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Rationale: Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. Objectives: To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates. Methods: We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone. Results: We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found that LIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration. Conclusions: These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Attention deficit/hyperactivity disorder (ADHD) is a common neurobehavioral and neuropsychiatric disorder in school-age children, and recent studies provide evidence implicating the metabolic abnormalities of dopamine (DA) for its pathophysiology. Methylphenidate, a kind of psychostimulant, is widely used in the treatment of ADHD, but some patients do not respond to it or cannot bear its side effects. As a traditional Chinese medicine preparation, Ningdong granule (NDG) has been used in the treatment of ADHD for several years in China. However, a systematical pharmacological study on its safety and mechanism still remains obscure. Objective: This paper aims to evaluate the efficiency, safety, and possible mechanism of NDG on ADHD children compared to methylphenidate. Methods: Seventy-two ADHD children were recruited to perform an 8-week, randomized, methylphenidate-controlled, doubled-blinded trial. The subjects were equally assigned to two groups receiving either NDG 5 mg/kg/day or methylphenidate 1 mg/kg/day for 8 weeks. The efficiency was assessed by the Teacher and Parent ADHD Rating Scales every 2 weeks for a total of 8 weeks. The side effects were recorded during the study. Blood, urine, and stool routine samples, liver and renal function test, and DA and homovanillic acid (HVA) concentration in sera were tested at the beginning and end of the trial. Results: NDG ameliorated ADHD symptoms after an 8-week medication with fewer side effects compared to methylphenidate ( P < 0.05). The result also showed NDG to be safe and tolerable for ADHD children as monitored by the blood, urine, and stool analysis and liver and renal function for 8 weeks ( P < 0.05). Moreover, the level of HVA in sera increased in NDG-treated group ( P < 0.05), while the content of DA had no significant change during the study. An analysis of Pearson correlation coefficients also showed that the increased content of HVA in sera was associated with the improved scores of Teacher and Parent ADHD Rating Scales. Conclusions: Compared to methylphenidate, NDG is effective and safe for ADHD children in the short term, increases the HVA concentration in sera to regulate DA metabolism, and promises to be an alternative medication, safely and effectively. [ABSTRACT FROM AUTHOR]

Rationale: Cognitive dysfunction in schizophrenia has been demonstrated to be dependent, in part, on dopaminergic activity. Clozapine has been found to improve some domains of cognition, including verbal memory, in patients with schizophrenia. Objectives: This study tested the hypothesis that plasma homovanillic acid (pHVA) levels, a peripheral measure of central dopaminergic activity, would predict the change in memory performance in patients with schizophrenia treated with clozapine. Methods: Twenty-seven male patients with schizophrenia received clozapine treatment for 6 weeks. Verbal list learning (VLL)-Delayed Recall (VLL-DR), a test of secondary verbal memory, was administered before and after clozapine treatment. Blood samples to measure pHVA levels were collected at baseline. Results: Baseline pHVA levels were negatively correlated with change in performance on VLL-DR; the lower baseline pHVA level was associated with greater improvement in performance on VLL-DR during treatment with clozapine. Baseline pHVA levels in subjects who showed improvement in verbal memory during clozapine treatment (n=13) were significantly lower than those in subjects whose memory performance did not improve (n=14). Conclusions: The results of this study indicate that baseline pHVA levels predict the ability of clozapine to improve memory performance in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

In laboratory animals, prostaglandins have been shown to act as endogenous neuromodulators of central dopamine (DA) activity. To examine the interaction between prostaglandins and DA in man, the effect of a prostaglandin synthesis inhibitor, indomethacin, was studied on plasma concentrations of the DA metabolite, homovanillic acid (pHVA). Indomethacin (150 mg PO) as compared to placebo significantly elevated mean pHVA concentrations in eight normal subjects. Results of this study support the hypothesis that, as in animals, inhibition of prostaglandin synthesis increases central DA turnover in man. [ABSTRACT FROM AUTHOR]

