Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers

The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n = 132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.     

Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis).

Social dominance is a fundamental component of both human and nonhuman primate sociality. However, its neurobiological correlates remain incompletely understood. We evaluated the association between dominance status and monoamine metabolite concentrations in cisternal cerebrospinal fluid (CSF) in adult male (n = 25) and female (n = 21) cynomolgus macaques (Macaca fascicularis) housed in unisexual social groups. Concentrations of the metabolites of dopamine (homovanillic acid [HVA]), norepinephrine (3-methoxy-4-hydroxyphenylglycol [MHPG]) and serotonin (5-hydroxyindoleacetic acid [5-HIAA]) were assayed. Dominant monkeys, both males and females, had significantly higher CSF HVA concentrations than did subordinates (p values <.05). Among males, but not females, dominants also had lower CSF 5-HIAA than subordinates (p <.05). The Dominance-HVA association observed here is consistent with recent speculation that social extraversion, a dominance-related personality trait in humans, may also reflect heightened central nervous system dopaminergic activity.     

Individual differences in basal cisternal cerebrospinal fluid 5-HIAA and HVA in monkeys. The effects of gender, age, physical characteristics, and matrilineal influences.

We examined the effects of gender, age, weight, length, body shape (ectomorphy), and matrilineal influences on cisternal cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and homovanillic acid (HVA) in 78 socially living adult and adolescent vervet monkeys. CSF 5-HIAA and the 5-HIAA:HVA ratio were higher (by 27% and 18%, respectively) in females. In both sexes, CSF 5-HIAA and the 5-HIAA:HVA ratio increased with age. Neither weight nor length were independently related to CSF 5-HIAA or HVA; however, shape correlated with CSF 5-HIAA and HVA in males (higher in thin, long subjects). Male offspring had CSF 5-HIAA concentrations and 5-HIAA:HVA ratios that were significantly closer to their mothers than did age-matched, maternally unrelated males. Repeated measures of CSF 5-HIAA and HVA in another 22 males living in unvarying settings showed that individual differences in these measures persisted over time. The data underscore the impact of gender, age, and matrilineal relationships on individual differences in CSF monoamine metabolites and highlight the importance of controlling for age and gender in neuropharmacological investigations of clinical populations.     

Cerebrospinal fluid monoaminergic metabolites differ in wild anubis and hybrid (Anubis hamadryas) baboons: possible relationships to life history and behavior.

The article reports monoaminergic metabolite [homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], values from the cerebrospinal fluid (CSF) of 27 wild baboons (Papio hamadryas) aged 40 to 140 months. Animals were either anubis, or anubis with hamadryas admixture; males of the latter subspecies generally have a reduced tendency to disperse from their natal groups. Overall, the values and interrelationships among the CSF monoamine metabolites resembled data reported from closely related, captive-housed animals. For example, age was significantly correlated with HVA concentrations (r = -60, p < .05), but not with the other metabolites. Notably, males characterized by hamadryas admixture had significantly higher concentrations of HVA, 5-HIAA, and MHPG (p < .05, respectively), a result possibly driven by differences in serotonergic activity. These data provide initial evidence that variation in central monoaminergic activity, as indicated by CSF monoamine metabolite concentrations, may reflect differences in behavior and life history that have taxonomic and, perhaps, evolutionary significance.     

Monoamine metabolite levels in rat CSF: kinetic studies

The kinetics of monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), in cisternal CSF were determined after monoamine oxidase (MAO) inhibition (pargyline, 100 mg/kg) and tyrosine hydroxylase inhibition (alpha-methyl-p-tyrosine, alpha-MPT, 250 mg/kg) in awake rats. In addition, the possibility of a peripheral contribution to CSF MHPG levels was investigated by infusing large amounts of the metabolite into vena jugularis. Pargyline induced an exponential decrease of CSF MHPG, 5-HIAA and HVA, with respective half-lives of 51, 86 and 46 min. alpha-MPT caused a slower decline of MHPG and HVA, while 5-HIAA was unaffected. Results from the MHPG-infusion experiments indicate minor peripheral contribution to CSF MHPG levels in acute pharmacological studies. The present paper gives further support for the validity of our new animal model in detecting acute changes in central monoaminergic activity.     

