Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.

Relationships between Cloninger's temperament and character dimensions and plasma sex hormone levels and biogenic amine turnover were studied in male prison inmates convicted of rape (n=61) or child molestation (n=24) and normal male controls (n=25). The participants completed the Temperament and Character Inventory (TCI), which includes the temperament dimensions Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence as well as the character dimensions Self-Directedness, Cooperativeness and Self-Transcendence. Plasma levels of testosterone, dihydrotestosterone, sex hormone binding globulin, luteinizing hormone (LH) and follicle-stimulating hormone were estimated in plasma samples and 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine samples. Both sex offender groups had higher Novelty, Seeking and lower Reward Dependence, Self-Directedness and Cooperativeness scores compared with the controls. Plasma levels of testosterone and dihydrotestosterone were significantly higher in rapists than in controls. Novelty Seeking scores were positively correlated with LH levels in rapists, and with testosterone levels in child molesters. Harm Avoidance scores were negatively correlated with 5-HIAA levels in rapists and with HVA levels in child molesters. In rapists, the calculated free androgen index showed a negative correlation with 5-HIAA. For the sex offender sample as a whole, the subgroup with high testosterone levels had higher Harm Avoidance scores, the subgroup with low HVA levels had lower Cooperativeness scores, and the subgroups with high 5HIAA or MHPG levels had lower Persistence scores. The results indicate that Novelty Seeking behavior in the group of rapists is associated with a hyperactive hypothalamic-pituitary-gonadal axis. In addition, low serotonin turnover and low dopamine turnover seem to be associated with a passive-avoidant behavioral style in rapists and child molesters, respectively.

The effects of four logarithmically increasing doses of intravenous diazepam or placebo on plasma homovanillic acid (HVA) were determined in benzodiazepine-naive patients with panic disorder (PD) or generalized anxiety disorder (GAD), and in healthy controls. Plasma HVA was measured at baseline and 3 min after the first and fourth doses of diazepam/placebo. Mean baseline plasma HVA levels were significantly lower in PD patients compared with GAD patients and controls. Although plasma HVA levels decreased significantly with time in all groups, there was no diazepam effect. This study suggests that low dopaminergic activity may occur in a subset of anxious patients (PD), and that diazepam does not significantly affect dopaminergic activity as measured by plasma HVA in humans.

Plasma homovanillic acid (pHVA) levels were measured and the Brief Psychiatric Rating Scale (BPRS) scores were evaluated in 26 schizophrenic patients who had either never been medicated (neuroleptic-naive, first-episode subjects) or whose condition had become exacerbated following neuroleptic discontinuance (exacerbated subjects). All the subjects received medication with a fixed dose of a neuroleptic (haloperidol or fluphenazine, both 9 mg/day) for the first week and variable doses for the subsequent 4 weeks. In the neuroleptic-naive subjects, pHVA levels increased significantly 1 week after starting the protocol; this increase correlated significantly with clinical improvement of the BPRS positive symptom scores at week 5. In the neuroleptic-naive subjects, pHVA levels had declined to the baseline level by week 5. In the exacerbated subjects, there were no significant correlations between pHVA level changes at week 1 and later improvements of the BPRS positive symptom scores. These results suggest that the rise in pHVA levels occurring within 1 week after starting a fixed neuroleptic dose may predict a favorable clinical response in neuroleptic-naive schizophrenic patients.

The objective of this study was to obtain direct neurochemical measures of the central nervous system's response to a typical neuroleptic, haloperidol, in human subjects. Nine healthy volunteers participated in this study. Central nervous system neuronal activity was assessed by measuring the plasma concentration and overflow from the brain of dopamine, norepinephrine, and their lipophilic and acidic metabolites after acute intravenous administration of haloperidol. By combining bilateral internal jugular vein blood sampling with cerebral blood flow scans we were able to differentiate between cortical and subcortical responses to haloperidol. The central nervous system response to haloperidol administration displayed a degree of regional specificity. Dopamine release, estimated from the overflow of homovanillic and dihydroxyphenylacetic acids, was reduced in cortical but not subcortical brain regions. Norepinephrine turnover was increased in cortical and subcortical brain regions. The overflow of homovanillic acid from the brain into the internal jugular veins was not related quantitatively to the arterial plasma concentrations of the catecholamines examined, homovanillic and dihydroxyphenylacetic acids or prolactin. Measurements of catecholamines and their metabolites in arterial plasma gave little indication as to monoaminergic neuronal activity in the brain.