In the present 6-week double-blind, randomised, multicentre study, the atypical neuroleptic remoxipride was compared to haloperidol in acute schizophrenic patients (DSM-III). Seventy-one patients entered the study, 36 in the remoxipride group and 35 in the haloperidol group. There were ten early withdrawals, four in the remoxipride group and six patients in the haloperidol group. The Present State Examination (PSE) profile revealed a similar reduction in the symptom clusters of psychosis in both treatment groups. Forty-seven per cent of the patients in the remoxipride group and 34% of the patients in the haloperidol group showed clinically relevant improvement (reduction of BPRS total score ≥ 50%). All extrapyramidal symptoms except 'glabella tap' occurred significantly less frequently in the remoxipride group as compared to the haloperidol group. Substantially lower incidences of EPS were found by active questioning in the remoxipride group compared to the haloperidol group. In addition, considerably lower incidences were observed in the remoxipride group with respect to drowsiness/somnolence, tiredness/fatigue and concentrating difficulty. At the end of treatment 66% of the patients in the haloperidol group and 22% in the remoxipride group were using anticholinergics. No consistent changes were found in the mean plasma HVA level in either treatment group. In responders (reduction of BPRS total score ≥ 50%) lower baseline HVA levels were observed in both treatment groups. This study indicates that the newly developed neuroleptic remoxipride is an effective antipsychotic compound, which is clinically safe and well tolerated. In particular, few EPS were induced by remoxipride, as compared to haloperidol. [ABSTRACT FROM AUTHOR]

Recent clinical research suggests that particular patterns of changes in presynaptic dopamine (DA) turnover accompany the therapeutic response to neuroleptics. We sought to determine whether daily versus weekly dosing of haloperidol for 3 weeks produced distinct effects on DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) concentrations in multiple brain areas. Daily dosing favored the development of tolerance to the DA-turnover elevating effects of haloperidol in the striatum and nucleus accumbens. Weekly dosing favored the development of sensitization in the striatum, posterior olfactory tubercle, and ventral tegmental area. These results suggest that dosing schedules may determine, at least in part, the effects of chronic neuroleptic administration on presynaptic DA function. [ABSTRACT FROM AUTHOR]

The concentration of the reversible monoamine oxidase type-A (MAO-A) inhibitor moclobemide (Ro 11-1163) was determined by high pressure liquid chromatography (HPLC) in the plasma of 16 depressives treated with moclobemide. Moreover, the inhibitory potency of organic extracts of the plasma on a standard MAO-A preparation from human placenta was measured spectrophotometrically. The inhibitory potency significantly correlated with the HPLC results. However, it overestimated the concentration of moclobemide by one order of magnitude possibly due to the presence of yet unknown metabolites more active than moclobemide itself. These have already been suggested in view of the higher inhibitory potency of moclobemide ex vivo than in vitro. This new methodological approach might represent a comfortable alternative to HPLC procedures in pharmacokinetic studies on reversible MAO inhibitors. Plasma biogenic amines and their metabolites might be indicative of the biologic activity of moclobemide. Plasma homovanillic acid (HVA) decreased and norepinephrine (NE) increased under moclobemide, although insignificantly. There was no significant correlation between the plasma concentration of moclobemide as estimated by either method and the therapeutic response and the change of plasma HVA and NE. [ABSTRACT FROM AUTHOR]

Striatal homovanillic acid (HVA) levels and drug concentrations in striatum and plasma were examined in guinea pigs after acute and subchronic administrations of haloperidol (HAL) and reduced HAL (RHAL). HVA and drug levels were measured by high performance liquid chromatography with electrochemical detection. HAL and RHAL were interconverted in 10 min. Both maximal HVA responses and peak levels of HAL and RHAL in the striatum were reached at 2 h after injections of both HAL and RHAL. The potency of RHAL in HVA elevation was about one-half that of HAL, consistent with the HAL levels after RHAL and HAL administration. The higher the dose of HAL or RHAL injected, or after repeated injections, the greater the RHAL to HAL ratio produced. In addition, the RHAL to HAL ratios after RHAL were higher than those after HAL. These results suggest that the oxidative drug metabolizing systems are weaker than the reductive processes. [ABSTRACT FROM AUTHOR]