马桑内酯对麻醉狗脑脊液中单胺类神经递质代谢物含量影响的初步探讨

作者通过狗口服丙磺舒阻断酸性物质向外周血循环转运的方法来测定肌注马桑内酯1mg/kg,前、后脑脊液中去甲肾上腺素、多巴胺和5-羟色胺的代谢物3-甲氧-4羟苯一乙二醇、高香草酸和5-羟吲哚乙酸的含量改变,以了解三者的更新率。初步结果表明:高香草酸的含量显著下降(P<0.05),5-羟吲哚乙酸的含量有所下降(P>0.05)但无统计学意义,3-甲氧-4羟苯一乙二醇影响不大。     

Effect of probenecid on free 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and its sulphate in human cerebrospinal fluid

In a mixed group of 46 patients with affective disorder, or with various neurologic disorders, high doses of probenecid (100 mg/kg over 18 hr) produced a significant increase in lumbar cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the major metabolite of norepinephrine centrally. This increase (averaging 60%) is modest in comparison to probenecid induced increases in homovanillic acid (HVA) or 5-hydroxyindo-leacetic acid (5-HIAA). Analysis for free MHPG and its sulfate showed no significant differences for either compound after nine hours. After 18 hours of treatment significant increases in free MHPG and small but not significant increases of MHPG.SO₄ were found. These results suggest that a probenecid sensitive active transport mechanism for MHPG.SO₄ of the degree demon-strated for HVA and 5-HIAA in humans, and for MHPG.SO₄ in rats, does not occur in human CSF.     

Minipump clorgyline administration and CSF amine metabolites in unrestrained monkeys.

The irreversible MAO-A inhibitor clorgyline was administered in doses of 0.5 mg/kg (N = 1), 1 mg/kg (N = 3), and 2 mg/kg (N = 1) to 5 young (age 5.5 to 23.9 months) pigtail (M. nemestrina) monkeys using a 28-day (Alza 2ML4) osmotic minipump. CSF MHPG, 5-HIAA, HVA, and plasma MHPG were measured before and at approximately weekly intervals after pump implantation. Implants were well tolerated. CSF MHPG decreased about 75%, 5-HIAA 30%, and HVA from 30-50% with a tendency to plateau by the second week. Plasma MHPG decreased to undetectable levels. The findings demonstrate that long-term inhibition of MAO-A can be produced in unrestrained monkeys by minipump administered clorgyline. There is an apparently greater effect on the norepinephrine system relative to the serotonin and dopamine systems.     

Effects of pentylenetetrazol and trimethadione on feline brain monoamine metabolism

The effects of pentylenetetrazol on behavioral excitation and brain monoamine metabolism were compared by monitoring the EEG and assaying feline cerebrospinal fluid (CSF) for monoamine metabolites. After a non-convulsant dose of pentylenetetrazol, neither the concentrations of the 5-hydroxytryptamine (5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA), nor the dopamine(DA) metabolite, homovanillic acid (HVA), were altered in CSF if the rectal temperature of the cat was maintained. After a convulsant dose there was an increase in 5-HIAA and HVA levels. The norepinephrine (NE) metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), was also increased, but returned to control within 3 hr, while 5-HIAA and HVA levels were elevated for 24 hr. Trimethadione produced a transient decrease in HVA levels. When the convulsions, but not EEG excitation, are prevented by trimethadione pretreatment, brain monoamine metabolism is increased. Plasma tryptophan levels decreased after convulsant doses of pentylenetetrazol. Pentylenetetrazol was not detectable in plasma or CSF 24 hr after injection, while CSF 5-HIAA and HVA levels were still increased. These data show that pentylenetetrazol directly increases brain NE, DA and 5-HT metabolism while causing EEG excitatory changes, an effect which may precede convulsions.     