Peripheral plasma levels of homovanillic acid (HVA), the deaminated and o-methylated metabolite of dopamine, are often used as an indicator of central nervous system dopaminergic activity. Using percutaneously placed catheters, we studied the regional inputs into the plasma HVA pool in 60 healthy volunteers. Veno-arterial differences and organ plasma flows were used to quantify the relative amounts of HVA contributed by various sites into the peripheral circulation. Positive arterio-venous HVA gradients were found in the pulmonary, hepatosplanchnic, skeletal muscle and jugular vessels of the normal volunteers. No HVA increment was found in the coronary sinus. The renal circulation was determined to be the principal site of HVA clearance, extracting 27 nmol/min. The regional contributions of HVA were as follows: lungs 21 nmol/min, hepatosplanchnic organs 3 nmol/min, skeletal muscle 3 nmol/min and the brain 4 nmol/min. The pattern of regional HVA production contrasted with that of the deaminated dopamine metabolite, dihydroxyphenylacetic acid, for which the heart was the principal site of production identified. Sixteen patients with chronic congestive heart failure (CHF) and 6 patients with pure autonomic failure (PAF) were also studied to investigate possible effects of sympathetic nervous system overactivity and underactivity on peripheral HVA production and plasma HVA concentration. The resting arterial plasma HVA concentration in CHF was increased approximately 3-fold. Unexpectedly, this was attributable to reduced HVA plasma clearance, not increased HVA production. Total HVA production in PAF was diminished by 40%. PAF patients had normal resting arterial HVA levels, this being accounted for by a 57% fall in the renal plasma clearance of HVA. Acute sympathetic nervous system activation in response to bicycle riding was accompanied by a 34% increase in the arterial concentration of HVA. It can be concluded that HVA is produced at a number of sites throughout the body not renowned for their dopaminergic innervation. Regional HVA production is associated, in part, with the metabolism of precursor dopamine in sympathetic nerves and at a rate which appears to be influenced by sympathetic nervous activity. To obtain an accurate indication of central dopaminergic activity the confounding influences of HVA plasma clearance and peripheral HVA production must be excluded.

This preliminary study investigated dopamine (DA) function in six hospitalized cocaine-dependent subjects (DSM-III-R) who received 1.5 mg/kg of active cocaine by mouth, t.i.d., for 3 days followed by 9 days of placebo cocaine. During early and late abstinence from cocaine, plasma growth hormone (GH), homovanillic acid (HVA), prolactin, and 3-methoxy-4-hydroxyphenethyleneglycol responses to the placebo-controlled administration of oral L-dopa 250 mg/carbidopa 25 mg (Sinemet) were measured. Sinemet caused significantly greater placebo-corrected increases in GH and HVA during early as compared with late abstinence. Acute abstinence from cocaine may be associated with increased DA responsivity, which normalizes over time.

Levels of dopamine (DA) and its derivatives homovanillic acid (HVA), 3-4 dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3MT) and norepinephrine+epinephrine (NE + E), and serotonin (5HT) and its derivative 5-hydroxyindolacetic acid (5HIAA) were determined from the urine of 156 autistic children aged two to 12 years 6 months, and compared with those of age-matched mentally retarded non-autistic and normal controls. Very significant group and age effects were found for DA, HVA, 3MT, NE + E and 5HT. High HVA, 3MT, NE + E and 5HT levels were found in autistic and non-autistic children. The DA, HVA, 3MT, NE + E, 5HT and 5HIAA levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol, compared with non-medicated autistic children. The results are discussed in relation to the hypothesis of a maturation defect of monoaminergic systems in autism.