Dose-response curves for the elevation of homovanillic acid (HVA) levels, determined by high performance liquid chromatography using electrochemical detection, in the pre-frontal cortex and caudate of rats after acute treatment with 12 antipsychotic drugs are presented. The order of potency in both brain regions was: haloperidol ≥ fluphenazine > loxapine > trifluoperazine > thiothixene > molindone > clopenthixol > chlorpromazine > metoclopramide > thioridazine > clozapine > sulpiride. This ranking is roughly correlated with that based on clinical potencies. The relative elevation of the content of HVA was weaker in the pre-frontal cortex than in the caudate for all drugs tested, except clozapine at a high dose. [ABSTRACT FROM AUTHOR]

BRL 20596 (N-(4-amino-5-chloro-2-methoxyphenyl)-1-phenylmethyl-4-piperidine-carboxamide) is a novel anilide related to clebopride (a gastric prokinetic benzamide) in which the sole change is reversal of the amide bond. Previous studies have shown conformational and electronic differences between these molecules which result in the anilide losing its gastric prokinetic activity, whilst retaining its central nervous system activity. Pharmacological and biochemical properties of BRL 20596 are compared here in animals with chlorpromazine, clebopride, haloperidol and sulpiride. BRL 20596 potently inhibited a number of behaviours, such as conditioned avoidance, amphetamine-induced stereotypy and turning, and apomorphine-induced climbing. Homovanillic acid (HVA) levels in the striatum and nucleus accumbens were raised at similar dose levels to those which inhibited these behaviours, whilst sedative activity was only exhibited at much higher dose levels. Haemodynamic changes were only observed with high IV doses of BRL 20596. Much lower doses of sulpiride were needed to raise prolactin levels than to raise HVA levels. This was not the case with BRL 20596 and the other drugs, where the doses needed for the two effects were similar. The results suggest that BRL 20596 is a central dopamine antagonist, with low sedative and haemodynamic activity. [ABSTRACT FROM AUTHOR]

A group of 45 male alcoholics were studied during acute withdrawal. Patients were kept in hospital and treated with amobarbital (15 patients), oxazepam (15 patients), and melperone (15 patients) respectively in a double-blind design. Clinical symptoms were rated with a modified version of the Comprehensive Psychopathological Rating Scale after 1, 4 and 7 days. Blood pressure, body temperature and pulse rate were also recorded. Lumbar cerebrospinal fluid was collected after 1 and 7 days. A group of healthy males served as controls. The three treatment groups showed only small differences with regard to the investigated clinical items, except for a higher incidence of epileptic fits being evidenced in the melperone group. Levels of HVA in the cerebrospinal fluid did not differ between the treatment groups and the controls and did not change during treatment. Statistically significant correlations were noted between levels of HVA and auditory and visual hallucinations as well as concentration difficulties. Assuming that HVA levels reflect the activity of the central nervous dopamine system, the findings indicate a connection between central dopamine metabolism, psychotic symptoms and possibly other symptoms during acute alcohol withdrawal in man. [ABSTRACT FROM AUTHOR]

The development of dopaminergic supersensitivity was evaluated, after single oral administration of the long-acting neuroleptic drug isofloxythepin, in nigrostriatal and tuberoinfundibular systems in the rat. Isofloxythepin (5 mg/kg orally) increased concentration homovanillic acid (HVA) in the striatum for up to 24 h after administration, whereas a significant decrease below control values was found after 4-5 days. A similar biphasic effect appeared in behavior, since there was an enhancement of apomorphine stereotypy 4-5 days after administration of isofloxythepin (5 and 10 mg/kg orally). Both findings agree with the hypothesis of development of nigrostriatal dopaminergic supersensitivity at long intervals after isofloxythepin. On the other hand, the increase in prolactin (PRL) secretion induced by isofloxythepin indicated only the blocking action of this drug on dopamine receptors in the tuberoinfundibular system, and provided no evidence for tuberoinfundibular dopaminergic supersensitivity after neuroleptic treatment. It is concluded that a single dose of isofloxythepin is capable of inducing dopaminergic supersensitivity in the nigrostriatal system, but not in the tuberoinfundibular system. [ABSTRACT FROM AUTHOR]

