A new approach to biochemical evaluation of brain dopamine metabolism

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.     

Catecholamine metabolites in human plasma as indices of brain function: Effects of debrisoquin

Metabolites of catecholamine neurotransmitters in plasma are, potentially, an easily available indicator of brain function in man. The peripheral contribution to these metabolites was lowered by debrisoquin sulfate, a monoamine oxidase inhibitor that does not enter the brain. In the monkey, it had been shown that debrisoquin decreased peripheral production of the dopamine metabolite, homovanillic acid (HVA), without changing production by brain; production of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) was decreased peripherally and in brain. Low-dose debrisoquin administration in man eliminated about 80% of the peripheral contribution to HVA and MHPG in plasma, resulting in a situation in which at least 75% of these metabolites in plasma were from the brain. Under these conditions, HVA and MHPG in plasma had a significant correlation. It could also be estimated that production of MHPG by brain was reduced 55%. Debrisoquin potentially provides a method for studying brain catecholamines through their metabolites in plasma and for treating conditions of brain noradrenergic excess.     

Relationship between urinary excretion of homovanillic acid and norepinephrine metabolites in normal subjects and patients with orthostatic hypotension

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.     

Variance in the production of homovanillic acid and 3-methoxy-4-hydroxyphenethyleneglycol by the awake primate brain

Previous experimental results, using a new technique whereby the production rates of the neurotransmitter metabolites homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) by the awake primate brain are determined, have shown a wide variance in metabolite production among both animal and human subjects. These data suggested that either individual subjects differ in the activity of brain dopamine (DA) or norepinephrine (NE) neurons and/or that the activities of these neurons fluctuate over time. For these reasons a series of experiments were performed in which measures of HVA and MHPG production were obtained at three time points in the same animal (monkeys) over a three hour period. It was found that the group mean values for the production of HVA and MHPG by brain were similar for each of the three time points. However, it was also found that marked variations in HVA and MHPG production occur within a single animal over a three hour period. The coefficients of variation for individual animals for HVA ranged from 9.3 to 31.9% and for MHPG from 10.1 to 62.3%. These variations were not correlated with grossly observable changes in behavioral states. Using an analysis of variance it was found that the variance in MHPG production was significantly greater than that for HVA (F = 6.2, p < 0.05) suggesting that brain NE systems are more liable and/or show greater change than do brain DA systems. These data are interpreted as indicating that in the awake, resting primate brain fluctuations in the activities of DA and NE neurons occur, i.e. there is not a steady, invariant production of metabolites but rather they are produced in pulses of varying lengths. This interpretation of the data is generally consistent with electrophysiological studies which indicate that catecholamine neurons fire in bursts which are then followed by silent periods. Finally, in terms of practical application of the V-A difference technique, these data indicate that replicable group mean estimates of brain HVA and MHPG production can be obtained by averaging values from a single time point whereas accurate information about an individual animal will require multiple samplings.Recent reports from this laboratory have described a method whereby a direct measure of the rates of production of neurotransmitter metabolites such as homovanillic acid (HVA), 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) by the awake primate brain can be determined (1, 2, 3, 4). Since the quantities of HVA, MHPG, and probably 5-HIAA in the brain vary as a function of the activity of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) neurons (1, 5, 6, 7, 8), it is likely that these measures of neurotransmitter metabolite production reflect the functional state of brain DA, NE, and 5-HT neuronal systems. The experimental results thus far obtained with this technique have shown a wide variance in the rates of neurotransmitter metabolite production across both animal and human subjects even though the subjects were not in clearly different behavioral or emotional states (1, 2, 4, 9). These data suggested that either individual subjects differ markedly in the activities of brain DA, NE, and 5-HT neurotransmitter systems and/or that the activity of these systems fluctuates markedly over time. For these reasons, experiments were undertaken in which repeated measures of HVA and MHPG production by brain within the same animal were determined over a three hour period. The results of these experiments, which are reported here, indicate that there are marked changes in brain metabolite production which occur within animals. The implications of these findings for our understanding of the functioning of brain neurotransmitter systems and for the practical applications of this technique are discussed.     