Dopamine (DA) and its metabolites homovanillic acid (HVA) in total, free and conjugated forms, dihydroxyphenylacetic acid (DOPAC) in total, free and conjugated forms, and 3 methoxytyramine (3 MT) levels were determined in the urine of autistic children from 2 years 8 months to 12 years of age and compared to those in normal children of identical age. Very significant group and age effects were found for DA, HVA and 3 MT. In the discussion, results are related to the hypothesis of a disorder in the maturation of the dopaminergic systems in infantile autism.

Alprazolam has been suggested as an adjuvant to neuroleptic drugs in the treatment of schizophrenic patients. In an attempt to investigate whether alprazolam has an effect on dopaminergic neurotransmission, plasma homovanillic acid concentrations were measured for 24 h following a challenge with 3 mg of alprazolam or placebo in eight healthy subjects. Alprazolam had no effect on plasma homovanillic acid which may suggest that this agent is devoid of activity at the dopaminergic system in normal subjects.

The plasma concentration of the dopamine (DA) metabolite, homovanillic acid (HVA), is used as an indicator of central nervous system dopaminergic activity. Using percutaneously inserted catheters we were able to obtain blood samples simultaneously from the right and left internal jugular veins. Veno-arterial HVA plasma concentration differences combined with adjusted organ plasma flows were used, according to the Fick Principle, to determine the HVA overflow from the brain. The HVA overflow from the liver was also measured. HVA overflow from the brain represented 12% of the total body HVA production. A similar amount was released from the liver, illustrating the limited validity of peripheral plasma HVA measurements as an indicator of central dopaminergic activity. HVA release from the human brain displayed a degree of asymmetry, the overflow into the left internal jugular vein being 36% greater than that into the right. Cerebral venous blood flow scans indicated that cortical cerebral regions drained preferentially into the right internal jugular; by inference the higher HVA overflow on the left originated from dopamine-rich subcortical brain areas. Since HVA in plasma may arise from the metabolism of DA existing either as a neurotransmitter or a norepinephrine (NE) precursor we measured the internal jugular vein plasma concentrations of NE, and its metabolite dihydroxyphenylglycol (DHPG), to determine whether they displayed a similar pattern of release to HVA. The overflow of both NE and DHPG into the right internal jugular vein was approximately double that on the left. Since the overflow of HVA did not parallel that of NE and DHPG it may be inferred that the origin of much of the subcortically produced HVA is from dopaminergic neurons and not from the metabolism of precursor DA in noradrenergic neurones or cerebrovascular sympathetic nerves.

1. Several lines of evidence suggest that abnormalities of central dopaminergic transmission may be involved in the expression of some schizophrenic symptoms. However, elucidation of the role of dopamine (DA) in schizophrenia has eluded investigative efforts partially because no accurate and easily repeatable measure of brain DA activity exists. 2. The development of a technique to measure homovanillic acid in plasma has offered the possibility of performing serial measurements of this major DA metabolite. 3. Assuming that plasma homovanillic acid (PHVA) concentrations is an index of brain DA activity, measurement of PHVA can play a role in elucidating the DA abnormality in schizophrenia. 4. Results to date suggest that plasma homovanillic acid concentrations are lower in chronic schizophrenic patients compared to normal controls, and that PHVA values correlate with schizophrenic symptom severity. 5. In addition, PHVA levels were shown to initially rise and subsequently decline during chronic neuroleptic administration in treatment responsive but not in treatment refractory schizophrenic patients.