The effects of chronic exposure to imipramine and thyrotropin-releasing hormone, alone and in combination, have been investigated on tyrosine hydroxylase activity as well as on the levels of norepinephrine, dopamine, and their respective metabolites in certain areas of rat brain. Repeated injections of thyrotropinreleasing hormone (20 mg/kg/24h, in two equally divided doses) for 10 days increased catecholamine synthesis and release, as shown by the increased activity of tyrosine hydroxylase and the enhanced levels of metabolites, homovanillic acid, and 4-hydroxy-3-methoxyphenylglycol. Chronic thyrotropin-releasing hormone treatment altered neither the steady state levels of norepinephrine in several brain areas, nor the uptake of H-norepinephrine in a crude synaptosomal (P pellet) fraction. By contrast, daily administration of imipramine (10 mg/kg) for 10 days significantly decreased the uptake of H-norepinephrine in P pellets by 27%. Whereas the levels of brain norepinephrine and dopamine were decreased, the concentrations of homovanillic acid and 4-hydroxy-3-methoxyphenylglycol were elevated after imipramine treatment. Furthermore, chronic imipramine treatment decreased the activity of striatal tyrosine hydroxylase, probably by receptor-mediated negative feedback mechanism. When thyrotropin-releasing hormone was injected concurrently with imipramine (10 mg/kg), this tripeptide significantly potentiated the effects of imipramine on the levels of homovanillic acid and 4-hydroxy-3-methoxyphenylglycol. These findings demonstrate that whereas thyrotropin-releasing hormone elicits its rapid mood-elevating effect probably by increasing the turnover of catecholamines, imipramine acts by blocking their neuronl re-uptake. In addition, our data provide a possible neurochemical basis for the reported potentiation of tricyclic antidepressant action by thyrotropin-releasing hormone in depressed patients. [ABSTRACT FROM AUTHOR]

Concentrations of the major monoamine metabolites homovanillic acid (HVA) 4-hydroxy-3-methoxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in lumbar CSF of psychotic women with a schizophrenic symptomatology before and 4 weeks after treatment with sulpiride (Dogmatil 200 mg×4). The metabolites were determined by a mass fragmentographic method. Prolactin concentrations in CSF and plasma were determined by radioimmunoassay. The clinical effects were evaluated by ratings according to the comprehensive psychopathology rating scale (CPRS) and a scale for side effects. Levels of HVA and prolactin in CSF and plasma were significantly elevated during treatment. No effects on concentrations of MOPEG or 5-HIAA were observed. The biochemical data indicate that clinical doses of sulpiride blocked dopamine receptors in the nigrostriatal pathway as well as in the tuberoinfundibular system. Treatment with sulpiride was associated with marked reductions in psychotic morbidity. [ABSTRACT FROM AUTHOR]

Recent reports have suggested that high doses of propranolol may be an effective treatment in schizophrenia. To determine whether such treatment has effects on cerebrospinal fluid (CSF) amine metabolites and prolactin similar to the effects of the neuroleptic drugs, we studied CSF from ten patients before and after propranolol therapy. The initial CSF sample was removed after a drug-free period and propranolol dosage was then increased over 1 week to 1000 mg daily in all ten patients. A second CSF sample was removed after 3 weeks of propranolol therapy. Propranolol levels and prolactin in CSF were measured by radioimmunoassay. Homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol were measured by gas chromatography-mass spectrometry. Propranolol had no effect on the prolactin or amine metabolite concentrations. CSF propranolol levels averaged 40 ng/ml (range <1-78). [ABSTRACT FROM AUTHOR]

At probenecid levels greater than 10 μg/ml, CSF cAMP was independent of CSF probenecid concentration. At these levels of probenecid, cAMP transport out of CSF is probably maximally blocked and cAMP levels reflect cAMP release into CSF. CSF cAMP was significantly higher in RDC-diagnosed schizophrenics than in other psychotics or depressives. A significant decrease in CSF cAMP was found in psychotic patients treated with chlorpromazine. No changes in CSF cAMP were observed in patients treated with tricyclic antidepressants or lithium. [ABSTRACT FROM AUTHOR]