Repetitive measurement of monoamine metabolite levels in cerebrospinal fluid of conscious rats: effects of reserpine and haloperidol

A simple high performance liquid chromatographic method with electrochemical detection is described for the simultaneous determination of unconjugated 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the principal central nervous system (CNS) metabolites of noradrenaline, serotonin and dopamine (DA), respectively, in small samples of cisternal cerebrospinal fluid (CSF) obtained repeatedly from freely moving rats. Amounts of 30-50 microliter of CSF could be collected repeatedly every 30-60 min allowing monitoring of monoamine metabolite concentration levels in CSF under physiological conditions. None of the metabolites showed any clear diurnal variation. A single injection of reserpine caused a prominent elevation in the concentrations of MHPG, 5-HIAA and HVA in CSF. However, after a rapid increase, the concentration of MHPG was decreased by 85% from the control values. Haloperidol caused a 3-fold increase in the concentration of HVA, indicating increased DA turnover in the CNS. The method enables the reliable quantitative determination of three major monoamine metabolites in small samples of CSF from freely moving rats and appears to be a useful tool in the evaluation of the validity of the clinically used research methods of monitoring drug-induced alterations in CNS monoaminergic activity by metabolite measurements in CSF.     

Effects of tiapride on homovanillic acid levels in human cerebrospinal fluid drawn at pneumoencephalography

The effect of tiapride on HVA and 5-HIAA levels in the CSF drawn at pneumoencephalography (PEG) was studied. Five consecutive 5 ml fractions of CSF were drawn from control and tiapride-treated subjects. In both groups, a linear increase in HVA concentrations was found between the first and subsequent fractions. On the contrary, no significant difference in 5-HIAA concentrations was found in sequential CSF samples. Tiapride increased the mean HVA concentrations and caused a steeper caudocranial gradient of this metabolite but failed to modify 5-HIAA concentrations. The results suggest that tiapride blocks dopamine (DA) receptors and increases DA synthesis.     

Relationship of age and mood to monoamine metabolites in cerebrospinal fluid in parkinsonism

Summary The concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) were measured in 63 patients with parkinsonism. HVA was lower than in healthy subjects, but it showed similar age-related changes. No age-related changes were found in 5-HIAA. These observations simply that the disturbances caused by the disease had also affected age-related alterations in the metabolism of 5-hydroxytryptamine. The levels of 5-HIAA and HVA in the CSF in patients suffering from depression and parkinsonism were the same as those found in non-depressed parkinsonian patients; in this respect the patients resembled others suffering from depression. There was no correlation between the therapeutic effects of drugs and the concentration of HVA in CSF. This finding, which differs from previous reports, means that analysis of monoamine metabolites in CSF was of no prognostic value.     

The effects of amiflamine on cerebrospinal fluid amine metabolites in the rhesus monkey

Amiflamine, a drug reported to be a reversible inhibitor of monoamine oxidase type A (MAO-A) selective for serotonergic neurons in rodents, was administered to rhesus monkeys over a 12-fold dosage range (0.5-6 mg/kg). Amiflamine produced small, essentially equivalent reductions in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA, 1-28%), 3-methoxy-4-hydroxyphenylglycol (MHPG, 4-26%), and homovanillic acid (HVA, 7-29%), suggesting that the effects of amiflamine are approximately equal on serotonin, norepinephrine and dopamine metabolism in nonhuman primates. Concentrations of amiflamine were very low in CSF 3-6 h after drug administration (less than 7 nmol/l), while those of its two major, biologically active metabolites were higher (22-150 nmol/l) and varied in relative proportions among the monkeys. Further investigation is required of some preliminary observations of a possible association between drug metabolite variations and the substantial individual differences in the amine metabolite changes following amiflamine treatment. MAO-B in platelets was not inhibited by 6 mg/kg amiflamine, indicating that MAO-A selectivity was maintained. At low amiflamine doses, early and transient increases in CSF 5-HIAA and HVA concentrations were observed, suggesting an amine-releasing effect of the drug within brain serotonergic and dopaminergic neurons.     