Major and minor pathways of metabolism in the mammalian CNS result in the formation of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NMN) from norepinephrine (NE), and homovanillic acid (HVA) and 3-methoxytyramine (3-MT) from dopamine (DA), respectively. The correlational relationships between HVA and 3-MT and between MHPG and NMN in primate CSF and plasma have not been described. These relationships may help to elucidate the usefulness of CSF and plasma metabolites as indices of CNS NE and DA activity. In addition, because NMN is unlikely to cross the blood-brain barrier. CSF NMN concentrations would not be confounded by contributions from plasma, which is a major issue with CSF MHPG. We have obtained repeated samples of plasma and CSF from drug-naive male squirrel monkeys and have measured the concentrations of MHPG, HVA, NMN, and 3-MT to define their correlational relationships. For the NE metabolites, significant correlations were obtained for CSF MHPG and NMN (r = 0.806, p less than 0.001), plasma MHPG and CSF NMN (r = 0.753, p less than 0.001), and plasma and CSF MHPG (r = 0.776, p less than 0.001). These results suggest that CSF and plasma MHPG and CSF NMN may reflect gross changes in whole brain steady-state noradrenergic metabolism. Only a single significant relationship was demonstrated for the DA metabolites, with CSF 3-MT correlating with plasma HVA (r = 0.301, p less than 0.025). The results for the DA metabolites probably reflect regional differences in steady-state brain dopaminergic metabolism.

As some of the pharmacological activities of neuroleptic medication may involve pathophysiological mechanisms underlying schizophrenia and tardive dyskinesia (TD), it is useful to study patients undergoing medication discontinuation. In this study, 19 stable, neuroleptic-maintained patients with persistent TD underwent taper and discontinuation of their neuroleptic medication over a 3-week period, and multiple behavioral and biochemical (plasma HVA, MHPG, and prolactin) measures were obtained. The major finding was that early relapsing patients had lower baseline and a significantly greater increase in plasma HVA levels after discontinuation than nonrelapsing patients. In addition, patients exhibiting withdrawal-exacerbated TD had significantly lower plasma MHPG levels than patients not exhibiting this phenomenon. The clinical and pharmacological implications of these findings are discussed.

Plasma and cerebrospinal fluid (CSF) levels of the major dopamine metabolite homovanillic acid (HVA) were measured in psychiatric patients after an average washout period of 19 days, and again after 4 weeks of pharmacological treatment. Absolute values of plasma HVA did not correlate with absolute values of CSF HVA either at baseline or after treatment. However, changes in plasma HVA were highly correlated with changes in CSF HVA. Further, while baseline levels of plasma and CSF HVA were not significantly correlated with baseline clinical measures, clinical improvement was associated with decreases in both plasma and CSF HVA. This reached statistical significance for the plasma HVA level/clinical response relationship.

Urinary catecholamines (DA, NE, E) and their main metabolites (HVA, DOPAC, MHPG) were analyzed both as free and conjugates in eight children diagnosed as autistic according to DSM-III criteria and eight normal children. Significant differences appeared for the urinary excretion of both DA and NE and their respective metabolites: Autistic children showed low DA, high HVA, high NE, low MHPG urinary levels. These results are consistent with previous findings on altered catecholamine metabolism in autistic children. They suggest that autistic behaviors might be related to an abnormal functional imbalance among monoamines either at a molecular level or at a system level. Furthermore, they emphasize the special interest of urinary assays in pediatric research.

1. Dopaminergic neurotransmission in brain is receiving increased attention because of its known involvement in Parkinson's disease and new methods for the treatment of this disorder and because of hypotheses relating several psychiatric disorders to abnormalities in brain dopaminergic systems. 2. Chemical assessment of brain dopamine metabolism has been attempted by measuring levels of its major metabolite, homovanillic acid (HVA), in cerebrospinal fluid, plasma, or urine. Because HVA is derived in part from dopamine formed in noradrenergic neurons, plasma levels and urinary excretion rates of HVA do not adequately reflect solely metabolism of brain dopamine. 3. Using debrisoquin, the peripheral contributions of HVA to plasma or urinary HVA can be diminished, but the extent of residual HVA formation in noradrenergic neurons is unknown. By measuring the levels of methoxy-hydroxyphenylglycol (MHPG) in plasma or of urinary norepinephrine metabolites (total MHPG in monkeys; the sum of total MHPG and vanillyl mandelic acid (VMA) in humans) along with HVA, it is possible to estimate the degree of impairment by debrisoquin of HVA formation from noradrenergic neuronal dopamine and thereby better assess brain dopamine metabolism. 4. This method was applied to a monkey before and after destruction of the nigrostriatal pathway by the administration of MPTP.