The influence of neonatal hypothyroidism on norepinephrine and dopamine metabolism in certain discrete regions of rat brain was studied. Intraperitoneal administration of I in a dose of 200 μCi to 1-day-old rats significantly impaired the ontogenesis of spontaneous locomotor activity and reduced tyrosine hydroxylase activity (by 35%) in the striatal region. A parallel decrease in norepinephrine levels was observed in hypothalamus, pons-medulla and striatum. Thyroid deficiency in neonatal life also decreased dopamine levels as well as its metabolite, 3,4-dihydroxyphenylacetic acid, in striatal region. A comparable, but statistically non-significant, change was observed in homovanillic acid as well. Whereas neonatal hypothyroidism decreased monoamine oxidase activity (by 14%) in the hypothalamus, a rise was noted in the mid-brain region. Hypothyroidism in young rats significantly increased catechol-O-methyl transferase activity in brain stem, striatum and mid-brain; however, a 40% decline in O-methylating enzyme was observed in hypothalamus. Data suggest that low levels of norepinephrine, dopamine and their metabolites can be attributed to the decreased synthesis and utilization of these catecholamines in brain. Replacement therapy with L-triiodothyronine (10 μg/100 g, s.c.) for 25 days, beginning 5 days after radiothyroidectomy, enhanced tyrosine hydroxylase activity and raised norepinephrine, dopamine and 3,4-dihydroxyphenylacetic acid levels to virtually normal values. Furthermore, the locomotor activity was significantly increased in hypothyroid rats given L-triiodothyronine treatment in infancy. However, when the initiation of L-triiodothyronine treatment was postponed until adulthood, no significant changes was observed in tyrosine hydroxylase or in norepinephrine and dopamine levels of rat brain. These findings are discussed in relation to the role of catecholamines in depressed behaviour seen during 'cretinoid' syndrome and the importance of thyroid hormone during the critical period of maturation of brain monoaminergic neurons. [ABSTRACT FROM AUTHOR]

The relationship of human brain levels of 3,4-dihydroxyphenylacetic acid (DOPAC) to cerebrospinal fluid levels of this dopamine (DA) metabolite was studied. The effect of postmortem delay was evaluated in the rat. DOPAC was resistant to postmortem changes in brain kept in situ. The level of DOPAC (free and conjugated) determined in DA-rich areas of six human brains amounted to only a fraction of the homovanillic acid (HVA) found in the same regions. The DOPAC/HVA ratio in human brain was similar to that found in CSF. We conclude that HVA is the major DA metabolite in human brain and that DA metabolite levels in CSF reflect DA metabolite levels in brain. [ABSTRACT FROM AUTHOR]

The effects of long-term treatment (36 weeks) with a neuroleptic drug (flupenthixol) were investigated behaviourally and biochemically in rats. Sixteen rats were trained on a DRL (differential reinforcement of low rate) 15-s schedule until stable responding was obtained. During the following 36 weeks 9 rats were injected weekly with flupenthixol dissolved in Viscoleo® [4 mg/kg (i.m.)] and seven rats received Viscoleo® alone. During this perod the animals were not run on the DRL schedule. Retesting on DRL 7 weeks after the last drug injection yielded highly significant differences between the flupenthixol-treated animals and the controls. Thorough neurological examinations of the animals just preceding the retesting period also revealed some deficits in the flupenthixol-treated animals. At sacrifice, 14-18 weeks after the last drug injection, levels of homovanillic acid (HVA) were measured in the corpus striatum and total 3-methoxy-4-hydroxyphenylglycol (MOPEG) in the rest of the forebrain. The results indicate a nonsignificant increase of 25% in the dopamine metabolite HVA, while the noradrenergic metabolite MOPEG was significantly decreased by 14% in experimental animals. The possibility of persistent functional and biochemical effects produced by prolonged treatment with a neuroleptic drug is highlighted in the results presented here. [ABSTRACT FROM AUTHOR]