Increased catecholamine output in the hypertensive fawn-hooded rat

The total 24 hour urinary outputs of the catecholamines norepinephrine (NE), epinephrine (E), dopamine (DA) and the DA metabolite homovanillic acid (HVA) were measured in hypertensive fawn-hooded rats and compared to the ancestral strain of normotensive Wistar rats. The hypertensive fawn-hooded rats demonstrated significantly higher urinary outputs of the catecholamines NE and DA, and of the DA metabolite HVA. Following treatment with the antihypertensive, debrisoquin sulfate, the blood pressure of the fawn-hooded rats decreased until it approached the levels observed in normotensive Wistar rats. By inhibiting sympathetic nervous activity and monoamine oxidase, the debrisoquin treatment significantly decreased the output of DA, NE and HVA but not E. The data suggest the fawn-hooded rat is a model of neurogenic hypertension which is characterized by an increased sympathetic output.     

Influence of dopamine agonists on plasma and brain levels of homovanillic acid

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.     

Direct determination of homovanillic acid release from the human brain, an indicator of central dopaminergic activity

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.     

Suppression of norepinephrine secretion by dopamine in children with neuroblastoma: evidence for precursor inhibition in catecholamine pathway

To elucidate catecholamine (CA) secretory dynamics in neuroblastoma, urinary excretion of CAs and their metabolites was serially measured in 6 patients aged 3 months to 3 years before and during treatment. After tumor extirpation, increased urinary CAs were promptly normalized; the reduction reflected the amount of CA production from the tumor. Urinary dopamine (DA) showed the most prominent reduction, whereas DA content in the tumor was very small, indicating that the DA produced was immediately released from the tumor and metabolized in extra-tumor tissues. In contrast, patients receiving chemotherapy continued to excrete excess DA and homovanillic acid (HVA), which were increased further at recidivation. One patient showed an inverse correlation between DA and norepinephrine (NE) excretion; a decrease in DA was associated with an increase in NE and plasma DA-beta-hydroxylase (DBH) activity. A similar inverse correlation was also noted between NE and vanillylmandelic acid (VMA) or 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, while HVA and dihydroxyphenylacetic acid (DOPAC) were positively correlated with DA excretion. Urinary HVA and VMA were lineally correlated but in a patient excreting an enormous amount of DA, urinary VMA was markedly suppressed in terms of HVA excretion. Excessive DA induced an increase in renal water output but did not enhance Na and K excretion. These results indicate that endogenous DA overload in neuroblastoma inhibits NE production by suppressing DBH activity as well as by forming VMA and MHPG. This precursor regulation appears to be the characteristic of the CA metabolic pathway.     

Clonidine Prevents Methylxanthine Stimulation of Norepinephrine Metabolism in Rat Brain

Methylxanthines can produce behavior resembling opiate withdrawal in rats. Since previous studies have demonstrated the involvement of central noradrenergic systems during naloxone-precipitated withdrawal, the effects of 3-isobutyl-1-methylxanthine (IBMX) on norepinephrine metabolism in rat brain were studied. It was found that administration of IBMX elevated levels of the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in areas innervated by the locus coeruleus. The increases in MHPG was noted 1 h after administration and was maximal (270% of control) after 3 h. Levels of another norepinephrine metabolite, 3,4-dihydroxyphenylglycol, followed a similar pattern and time course. Coadministration of naloxone with IBMX did not affect the IBMX-induced elevation in MHPG. Administration of the alpha-agonist clonidine, however, antagonized the effects of IBMX on MHPG levels. The effects of IBMX and clonidine were dose dependent; the lowest dose of IBMX needed to elevate MHPG was 30 mumol/kg (i.p.), and clonidine (180 nmol/kg) reduced the effect of IBMX (100 mumol/kg) by 50%. The data, discussed in terms of a methylxanthine-noradrenergic interaction, suggest that withdrawal behaviors in general may be subserved by hyperactive noradrenergic neurons.     

Plasma homovanillic acid as an index of brain dopamine metabolism: Enhancement with debrisoquin

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.     