Effects of the alpha 2-antagonist idazoxan on monoaminergic parameters measured in the cerebrospinal fluid of rabbits

The alpha 2-antagonist idazoxan was administered intravenously to rabbits. The increase in central noradrenergic, dopaminergic and serotonergic activity was followed as a function of time by determining neuronal parameters in the cerebrospinal fluid (CSF) and was compared with changes previously determined after yohimbine. These parameters include the enzyme dopamine-beta-hydroxylase (D beta H), the noradrenergic metabolites 3-methoxy-4-hydroxyphenylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the dopaminergic metabolite 3-methoxy-4-hydroxyphenylacetic acid (HVA) and the serotonergic metabolite 5-hydroxyindole acetic acid (5-HIAA). Control experiments with physiological saline were also performed. D beta H activity increased to 211% in control experiments, and to 570 and 530%, respectively after yohimbine and idazoxan. Compared to the control experiments yohimbine was able to elevate VMA, MHPG and HVA concentrations, but 5-HIAA levels were reduced. Idazoxan caused increased MHPG concentrations, slight increases in VMA, little effect on HVA and no effect on 5-HIAA levels. We conclude that idazoxan was as potent as yohimbine as an alpha 2-antagonist in our in vivo experiments and that idazoxan shows a much greater selectivity with regard to the noradrenergic system.     

Tofisopam and midazolam: differences in clinical effects and in changes of CSF monoamine metabolites.

The effect of two repeated oral doses of 100 mg tofisopam 15 mg midazolam and placebo on the concentrations of monoamine metabolites (MHPG, 5-HIAA, HVA) in lumbar CSF were studied in general surgical patients operated on under spinal analgesia (n = 12 in each group). Midazolam, but not tofisopam, improved the quality of sleep the night before surgery. Both active agents reduced preoperative anxiety of the patients, but tofisopam was without subjective sedative action. In the placebo group, in contrast to the active drug groups, there was a slight positive correlation between the MHPG concentration and degree of anxiety before surgery. The only significant difference in the monoamine metabolites in lumbar CSF was found in the concentrations of HVA between tofisopam and placebo treated patients. The lower HVA concentrations suggest that the curious 3,4-benzodiazepine derivative, tofisopam, modifies central dopaminergic activity.     

Neurochemical changes in pigeon cerebrospinal fluid during chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

Cerebrospinal fluid (CSF), collected repeatedly from White Carneau pigeons chronically implanted with guide cannulae located in the lateral ventricles, was analyzed for metabolites of serotonin, dopamine and norepinephrine after acute and chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Following the acute administration of 3.0 mg/kg buspirone, levels of 5-hydroxyindoleacetic acid (5-HIAA) decreased, while increases occurred in the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Decreases in 5-HIAA persisted throughout the chronic dosing regimen (36 days), while dopamine metabolites returned to control levels within 8 days. When chronic buspirone was discontinued, levels of 5-HIAA were restored to predrug control levels, while levels of HVA, DOPAC and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) decreased. All metabolites returned to predrug control levels within one week following buspirone discontinuation except for MHPG, which remained depressed. When the acute effects of buspirone were reexamined, levels of 5-HIAA were again significantly decreased, while HVA and DOPAC levels, as well as those of MHPG, increased significantly. Acute administration of the 5-HT1A receptor ligand 8-OH-DPAT (3.0 mg/kg) resulted in large decreases in 5-HIAA levels that persisted throughout the period of chronic administration. Neither acute nor daily administration of 8-OH-DPAT changed levels of HVA, DOPAC or MHPG. Large increases in 5-HIAA occurred when chronic 8-OH-DPAT was discontinued but declined within one week to control levels. Following a two-week drug-free period, 8-OH-DPAT again caused a significant reduction in 5-HIAA levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls.

Dysfunctions of central monoaminergic systems are important elements of the leading biological hypotheses of suicide and depression. The purpose of the present paper was to study the levels and the relationships between the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebrospinal fluid (CSF) in 120 hospitalised suicide attempters and 47 controls (healthy volunteers or patients admitted for minor surgery). The suicide attempters showed significantly lower HVA levels (174+/-82 vs. 216+/-96 nmol/L, P=0.004), HVA/5HIAA ratios (1.6+/-0.5 vs. 2.1+/-0.6, P=0.0001) and HVA/MHPG ratios (4.2+/-2.1 vs. 4.8+/-1.7, P=0.02) than the controls. The correlations between the monoamine metabolites were markedly lower in patients than in controls. CSF 5-HIAA showed no significant differences between patients and controls (107+/-40 vs. 108+/-51 nmol/L) or between violent and non-violent attempters (112+/-58 vs. 105+/-33 nmol/L). The monoamine metabolites showed no significant differences between survivors and patients who subsequently completed suicide, or between suicide attempters subgrouped by psychiatric diagnoses. The results suggest that low HVA levels and altered relationships between the monoamine metabolites are associated with suicidal behaviour.     