Chlorpromazine (CPZ), demethylated(nor)-CPZ, 7-hydroxy(7-OH)-CPZ, and CPZ-nitrogenoxide-(NO) were administered to rats. Levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MOPEG) in the brain and prolactin in serum were determined. The HVA increase calculated per nmole unchanged drug in brain was about the same in the CPZ and 7-OH-CPZ groups, but nor-CPZ was less than 50% as effective in this respect. When CPZ-NO was administered, high amounts of CPZ and nor-CPZ were formed. The amounts of these products could fully explain the HVA elevation induced by CPZ-NO. The HVA levels were significantly correlated to the amount of the respective drug in the brain. After CPZ and 7-OH-CPZ the levels of unchanged drug in serum were about 3% of the brain level, while the drug serum/brain ratio was significantly lower in the nor-CPZ-treated group. The prolactin level in serum was raised to about 200% of control 90 min after all drugs were administered. This may be explained by assuming a supramaximal stimulation of the prolactin release mechanism already being achieved at low drug levels in the brain. At 7.5 mg/kg none of the drugs affected the levels of MOPEG or 5-HIAA. After high doses of CPZ the level of MOPEG in the brain was increased. [ABSTRACT FROM AUTHOR]

N,N-dimethyltryptamine (DMT) is a psychotomimetic indolealkylamine that has been suspected of being an endogenous causal factor in the aetiology of schizophrenia. Some aspects of its interaction with the dopaminergic system of the rat brain have been studied neurochemically, and comparisons have been made with the effects of d-amphetamine and apomorphine. In contrast to these two compounds, DMT has proved to be a potent, but short-acting MAO inhibitor with a rather selective effect on MAO A (serotonin-deaminating MAO). Like classical MAO inhibitors, DMT also greatly increases the accumulation of H-dopamine plus H-3-methoxytyramine newly formed from H-Dopa. Amphetamine and apomorphine have no comparable effect. Striatal levels of 3,4-dihydroxyphenylacetic acid are more efficiently lowered by DMT than those of homovanillic acid. the reverse has been observed with apomorphine, whereas amphetamine increases the concentrations of homovanillic acid and decreases those of 3,4-dihydroxyphenylacetic acid. Thus, in addition to its MAO inhibitory action, DMT probably also possesses dopamine-releasing effects. Both these properties could result in an indirect dopaminomimetic activity of DMT. It may be assumed, therefore, that the psychotomimetic activity of this compound is not noly linked to its effects on cerebral serotonergic mechanisms, but to a combination of these with an indirect dopaminergic stimulant activity. [ABSTRACT FROM AUTHOR]

The location of probenecid-sensitive elimination mechanisms of monoamine metabolites from the cerebrospinal fluid of the cat was determined with ventriculo-cisternal or ventriculo-lumbar perfusion techniques. These techniques were described in detail. Levels of endogenous homovanillic acid and 5-hydroxyindoleacetic acid were assayed in the perfusate. Probenecid administration induced the most marked increase of the levels of the monoamine metabolites in the ventriculo-lumbar perfusates. It was concluded that probenecid blocked the transport of both metabolites from the spinal subarachnoid space. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Probenecid retards the efflux of acid monoamine metabolites from the brain tissue and CSF to the blood. The probenecid-induced accumulation of these metabolites is held to be indicative of the turnover rate of the corresponding amines. Although the penetration of probenecid into the CSF does not proceed at a constant rate, Korf et al. (1972) and Sjöstrom (1972) have shown a correlation between CSF levels of probenecid and that of HVA and 5-HIAA. In this study an attempt was made to establish the relationship between doses of probenecid and levels of this compound in plasma and CSF; between levels in plasma and CSF; and between CSF levels of probenecid and of HVA and 5-HIAA. This study was performed in a homogeneous group of laboratory rabbits. All correlations proved to be significant. The implications of these results for studies using the probenecid technique are discussed. [ABSTRACT FROM AUTHOR]

The acid metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) by a new procedure. After gas Chromatographic separation, the pentafluoropropionyl 2,2,3,3,3-pentafluoro-1-propionyl esters of DOPAC and HVA were analyzed by electron capture detection. Normal HVA levels were quantitated in as little as 0.1 ml CSF. No significant amounts of DOPAC (< 1 ng/ml) were found in any of the drug-free samples analyzed. Levels of DOPAC increased only marginally in the CSF of patients receiving acute or chronic doses of lDopa. Baseline HVA levels ranged from 4.5-50 ng/ml with a mean value of 23 ng/ml. These studies demonstrate that HVA is the major dopamine metabolite in human CSF. [ABSTRACT FROM AUTHOR]