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma dopamine-beta-hydroxylase (DBH) activity, and platelet monoamine oxidase (MAO) were obtained in 42 boys (7-14 years old) consecutively evaluated at a community mental health clinic. The boys were diagnosed according to DSM-III criteria by a child psychiatrist using a semistructured interview with the parent and child. The Revised Behavior Problem Checklist (RBPC) and the Revised Children's Manifest Anxiety Scale (RCMAS) were consecutively obtained on the last 24 subjects. No relationship of any of the plasma measures was found with respect to the DSM-III diagnoses. Plasma MHPG was positively correlated with the parent's rating of the child's anxiety on the Anxiety-Withdrawal factor of the RBPC. Plasma MHPG as well as platelet MAO activity, correlated positively with the child's self-rating of anxiety on the RCMAS. Children classified by the RBPC as having high conduct symptoms and low anxiety symptoms had significantly lower plasma MHPG than those subjects with low conduct problems and high anxiety. Platelet MAO activity was found to be negatively correlated to the child's score on the Lie Scale of the RCMAS.

During debrisoquin administration to three monkeys there were significant reductions in excretion rates of HVA, the major dopamine metabolite, and MHPG, the major norepinephrine metabolite. Excretion rates of HVA were highly correlated to those of MHPG. The regression line relating HVA and MHPG excretion suggests that a portion of HVA (about 25%) is derived from a source independent of norepinephrine metabolites. There was a striking reduction of this portion of HVA excretion after MPTP-induced destruction of dopaminergic nigrostriatal neurons. These results support the view that the rate of HVA formation in brain dopaminergic neurons can be estimated from the relationship of urinary excretion rates of HVA and MHPG before and during debrisoquin treatment.

Patients with neurogenic orthostatic hypotension due to multiple system atrophy (MSA) or pure autonomic failure (PAF) excrete lower amounts of homovanillic acid (HVA) than do normal subjects. There is a highly significant correlation between the rates of excretion of HVA and norepinephrine metabolites. The regression line relating excretion of the dopamine and norepinephrine metabolites suggests that about one third of dopamine formed in noradrenergic neurons is converted to norepinephrine and the remainder metabolized, mainly to HVA. About one fourth of urinary HVA appears to be derived from a source independent of norepinephrine; this source is probably brain dopaminergic neurons.

Prior studies have shown that homovanillic acid is the principal metabolite of dopamine in the primate central nervous system (CNS). In studies of primates given deuterated homovanillic acid systemically, however, only 50% of the administered amounts have been recovered in the urine over the next 4-48 hr. These findings have left it unclear whether there is a slowly turning-over compartment of homovanillic acid, conversion of homovanillic acid to another compound, or excretion of homovanillic acid from the body by a nonrenal route. We synthesized [3H]homovanillic acid and administered it intravenously to four rhesus monkeys. Over the subsequent 4 hr, 94.9 +/- 8.9% (SD) of the administered radioactivity was recovered in the urine, almost entirely as homovanillic acid. These results are consistent with the interpretation that, in primates, there is not a major body pool of homovanillic acid with slow turnover, nor is metabolism to other compounds significant, nor is there evidence for nonrenal excretion.

