA and MHPG, although the Alzheimer's group was severely demented. Platelet monoamine oxidase (MAO) enzyme kinetics were measured and did not differ between controls and Alzheimer patients. The degree of dementia did not show any significant correlation with the levels of HVA or MHPG. It was concluded that, unlike previous reports in the literature, the dementia of Alzheimer's disease was not related to changes in central catecholamine metabolism nor was it associated with increased platelet MAO activity.

HVA and 5-HIAA levels were determined in the lumbar CSF of 17 patients affected by endogenous depression. The modification of the amine metabolites after treatment (tryciclics, bromocriptine, trazodone, ECT) were not related to the specific therapy nor to the clinical improvement. In 11 patients, HVA and 5-HIAA showed opposite modificatons. The possible role of interactions between dopaminergic and serotoninergic systems in the pathogenesis of endogenous depression is discussed.

As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function.

In head injured patients changes were found in the CSF levels of metabolites of the dopaminergic and the serotonergic neurotransmission (HVA and 5-HIAA). After the fifth day following trauma a significant decrease of the HVA levels in the lumbar CSF after probenecid treatment was found. The intensity of this decrease was found to be related to the severity of the trauma (period of unconsciousness), but not to the state of consciousness. Also the probenecid-induced 5-HIAA levels in conscious patients were decreased after the fifth post-traumatic day. In unconscious patients, the period of unconsciousness, particularly in the period of 5-20 days after trauma. Between 21 and 60 days after trauma the 5-HIAA concentrations in unconscious patients decreased remarkably, but they were still significantly higher than in the conscious patients. It can be concluded that during unconsciousness serotonergic neurons have a high rate of turnover, but that both neurotransmitter systems are damaged by the direct or indirect consequences of the injury.

Methionine-enkephalin, substance P, and homovanillic acid concentrations were measured in the CSF of subjects not affected by neurologic disorders (group 1), and in parkinsonian patients who had a slight or moderate (group 2) or severe (group 3) disability. Homovanillic acid and substance P concentrations in the CSF of groups 2 and 3 were respectively lower and higher than in group 1. On the contrary, an increase in CSF methionine-enkephalin content was found only in group 2. Our results confirm in humans the close relation between the dopaminergic and peptidergic transmissions in the nigrostriatal system that has been observed in experimental animals.

The time-course of psychopathological symptoms, of extrapyramidal side effects, and of changes in cerebrospinal fluid (CSF) concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were simultaneously studied during Haloperidol treatment of 14 psychotic patients with chronic organic brain damage. After 15 days of treatment significant antipsychotic effect was found, while Parkinsonism scores in clinical and experimental tests increased only slightly. CSF concentration of HVA increased significantly by 150% compared to the baseline value (p less than 0.05) and 5-HIAA remained unchanged. No correlation was found between the clinical and biochemical variables studied. The comparison of these results with those obtained in patients without brain damage suggests that different psychopathological and extrapyramidal responses to neuroleptics are not strictly associated with specific HVA changes in CSF.

Cerebrospinal fluid 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and tryptophan in both CSF and plasma were measured in a carefully selected group of 33 depressed women. Strict and explicit inclusion and exclusion criteria were used, and CSF was taken under controlled circumstances. Seventeen operationally defined and uniformly rate psychiatric symptoms as well as global depression severity and 12 clinical background variables were correlated with the four biochemical parameters, using multivariate regression analysis based on Spearman's rank correlation coefficient according to the nature of the data. Global depression severity did not correlated with any of the biochemical variables; there were, however, significant correlations between CSF 5HIAA and anxiety, insomnia, and suicide on the one hand, and between CSF HVA and motor symptoms and paranoidity on the other hand. Background variables showed only a few--and much weaker--correlations. It was concluded that central monoamine metabolism does affect some particular psychiatric symptoms but is not parallel with the complex clinical construct of the depressive disease. Further studies using isolated psychopathological symptoms instead of nosological categories are suggested in clinical neurochemistry.

gamma-Aminobutyric acid (GABA) and homovanillic acid (HVA) levels were determined in the lumbar cerebrospinal fluid (CSF) of hospitalized patients suffering from depression and in a control group. Both mean CSF GABA and HVA levels in the patients with depression were significantly lower than those of the control group (p less than 0.05, p less than 0.01, respectively). No positive correlation was found between the changes in CSF GABA and HVA levels in the patients with depression. The Hamilton Rating score in these depressed patients, age, and sex showed no correlation to CSF GABA levels. It is suggested that decreased activity in the central GABAergic and dopaminergic system may be involved in the pathogenesis of depression.

Concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in CSF obtained after injection of air during pneumoencephalography (PEG) than in lumbar CSF, as drawn before the injection. There was a high correlation between levels in the `mixed' and lumbar samples of CSF in the case of each of the two acids. The concentration of lumbar HVA, but not that of 5-HIAA, was negatively correlated with CSF pressure. 5-HIAA levels were low in both samples of CSF in a group of epileptics, by comparison with controls. In two patients with Kufs disease and in one with Niemann-Pick disease, the concentration of HVA was very low in the lumbar sample. The application of a standardized PEG technique in the study of monoamine metabolism in man is suggested.

Fifteen patients, 48 to 72 years old, with Alzheimer's disease were studied. Clinical status was assessed by neurologic and neuropsychologic examinations and psychometric testing. Patients were divided into two groups on the basis of clinical assessment: group 1, little mental deterioration, and group 2, serious mental deterioration. Nineteen subjects, 27 to 72 years old, without neurologic disease served as controls. Levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and gamma-aminobutyric acid (GABA) were determined in lumbar CSF by fluorimetric or radioreceptor binding (GABA) methods. The HVA concentrations increased with age in the controls, whereas the GABA levels decreased with age and 5-HIAA levels were not modified. When compared with the age-matched controls, the patients with Alzheimer's disease showed low concentrations of HVA but not of 5-HIAA or GABA. The decrease in HVA level was more pronounced in patients with severe mental deterioration and therefore appeared to be disease related.

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)

Phenylacetic acid, p-hydroxyphenylacetic acid, m-hydroxyphenylacetic acid, phenylalanine, indoleacetic acid, 5-hydroxyindoleacetic acid and tryptophan were measured in lumbar and cisternal cerebrospinal fluid (CSF) taken during pneumoencephalography. The data suggest that the concentration of the acid metabolites of the trace amines tryptamine, phenylethylamine, p-tyramine and m-tyramine in lumbar CSF are influenced by the system that transports these acids out of CSF. In cisternal CSF this mechanism does not operate and more information can be obtained on the metabolism of the parent amines in the CNS. Our data indicate that (1) m-tyramine is relatively unimportant quantitatively (2) the rate of metabolism of phenylethylamine in human brain is similar to that of 5-hydroxytryptamine (3) the most important variable controlling the synthesis of phenylethylamine is the activity of aromatic amino acid decarboxylase (4) p-tyramine is synthesised at about half the rate of phenylethylamine and is thus quantitatively important in metabolic terms.

Phenylacetic acid has been detected in human cerebrospinal fluid and plasma. Free acid and total acid values obtained after hydrolysis have been quantified as the pentafluorobenzyl ester by selected ion monitoring, using [2H7]phenylacetic acid as internal standard.

In 26 patients with psychiatric disorders, EEG, and visual averaged evoked responses (VAER) were recorded. In the analysis of the EEG, the mean integrated amplitude (MIA), its within patient variance (WPV), and the coefficient of variation CV=(square root of WPV/MIA) X 100 were calculated. Patients were grouped as augmenters on reducers according to their tendency in the VAER recording to augment or to reduce the intensity of incoming signals with increasing stimulus intensity. The content of monoamine metabolites, 5-hydroxyindoleacetic acid, 5-HIAA, and homovanillic acid (HVA), and --for 17 patients-- tryptophan, in the cerebrospinal fluid was determined. In the analysis of the results, WPV in the alpha-band was found to be significantly correlated to HVA (r=0.45, p less than 0.02) and to 5-HIAA (r=0.34, p less than 0.05). In a multiple regression analysis, the correlation between WPV and HVA was found to be the most important. CV was found to be signfiicantly correlated to tryptophan (r=0.68, p less than 0.01). In the analysis of the results of the VAER, reducers were found to have higher levels of 5-HIAA and tryptophan and significantly higher values of HVA. The results are discussed in relation to earlier neurophysiological and biochemical theories about psychiatric patients.

In an earlier, separate study, the authors found that human aggression and suicide (a specific aggression-related behavior) were associated with lower levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite. That study focused on subjects with personality disorders without affective illness. In the present study they examine the life history of aggression and history of suicidal behavior in 12 subjects with borderline personality disorders without major affective disorder. Histories of aggressive behaviors and of suicide attempts were significantly associated with each other, and each was significantly associated with lower 5-HIAA levels. Altered serotonin metabolism may be a highly significant contributing factor to these behaviors in whatever diagnostic group they occur.

c-AMP, c-GMP, HVA and 5 HIAA cerebrospinal fluid levels were investigated in 18 patients with subarachnoid haemorrhage (SAH). The main findings in the acute stage after SAH were represented by a marked increase of c-AMP and 5 HIAA values, whereas HVA levels were only slightly higher. In the chronic phase c-GMP levels turned out to be significantly increased, and were clearly related to intracranial hypertension. 5 HIAA and particularly HVA levels were decreased, probably due to the functional and anatomical lesion of the periventricular adrenergic structures, following the raised intracranial pressure.