The present study has compared the abilities of clozapine, haloperidol, chlorpromazine and loxapine to induce dopamine (DA)-receptor hypersensitivity in rats, as measured by the apomorphine response after withdrawal of the antipsychotic drugs. Haloperidol, chlorpromazine and loxapine, but not clozapine, potentiated the apomorphine response during 1-2 weeks after withdrawal. Clozapine, given prior to apomorphine, reduced the responses of the haloperidol and loxapine groups to the control level. The effects of haloperidol and clozapine were quantified in rats with unilateral striatal lesions. Biochemical investigations showed that tolerance developed to the increase in striatal homovanillic acid (HVA) after chronic treatment with haloperidol, chlorpromazine and loxapine, whereas clozapine (20 mg/kg p.o.) failed to affect the HVA content, and no tolerance developed to the increase seen at 80 mg/kg. Cross-tolerance to the rise in HVA was seen with haloperidol, chlorpromazine and loxapine, but chronic pretreatment with clozapine failed to affect the rise in HVA induced by a single dose of the former compounds. On the basis of these results, it is predicted that tardive dyskinesias are unlikely to develop after this drug, and that clozapine may attenuate or abolish neuroleptic-induced tardive dyskinesias. [ABSTRACT FROM AUTHOR]

8 male schizophrenic patients participated in a double-blind, cross over study of the extrapyramidal side-effects of haloperidol and clozapine (acute dystonia, Parkinsonism and tardive dyskinesia), together with their effect on homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Haloperidol (9 mg/day) caused Parkinsonism, reduced tardive dyskinesias and increased the HVA concentration in the CSF. Clozapine (225 mg/day) had no effect on the neurological phenomena but reduced HVA and 5-HIAA concentrations in the CSF. During the discontinuation phase following the administration of haloperidol, tardive dyskinesia occurred or was aggravated; this did not occur after administration of clozapine. Accordingly, it is suggested that clozapine does not induce dopaminergic hypersensibility and, therefore, will not induce tardive dyskinesias. [ABSTRACT FROM AUTHOR]

The preparation and use of HVA-d for the mass fragmentographic determination of HVA levels in the CSF was described. Following extraction and synthesis of the methyl ester heptafluorobutyryl derivatives samples were injected into a combined gas chromatograph-mass spectrometer connected to a multiple ion detector. The two fragments set into focus were the molecular ions of authentic HVA and HVA-d respectively. The experimental error was less than 4%. The recovery of small amounts of authentic HVA added to CSF was satisfactory. Multiple ion determination using two sets of fragments gave similar results demonstrating high specificity and reproducibility of the method used. The mass spectral characteristics of the methyl ester heptafluorobutyryl derivative of ISO-HVA suggested that this compound could be differentiated from HVA by mass fragmentography. Thus the base peak did not constitute the molecular ion in the spectrum of the ISO-HVA-derivative as it is for the derivative of HVA. Multiple ion analysis of CSF before and after the addition of ISO-HVA failed to supply positive evidence for the presence of ISO-HVA in CSF in neurological or schizophrenic patients. [ABSTRACT FROM AUTHOR]

A mass fragmentometric method was used for determination of homovanillic acid levels in cerebrospinal fluid of acutely admitted schizophrenic patients. Spinal puncture was performed before and 12 days following the beginning of chlorpromazine treatment (200-600 mg/day). The level of homovanillic acid in cerebrospinal fluid before treatment was significantly higher in women than in men. Chlorpromazine treatment resulted on the average in a more than 2-fold elevation of the homovanillic acid level in cerebrospinal fluid. There were marked individual differences in the effect. The results are compatible with the view that therapeutic doses of chlorpromazine accelerate brain dopamine synthesis in man. A close analysis of the relation between effects of chlorpromazine on brain dopamine synthesis and psychotic and motor behaviour in schizophrenic patients seems required. [ABSTRACT FROM AUTHOR]