Within- and across-day stability of plasma-free homovanillic acid (pHVA) was assessed in children and adults with Tourette's syndrome. A diurnal fall in pHVA was observed in 13 of 15 subjects. There was a small but significant (p less than .0001) decrease (8%) in mean morning pHVA levels obtained just 20 minutes apart (8:30 A.M. and 8:50 A.M.). A substantial and significant (p less than .001) mean decrease in pHVA (25%) was observed when samples obtained between 8:00 and 8:30 A.M. were compared with samples obtained at 12:00 noon. Changes in pHVA levels observed during the afternoon (between 12:00 noon and 4:00 P.M.) were small, nondirectional, and nonsignificant. Repeated measurement of morning pHVA in the same individual after 24 or more hours revealed marked increases or decreases in many individuals, suggesting that morning pHVA is not a stable measure. The results of this and previous studies suggest that pHVA obtained at 12:00 noon or later in the day may be a more reliable measure of centrally produced HVA. Further studies are needed regarding the stability of pHVA over time.

In 16 patients with chronic schizophrenia, cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) showed a significant negative correlation with computed tomographic measures of brain third ventricle size. Clinical state during a drug-free period was also significantly correlated with CSF HVA level, but not with third ventricle size when the effect of CSF HVA was partialed out. The authors propose that these findings may reflect an atrophic process involving structures around the third ventricle and a decrease in dopaminergic activity.

Central dopaminergic (DA) function in children was assessed by monitoring plasma-free homovanillic acid (pHVA) levels after brief (18 hour) administration with debrisoquin sulfate, a peripherally active antihypertensive agent that blocks peripheral, but not central, HVA production. Brief debrisoquin administration resulted in marked reductions in pHVA in each of six patients studied. In five of the six patients, post-debrisoquin pHVA levels remained relatively stable over the six-hour period of observation. No significant cardiovascular or behavioral side effects of debrisoquin were observed. The brief debrisoquin administration method appears to be a safe, simple, and potentially valid peripheral technique for evaluating aspects of central dopaminergic function in children with neuropsychiatric disorders. Additional work is needed to further establish this method's validity and reliability.

Central dopaminergic (DA) function in children and adults was assessed by monitoring plasma-free levels of the dopamine metabolite homovanillic acid (pHVA) before and after a single oral dose and chronic oral administration of debrisoquin. Debrisoquin inhibits peripheral metabolism of dopamine to HVA and does not cross the blood-brain barrier. By reducing peripheral formation of HVA through the use of debrisoquin, the remaining HVA in plasma more accurately reflects central DA activity. Debrisoquin administration resulted in marked reductions of pHVA in each of 12 patients studied. Eleven of the 12 subjects tolerated debrisoquin without physical or behavioral side effects. The debrisoquin administration method appears to be a safe and potentially valid technique for evaluating aspects of central dopaminergic function in children and adults.

Data from animal studies indicate neuroleptic drugs act via their properties as antagonists of CNS dopamine (DA) receptors and this finding has led to the suggestion that alterations in CNS DA neuronal function are associated with psychotic disorders. Clinical investigations of this hypothesis, however, have been hindered by the lack of the availability of a direct and relatively easily obtained index of CNS DA neuronal activity. The work reported here was aimed at the development of such an index. Using a double blind design, human male subjects were given either placebo or debrisoquin, which is a monoamine oxidase inhibitor which does not penetrate brain. On the baseline day (no debrisoquin) and after 6 and 13 days of drug administration blood samples were obtained. In addition, for some patients CSF specimens were obtained via lumbar puncture on the baseline day and after 13 days of drug administration. It was found that debrisoquin produced a highly significant decrease in plasma homovanillic acid (HVA) concentrations whereas the concentrations of HVA in CSF were unchanged. In addition, it was found that the correlation between CSF and plasma HVA prior to debrisoquin was non-significant (r = 0.39, p = N.S., N = 10) whereas after 13 days of debrisoquin treatment the correlation was highly significant (r = 0.95, p less than .01, N = 7). These findings suggest that the administration of debrisoquin produces a situation in which plasma HVA reflects CNS HVA production, and as such debrisoquin may be a useful tool for the clinical investigator who is interested in studying relationships in human subjects between CNS DA neuronal system function and psychopathological states or other disorders which may be mediated via brain DA systems.