CSF monoamine metabolites and lethality of suicide attempts in depressed patients with alcohol dependence.

BACKGROUND: Alcohol dependence (alcoholism) and major depressive disorder are frequently comorbid and are risk factors for suicidal behavior. Monoaminergic abnormalities have been implicated in the pathophysiology of depression, alcohol dependence, and suicidal behavior. Lower cerebrospinal fluid (CSF) 5-hydroxyindolacetic acid (5-HIAA) levels are associated with higher lethality of suicide attempts in major depression and predict a higher rate of future suicide. We sought to study the relationship of CSF monoamine metabolites to lethality of suicidal acts in depressed subjects with comorbid alcoholism. METHODS: We compared 16 high- and 16 low-lethality drug-free depressed suicide attempters with comorbid alcoholism. Subjects were free from any substance use disorder for at least two months. Demographic and clinical parameters, and CSF 5-HIAA, homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were examined. RESULTS: The two groups did not differ with regard to the demographic characteristics. CSF 5-HIAA levels were lower in high-lethality attempters compared to low-lethality attempters. There were no group difference in CSF HVA or MHPG levels. CONCLUSION: Higher lethality of suicidal behavior in depressed patients with alcoholism is related to lower serotonergic activity.     

Lower CSF homovanillic acid levels in depressed patients with a history of alcoholism.

Major depression and alcoholism are often comorbid, resulting in more impairment and more suicidal behavior compared with either diagnosis alone. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in depressed subjects with and without a history of alcoholism and healthy volunteers. We hypothesized that depressed subjects with a history of alcoholism would be more aggressive, impulsive, and suicidal than depressed subjects without a history of alcoholism, and would have lower CSF monoamine metabolite levels. We compared 63 subjects with a current major depressive episode (MDE) and a history of alcoholism, 72 subjects with a current MDE but without a history of alcoholism, and 22 healthy volunteers. Participants with a history of alcoholism were in remission for at least 6 months. All subjects were free from prescribed medications known to affect brain serotonin, dopamine, or norepinephrine systems for a minimum of 14 days. Depressive symptoms, lifetime aggression, impulsivity, Axis II disorders, and suicidal behavior were assessed. CSF was sampled and homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-performance lipid chromatography with electrochemical detection. Depressed subjects with a history of alcoholism did not differ from depressed subjects without a history of alcoholism in current severity of depressive symptoms, or in past suicidal behavior. Depressed subjects with a history of alcoholism had lower CSF HVA levels, and higher lifetime aggression and current suicide ideation scale scores and were more likely to be tobacco smokers compared with depressed subjects without a history of alcoholism. Low HVA was present after adjustment for sex, aggression and depression scores, cigarette smoking, antisocial and borderline personality disorders, psychomotor retardation, and delusions. Controls had CSF HVA levels intermediate between the two depressed groups. We found no group difference in CSF 5-HIAA and MHPG levels. In individuals with current MDE, those with a history of comorbid alcoholism had lower CSF HVA levels compared with those without a history of alcoholism. Low CSF HVA suggests that impaired dopaminergic activity is associated with a history of alcoholism in persons with current MDE.     

Effects of acute cannabis use on urinary neurotransmitter metabolites and cyclic nucleotides in man

The noradrenaline, dopamine and serotonin metabolites methoxy-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), as well as the cyclic nucleotides c-AMP and c-GMP were estimated in urine samples of five normal volunteers. Ten control samples and two samples after cannabis use were analyzed for each volunteer. Cannabis use caused significant decreases in MHPG and c-AMP, and increases in HVA, while 5-HIAA and c-GMP excretion remained unchanged. The results indicate that cannabis use interferes with catecholaminergic mechanisms in man, decreasing the noradrenaline and increasing dopamine turnover, probably through action on presynaptic receptors.