Lumbar CSF 5 HIAA and HVA were measured following probenecid administration in acute psychotic patients before and during treatment with phenothiazines. Patients with more classical schizophrenic symptoms had higher values for 5 HIAA/HVA than other psychotics, depressives, and inmate volunteers. Prior to treatment CSF 5 HIAA, but not HVA, correlated significantly with several clinical items related to psychotic disorganization. Phenothiazine treatment produced significant increases in CSF HVA which could not be correlated with the dose of antipsychotic or antiparkinson drugs. [ABSTRACT FROM AUTHOR]

Our preliminary observations on the relationship of sleep and lumbar CSF acid monoamine metabolite levels suggested a greater decrease in lumbar CSF HVA as compared to 5HIAA following clinical doses of phenelzine in the presence of virtually total REM suppression. This report on nine psychiatric patients confirms these findings in a larger sample and thus supports an inhibitory role for dopamine or other catecholamines in REM sleep mechanisms. The drug-withdrawal results indicate that the four patients with REM rebound showed increases in HVA levels compared to treatment levels, while the single patient with no REM rebound also had no increase in HVA levels. [ABSTRACT FROM AUTHOR]

Lumbar cerebrospinal fluid 5-HIAA, HVA, and the ratio 5-HIAA/HVA were measured followed probenecid administration in eleven patints with unipolar depression before and during treatment with amitriptyline (AMI). Control values were obtained from a group of inmate volunteers. Prior to treatment CSF 5HIAA formation in the depressives was not different from controls. During treatment with AMI, CSF 5-HIAA formation decreased. One patient with psychotic symptoms prior to AMI and two patients who developed psychotic reactions on AMI showed relatively low CSF 5HIAA formation prior to antidepressant therapy. Compared to controls CSF HVA values were higher in the depressives prior to AMI therapy. [ABSTRACT FROM AUTHOR]

A single electroshock stimulation (EST) by means of a conventional clinical EST apparatus was administered to 40 rats. Ten minutes after the start of general convulsions the animals were sacrificed. Corpus striatum was analyzed for dopamine (DA) and homovanillic acid (HVA). A statistically not significant increase of DA and a highly significant increase of HVA was noted in the EST group compared to the control animals. The data indicate an acceleration of the DA synthesis induced by EST. The results are discussed in relation to the action of antidepressive drugs on the monoaminergic neurons and a supposed biochemical correlate of endogenous depression. [ABSTRACT FROM AUTHOR]

Phencyclidine combined with footshock stress produced a greater increase in the homovanillic acid content of prefrontal cortex than either phencyclidine or footshock alone. Phencyclidine decreased both substance P and substance K in the ventral tegmental area. The results suggest that phencyclidine and footshock activate forebrain dopaminergic systems in part by separate mechanisms. [ABSTRACT FROM AUTHOR]

Homovanillic acid (HVA) was measured in rat caudate and pre-frontal cortex after single and repeated doses of several types of neuroleptic drugs. Twice daily administration of low or high doses of haloperidol, fluphenazine, or (-) sulpiride resulted in greater tolerance to the initial HVA increase in caudate compared to prefrontal cortex. [ABSTRACT FROM AUTHOR]

Dopamine (DA), homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), noradrenaline (NA), and 5-hydroxyindolacetic acid (5HIAA) were measured in cerebrospinal fluid (CSF) of 15 chronic schizophrenic patients before and 2 weeks after withdrawal of long-term neuroleptic treatment. Total neuroleptic-like activity in serum (NLA) was determined at the same times. Levels of DA and its metabolites (DOPAC and HVA) and NA were significantly reduced after the discontinuation of neuroleptic treatment. No change was observed in 5HIAA values. NLA was substantially reduced, but still remained detectable. The decrease in DA, DOPAC, and HVA all showed positive correlations with each other, and correlated negatively with NLA measured after 2 weeks. Our data implies that the decrease in DA turnover is the result of the discontinuance of DA receptor blockade, while the change in NA level is independent of it. [ABSTRACT FROM AUTHOR]

Eleven psychotic patients treated with neuroleptics for 1 month showed a relatively poor response, more side effects, and a no-tolerance pattern with respect to cerebrospinal fluid (CSF) homovanillic acid (HVA). Within this group the severity of neuroleptic catatonia and Parkinsonian side effects was positively associated with an increase in CSF HVA turnover during the treatment period. [ABSTRACT FROM AUTHOR]