Concentrations of plasma homovanillic acid before treatment were highly correlated with global severity of illness in schizophrenic patients, both before and after treatment. In contrast, a fixed dose of haloperidol did not affect those concentrations. Thus, in patients with a diagnosis of schizophrenia, plasma homovanillic acid may reflect the severity of illness, but not be influenced by short-term pharmacological perturbations by neuroleptics.

The effect of a single oral gavage with a mixture of Aroclors 1254 and 1260 on 24-h production of urinary homovanillic acid was determined in the laboratory rat. Adult male Wistar-derived rats were exposed to a single dose of corn oil, either alone or containing equal amounts of Aroclors 1254 and 1260 at a dosage of 500 or 1000 mg/kg. Urinary homovanillic acid concentrations were determined by high-performance liquid chromatography with electrochemical detection. The 500-mg/kg group showed a transient increase in homovanillic acid production, while the 1000-mg/kg group showed a biphasic response-an initial decrease (due to decreased food consumption) followed by a prolonged elevation. Only transient changes in body weight, food and water consumption, and urine output were observed. The results demonstrate that peripheral measurement of a dopamine metabolite may provide a means of monitoring changes in an important neurotransmitter system after exposure to a putative neurotoxin.

The concentrations of free and sulfated 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in rat plasma to investigate their potential central or peripheral origin. Stimulation of central dopamine (DA) metabolism by a long-acting neuroleptic, pipotiazine (PPZ) selectively increased plasma levels of DOPAC sulfate whereas peripheral inhibition of monoamine oxidase by debrisoquin sulfate decreased free DOPAC levels only. These data suggest that the two forms of plasma DOPAC (free and sulfate) may have independent topographic origins. Peripheral DA pools seem to be the most likely sources for plasma free DOPAC whereas central dopaminergic neurons mainly contribute to plasma sulfated DOPAC. Our findings thus demonstrate that plasma DOPAC sulfate may be a useful indicator for central DA function in rat. Although further experiments are necessary to extrapolate our findings from rat to man, arguments are given indicating that measurements of plasma DOPAC sulfate might be of interest in human pathological and pharmacological investigations.

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

Plasma levels of the dopamine (DA) metabolite homovanillic acid (HVA) may be a useful measure of brain HVA production by central DA systems. Even though there is a significant peripheral contribution to plasma HVA, experimental manipulations that alter brain HVA produce parallel changes in plasma HVA levels. This study was designed to assess whether the ability of plasma HVA to reflect haloperidol induced increases in brain HVA could be strengthened by reducing the contribution to plasma HVA from peripheral sources. Debrisoquin sulfate, a monoamine oxidase inhibitor that does not enter the brain, was given in a low dose schedule to rats and lowered the peripheral contribution to plasma HVA by between 42 and 68%, resulting in a situation where between 62 and 87% of plasma HVA derived from brain. Using this dose schedule, rats pretreated with debrisoquin displayed a significant increase in plasma HVA following a lower dose of haloperidol than that required in the vehicle pretreated rats. In the debrisoquin pretreated group, a 71% increase in brain HVA was accompanied by a significant 60% increase in plasma HVA, whereas the vehicle pretreated group required a 136% increase in brain HVA to display a significant 50% increase in plasma. These findings indicate that debrisoquin pretreatment improves the reliability of plasma HVA to reflect changes in brain DA metabolism. Plasma HVA samples obtained from humans following debrisoquin may provide a clinically applicable method for assessing brain DA systems in neurologic and psychiatric illness.