Maturation of monoamine neuronal systems was studied by measuring cerebrospinal fluid metabolites of dopamine (homovanillic acid) and serotonin (5-hydroxyindoleacetic acid) in 38 children with epilepsy and other neurological disorders, to whom probenecid had previously been administered. The turnover of brain dopamine decreased with age. This ontogenetic course may be associated with developmental processes involving activity or cognitive maturation. Boys tended to have higher turnover of dopamine; girls tended to have higher turnover of serotonin. The sex effects may be related to the markedly greater vulnerability of boys to major neuropsychiatric disorders of childhood.

To determine whether 1-tyrosine administration can enhance dopamine synthesis in humans as it does in rats, we measured levels of tyrosine and the major dopamine metabolite, homovanillic acid, in lumbar spinal fluids of 23 patients with Parkinson's disease before and during ingestion of 100 mg/kg/day of tyrosine. Nine patients took 100 mg/kg/day of probenecid in six divided doses for 24 hours prior to each spinal tap; 14 patients did not receive probenecid. L-tyrosine administration significantly increased CSF tyrosine levels in both groups of patients (p less than .01) and significantly increased homovanillic acid levels in the group of patients pretreated with probenecid (p less than .02). These data indicate that l-tyrosine administration can increase dopamine turnover in patients with disorders in which physicians wish to enhance dopaminergic neurotransmission.

The influence of probenecid administration on 5HIAA and HVA concentrations in the CSF of depressed patients, was studied before and after treatment with imipramine or ECT. The average increase of the two metabolites in the CSF after probenecid was similar in the untreated depressed patients and in the same patients improved after both imipramine or ECT treatment. The treatment determined a significant increase in the CSF concentration of the acid metabolites also before the probenecid administration.

The influence of prodipin, a putative dopamine releasing compound, on the concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the spinal liquor of 28 patients with Parkinson's disease was investigated. The patients were divided into three groups. In group 1 the combined antiparkinson therapy was interrupted, and 20 mg prodipin was infused. In group 2 and 3 the therapy was continued, while an additional 20 mg of prodipin was administered by infusion only to group 3. 4 Liquor-samples were obtained from each patient: 1 basic value and three additional samples 5, 8 and 24 hours after administration of 2 g probenecid. The base concentration of HVA was 15 ng/ml and this was not increased by probenecid in group 1; the concentration of 5-HIAA was 11.6 ng/ml and this was doubled by probenecid to 22.9 ng/ml. The HVA concentration increased to a maximum of 28.9 ng/ml during continued therapy (group 2); the elevated 5-HIAA remained unchanged. Prodipin does not cause an alteration in metabolite concentration in cases of interrupted therapy (group 1), but leads, in the case of continued therapy, to a 1.8-fold increase in HVA, and a 1.6-fold increase in 5-HIAA (group 3).

Clinical effects, levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) and lithium levels in serum were examined in 13 manic depressive patients acutely admitted because of a manic or hypomanic episode. Patients were examined before and 12 days after the beginning of lithium treatment. Manic scores were significantly reduced during treatment. The levels of 5-HIAA as well as HVA increased significantly during treatment. The HVA to 5-HIAA ratio was significantly reduced, indicating a more pronounced change in 5-HIAA than in HVA. The 5-HIAA and HVA levels before as well as after 12 days of treatment were significantly correlated. No significant correlation was found between manic scores and monoamine metabolites in CSF or between lithium level in serum and reduction of manic scores or elevation of monoamine metabolites in CSF in the relative small number of patients studied.

26 patients with a paranoid-hallucinatory syndrome were treated with a fixed daily dose of haloperidol. Psychopathological symptoms and parkinsonism were studied before and during the treatment. HVA and 5-HIAA concentrations in CSF were determined immediately before and after 5 or 15 days of treatment. After 5 days of treatment a slight effect was observed on psychotic symptoms and on the extrapyramidal motor system, as well as an elevation of HVA and 5-HIAA concentrations in CSF. After 15 days of treatment the extrapyramidal and antipsychotic effects were significant, but the rise of HVA was smaller than after 5 days of treatment; 5-HIAA remained unchanged. These different time courses of the neuroleptic effects on psychopathological symptoms, on extrapyramidal system and on monoamine metabolites concentration in CSF could be interpreted as a development of drug tolerance in relation to the biochemical parameters.