The acute effects of central- and peripheral-acting dopamine antagonists on plasma HVA in schizophrenic patients

The short-term effects of fluphenazine on plasma HVA concentrations were compared with the effects of fluphenazine and concurrent administration of debrisoquin, a monoamine oxidase inhibitor which does not cross the blood brain barrier and is used to enhance the CNS contribution to circulating plasma HVA concentrations. Fluphenazine significantly increased plasma HVA with or without debrisoquin 24 hours following the initiation of treatment. Domperidone, a butyrophenone dopamine antagonist which acts only in the peripheral nervous system, failed to alter plasma HVA concentrations. These data suggest that the acute effects of neuroleptic drugs on plasma HVA concentrations are dependent upon interaction with CNS dopaminergic systems and provide additional support for the use of plasma HVA as a reflection of CNS dopamine system activity in clinical studies.     

Higher plasma catecholamine and metabolite levels in the early phase of nonsegmental vitiligo

The etiology of vitiligo is still being debated, although neural factors seem to play a pivotal role in its pathogenesis. In our search for a link between vitiligo and the activity of monoaminergic systems, we used high-pressure liquid chromatography and electrochemical detector (HPLC-ED) methods to measure the plasma levels of the following substances in 35 healthy subjects and in 70 patients suffering from nonsegmental vitiligo at the different stages of the disease: catecholamines [norepinephrine (NE), epinephrine (E), and dopamine (DA)], their precursor 3,4-dihydroxyphenylalanine (DOPA), their metabolites [3-methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine (NMN), metanephrine (MN), and homovanillic acid (HVA)], and 5-hydroxyindolacetic acid (5-HIAA) as the major metabolite of serotonin. We found that the levels of NE, E, NMN, MN, HVA, and 5-HIAA were significantly higher in patients compared to controls. The patients at an active phase of the disease (n = 49/70) showed significantly higher levels of NE, NMN, MHPG, and HVA than ones at a stable phase. The patients with progressive vitiligo and at its more recent onset (< 1 year) showed significantly increased levels of E, NE, and MN in comparison with longer-term sufferers. No significant differences were observed when the patients were subdivided according to the type of vitiligo or their age at its onset. The higher catecholamine and metabolite levels in the early phase of the disease may reflect increased activity by monoaminergic systems, probably due to stressful events, including the onset of vitiligo itself.     

Relationship Between Plasma and Cerebrospinal Fluid Norepinephrine and Dopamine Metabolites in a Nonhuman Primate

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.     

Brief debrisoquin administration to assess central dopaminergic function in children

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.     

NOREPINEPHRINE METABOLISM IN THE CENTRAL NERVOUS SYSTEM OF MAN: STUDIES USING 3-METHOXY-4-HYDROXYPHENYLETHYLENE GLYCOL LEVELS IN CEREBROSPINAL FLUID

—Levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), a major metabolite of norepinephrine, were measured in human CSF by gas-liquid chromatography. MHPG concentrations were similar in both ventricular and lumbar CSF samples; about 30 per cent of the MHPG from either source occurred as the sulphate conjugate. There was relatively little entry of intravenously infused [¹⁴C]MHPG into lumbar spinal fluid. Both α-methylparatyrosine, an inhibitor of tyrosine hydroxylase, and fusaric acid, an inhibitor of dopamine-β-hydroxylase, significantly diminished MHPG values. On the other hand, doses of l -DOPA or probenecid, sufficient to substantially elevate CSF levels of the dopamine metabolite, homovanillic acid, failed to alter the spinal fluid content of MHPG. CSF concentrations of MHPG in patients with Parkinson's disease or the other central nervous system disorders studied did not differ significantly from control levels. The results suggest that MHPG values in CSF may provide an index to norepinephrine metabolism in the central nervous system of man.     

The effect of dietary precursors on the excretion of amines and their metabolites in the rat

The influence of diet on the excretion of catecholamines, some of their metabolites, and pHPG, an octopamine metabolite, was examined. Two groups of rats were fed either a cereal-containing standard laboratory Purina rat chow or a cereal-free casein diet. Use of the standard chow resulted in significant increases in the urinary values for total MHPG, pHPG, DHPE, MHPE, and free and total DOPAC by the seventh day in comparison to the casein diet. No changes were noted in the excretion of free and total NE, DA, and HVA. The data indicate that it is necessary to place the animals on the casein diet several days before determining the excretion of the aforementioned metabolites.     