This study examines the effect of diet and moderate physical activity on plasma levels of the dopamine metabolite homovanillic acid (HVA) in healthy young males. At weekly intervals, subjects were fed four isocaloric meals: polycose (pure carbohydrate), sustecal, low monoamine, and high monoamine. Moderate physical activity consisted of 30 minutes of exercise on a bicycle ergometer. The effect of diet on plasma HVA (pHVA) was highly significant. Compared to the polycose meal, the high monoamine meal significantly increased pHVA. Moderate physical activity also significantly increased pHVA. Future clinical studies using pHVA in man as an index of brain dopamine function should control for the effects of both diet and physical activity.

In order to assess the relationship between tardive dyskinesia (TD) and baseline circulating concentrations of estradiol, prolactin and homovanillic acid, we studied 43 outpatient men and postmenopausal women on chronic antipsychotic medication. Serum estradiol did not correlate with severity of TD, antipsychotic medication dose, serum prolactin or plasma HVA. Multiple regression analysis indicated a significant relationship between plasma HVA and severity of TD in postmenopausal women. These findings support the hypothesis that estrogen might serve a protective role against neuroleptic-induced striatal dopamine pathology.

The response of the plasma dopamine (DA) metabolite, homovanillic acid (HVA), to two DA agonists was investigated in the rat. Apomorphine administered i.p. (2 mg/kg) produced, within one hour, a significant decrease in plasma HVA. The response of plasma HVA to apomorphine was also investigated after pretreatment with debrisoquin, a drug which selectively blocks peripheral HVA production by inhibition of MAO. Pretreatment with debrisoquin did not significantly alter the decrement in plasma HVA produced by apomorphine indicating that a substantial portion of the plasma HVA response to apomorphine is due to the drug's action on brain. Bromocriptine (2 mg/kg) was also found to produce a significant decrease in plasma HVA. Since the response of brain HVA to DA agonists reflects the sensitivity of the DA receptor, the plasma HVA response to DA agonists might be a practical method of assessing brain DA receptor sensitivity in humans.

Haloperidol increases the plasma concentration of the dopamine (DA) metabolite homovanillic acid (HVA). Since a substantial proportion of plasma HVA originates outside the brain, this effect could be due to a combination of both peripheral and central actions of haloperidol. In order to evaluate the relative contribution of central versus peripheral effects of haloperidol on plasma HVA, the effect of pretreatment with a peripheral monoamine oxidase inhibitor, debrisoquin, on the plasma HVA response to haloperidol was examined. In addition, the effect of haloperidol on plasma HVA was compared with that of domperidone, a peripheral DA receptor blocking agent. Debrisoquin pretreatment did not alter the haloperidol-induced increase in plasma HVA and domperidone had no effect on plasma HVA. Thus, the haloperidol effect on plasma HVA did not appear to be due to increased peripheral HVA production or blockade of peripheral DA receptor sites. It is concluded that the haloperidol-induced increase in plasma HVA is due largely or exclusively to the drug's action on the brain.

A direct method has been employed to estimate the rate of production by human brain of 3-methoxy-4-hydroxyphenethyleneglycol, the major metabolite of brain norepinephrine, a brain neurotransmitter. Venous specimens were obtained from the internal jugular vein from ten awake human subjects at a puncture site above the common facial vein, the first major source of extracranial inflow. Arterial specimens were simultaneously obtained from the radial artery. Plasma samples were assayed and a highly significant difference was found in the concentration of the metabolite in plasma coming out of the brain (venous blood) as compared to plasma entering the brain (arterial blood). This venous-arterial difference was calculated to be 0.7 +/- 0.1 nanogram per milliliter of blood. Assuming an adult brain weight of 1400 grams and normal cerebral blood flow, it is estimated that the rate of production of 3-methoxy-4-hydroxyphenethyleneglycol by the awake human brain is approximately 597 nanograms per minute or 35.8 micrograms per hour. Urine specimens were also collected from six of these subjects during a period of 1 to 3.5 hours, which bracketed the time the blood samples were obtained. For these six subjects the output of 3-methyoxy-4-hydroxyphenethyleneglycol by whole brain was estimated to be 40.9 micrograms per hour, whereas the rate of its excretion into urine was 64.5 micrograms per hour.