Homovanillic acid and 5-hydroxyindoleacetic acid, respectively the major metabolites of the central neurotransmitters dopamine and serotonin, are present in human lumbar cerebrospinal fluid, and their determination during the probenecid test is used to study brain monoamine abnormalities in man. We developed a high performance liquid chromatographic technique coupled with electrochemical detection which allows the simultaneous determination of homovanillic acid and 5-hydroxyindoleacetic acid on 10 microliter of human lumbar cerebrospinal fluid. Another liquid chromatographic technique coupled with ultra-violet detection was applied to the measurement of probenecid after injection of 10 microliter of native cerebrospinal fluid. The main advantages of these two techniques are their simplicity, sensitivity, rapidity (five cerebrospinal fluid samples are analysed within one hour) and their good day-to-day reproducibility . These methods were applied to probenecid tests performed in several neurological patients.

Descending bulbospinal pathways that employ specific neurotransmitter substances are known to be capable of modulating segmental reflex activity in the experimental animal. To determine whether this might also occur in man correlations have been sought between the activity in spinal reflex pathways and the lumbar cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA), 3 methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) in 12 patients with complete or virtually complete spinal lesions. The concentrations of 5-HIAA and MHPG in lumbar CSF ARE REDUCED AFTER COMPLETE OR VIRTUALLY COMPLETE SPINAL LESIONS IN MAN. This may occur within 18 days of the lesion. MHPG concentrations appear to be inversely related to the level of the lesion. The HVA concentration in lumbar CSF is reduced when there is obstruction of the CSF pathways. No relationship could be demonstrated between the concentrations of 5-HIAA or MHPG in lumbar CSF and the activity in the spinal monosynaptic pathway (estimated from the proportion of the motoneurone pool activated by the Achilles tendon reflex or H reflex) or the activity of a spinal inhibitory mechanism (estimated by the degree of vibratory inhibition of the monosynaptic reflex). Patients with a tonic vibration reflex (TVR) tended to have higher MHPG levels. There appeared to be an association between low CSF HVA and enhanced vibratory inhibition of the monosynaptic reflex in the nine patients whose spinal lesions were complete.

The monoamine metabolites 3-methoxy-4-hydroxyphenyglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the cerebrospinal fluid (CSF) of 16 psychiatrically health controls and in 28 schizophrenic patients. There was no difference in CSF MHPG and HVA levels between the group of patients and the controls. CSF levels of 5-HIAA were significantly lower in schizophrenic patients than in controls. Differential analysis of patients with and without neuroleptics revealed that these findings were not due to drug treatment. Positive correlations were found between the level of 5-HIAA and the items: hallucinatory behaviour, grandiosity, and tension as rated on the Brief Psychiatric Rating Scale. As 5-HIAA CSF data are controversial for nosological entities, the search for correlations between 5-HIAA and individual psychopathological variables could provide more specific indices for psychiatric diagnosis, treatment or prophylaxis.

Lumbar CSF HVA and 5-HIAA levels were assayed in 3 groups each of 10 subjects, which were respectively deprived of sleep for 30 h, deprived of REM sleep and disturbed with several awakenings during SW sleep for two consecutive nights. HVA levels after total sleep (39 +/- 20 ng/ml) or REM (35 +/- 11 ng/ml) deprivation as well as after SW sleep awakenings (32 +/- 26 ng/ml) were not different from controls (42 +/- 14 ng/ml). 5-HIAA levels after REM deprivation (32 +/- 15 ng/ml) appeared increased when compared with controls (21 +/- 7 ng/ml), total sleep-deprived subjects (21 +/- 10 ng/ml) or subjects with SW sleep awakenings (27 +/- 13 ng/ml). Possible increase in 5-HT turnover after REM deprivation and possible 5-HT role in REM sleep regulation in humans are discussed.

The monamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), vanillylmandelic acid (VMA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were analysed in CSF from different regions of the CSF system to study the caudocranial concentration gradient of the metabolites. Four consecutive 10 ml fractions of CSF were withdrawn in 17 patients during the course of four minutes. The CSF pressure was monitored through a lumbar cannula because of suspected adult hydrocephalus. A pronounced gradient of the HVA concentration was found with a ratio between the last and the first fraction of 1,7. 5-HIAA showed a slight increase while HMPG and VMA showed no increase at higher levels of the CSF system. The results suggest that lumbar HVA reflects dopaminergic activity in the brain, whereas lumbar 5-HIAA and HMPG/VMA reflect the activity of 5-hydroxytryptamine and noradrenaline secreting neurones in both the brain and the spinal cord.