Monoamine Neurotransmitter Metabolites in the Cerebrospinal Fluid of a Group of Hybrid Baboons (Papio hamadryas × P. anubis)

Comparatively little is known about the pathways of proximate causation that link divergent genotypes, via neurophysiological differences, to distinct, species-specific social behaviors and systems. One approach to the problem compares gross activity levels of monoamine neurotransmitters (norepinephrine, dopamine, and serotonin), evidenced by their metabolites —3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), respectively— in cerebrospinal fluid (CSF). We have applied this method to Papio hamadryas and P. anubis, closely related baboon species with divergent social behavior, living in the Awash National Park (ANP), Ethiopia. We had previously shown that adult males of the two species differ in the ratio of HVA to 5-HIAA, and in concentrations of MHPG and HVA, but not 5-HIAA. Here, we compare monoamine metabolite levels of the parental species with those of 49 members of a naturally formed, multigenerational hamadryas × anubis hybrid group. We cage-trapped the baboons in July 1998, sampled their CSF by cisternal puncture, and assayed monoamine metabolites by high-performance liquid chromatography. Previous findings suggested, anomalously, that hybrid males showed the high 5-HIAA levels predicted by the low-serotonin–early-dispersal hypothesis (originally based on observation of rhesus macaques, Macaca mulatta), while hamadryas did not. The present study failed to find higher 5-HIAA levels in hybrids, resolving the anomaly, but leaving the previous result unexplained. Among adult females (underrepresented in our sample) and juveniles, metabolite levels of the hybrids did not differ significantly from either parental species. Overall, adult male hybrids resembled anubis in HVA and HVA/5-HIAA ratio, but did not show the low MHPG levels characteristic of that species. Consistent with a significant genetic influence on species differences in these metabolites, the adult hybrids showed intermediate means and greater intra-population diversity than the parental species for most variables, but showed no indication of hybrid dysgenesis in the form of low intermetabolite correlation. To the contrary, an enhanced HVA–MHPG correlation in the hybrids suggested a species-associated factor (not necessarily genetic) influencing both of these monoamine neurotransmitter systems.     

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

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

Cerebrospinal Fluid Monoaminergic Metabolites in Wild Papio anubis and P. hamadryas are Concordant with Taxon-specific Behavioral Ontogeny

We used a cross-sectional sample to compare ontogenetic trajectories in the concentrations of monoamine neurotransmitter metabolites in cerebrospinal fluid of wild anubis (Papio anubis, n = 49) and hamadryas (P. hamadryas, n = 54) baboons to test the prediction that they would differ, especially in males, in association with their distinct behavioral ontogenies. Values of all 3 metabolites [3-methoxy-4-hydroxyphenylglycol (MHPG), the norepinephrine metabolite; 5-hydroxyindoleacetic acid (5-HIAA), the serotonin metabolite; and homovanillic acid (HVA), the dopamine metabolite] declined consistently with dentally-calibrated maturation, and few taxon-related differences were apparent among juveniles. Adult females were too few for adequate comparison, but a discriminant function suggested that they might differ by taxon. Adult males of the 2 species differed strikingly from juveniles and from each other. Contrary to our initial hypothesis, adult male anubis had significantly lower HVA and MHPG, and higher 5-HIAA levels, than predicted from the overall, age-related trend, and MHPG continued to decline with age among adults. As young adults, male hamadryas had low 5-HIAA and a high HVA/5-HIAA ratio, while older males [normatively one-male unit (OMU) leaders] showed a reversal in the trend, with 5-HIAA rising and the HVA/5-HIAA ratio tending to fall. We speculate that the results are related to the dispersing and philopatric ontogenies of anubis and hamadryas males, respectively. Adult male anubis, whose fitness depends on building social networks with nonkin, have high relative serotonin activity, commonly associated with greater social circumspection and skill. Young adult male hamadryas, living among agnatic kin and mating opportunistically, exhibit low 5-HIAA levels, generally associated with impulsivity and social irresponsibility. This reverses as a male approaches the age at which he is normatively the leader of a one-male unit (OMU), and his fitness depends on his maintaining stable relationships with other leaders and with females. An erratum to this article can be found at     

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

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