Cerebrospinal Fluid 5-hydroxyindoleacetic Acid Concentrations Research Articles

Haplotype-Based Linkage of Tryptophan Hydroxylase 2 to Suicide Attempt, Major Depression, and Cerebrospinal Fluid 5-Hydroxyindoleacetic Acid in 4 Populations

Tryptophan hydroxylase 2 (TPH2) encodes the rate-limiting enzyme for brain serotonin biosynthesis. It was recently reported that the TPH2 haplotype was linked to depression in humans. To determine the association of TPH2 with suicide attempt, major depression, and a neurochemical intermediate phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid. We resequenced TPH2 coding, 5' promoter, 3'-untranslated region, and splice junction regions in 190 individuals selected for ethnic and clinical diversity, determined haplotype structure using 15 single nucleotide polymorphisms spanning 106 kilobases (kb), and performed linkage analysis in 1798 cases and controls representing 4 populations (657 African Americans, including 104 suicide attempters and 135 with major depression; 513 Finnish whites, including 150 suicide attempters; 146 US whites, including 81 with depression, anxiety disorder, or both; and 482 southwestern American Indians, including 123 suicide attempters and 191 with depression, anxiety disorder, or both) and in 94 Finnish whites for cerebrospinal fluid 5-hydroxyindoleacetic acid levels. Sixteen single nucleotide polymorphisms, including Pro206Ser, were detected. The 15-locus panel defined and maximized information content from 2 haplotype blocks in whites, 3 haplotype blocks in African Americans, and the single haplotype block spanning TPH2 in southwestern American Indians. Among common Block1b haplotypes were 2 in yin and yang (opposite) configuration, indicating ancient origin. The yin haplotype, 212121, was increased in frequency in suicide attempters in both populations tested (Finnish whites and African Americans). It was associated with major depression and anxiety disorders in US whites and with major depression in African Americans. The yin haplotype was moderately predictive of lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations in controls but not in cases. Haplotype linkage of TPH2 to suicide attempt and major depression and to a mediating phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid, provides preliminary evidence of a functional locus potentially within a haplotype block at least 52 kb in size.

Variation in Reproductive Outcomes for Captive Male Rhesus Macaques (Macaca mulatta) Differing in CSF 5-Hydroxyindoleacetic Acid Concentrations

In rhesus macaque males, lower than average cerebrospinal fluid (CSF) concentrations of the principle metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), have been linked to impulsivity, involvement in escalated aggression, failure to elicit consort relationships, production of fewer sperm plugs, and a relatively early age of mortality. Given these potential fitness costs, we performed two studies aimed at elucidating the effects of CSF 5-HIAA on reproduction. Study 1 retrospectively evaluated over a four-year period, the relative reproductive outcome for pairs of adult male rhesus macaques (n = 15) who lived in social groups and who differed in concentrations of CSF 5-HIAA. Study 2 examined the relationship between CSF 5-HIAA and sperm motility and density (n = 12), as a potential mechanism for maintaining variability in CSF 5-HIAA. For Study 1, an average measure from two CSF 5-HIAA samples was calculated for the two males who were present during the time when conception most likely took place (offspring birth date –165 ± 14 days). Within-pair comparisons of CSF 5-HIAA concentrations between the sire and the non-successful male were drawn for each of the 72 offspring in the study. We found that while sires were typically the male with relatively higher CSF 5-HIAA within the pair, there were no absolute differences in CSF 5-HIAA between males who sired at least one offspring (sires) and those who failed to reproduce (non-sires). Furthermore, while absolute age was not predictive of reproductive outcome, sires with relatively high CSF 5-HIAA also tended to be also relatively older than their competitors. By contrast, for the males with relatively low CSF 5-HIAA who reproduced, sires were relatively younger than the non-sires. These differences in reproductive outcome for males differing in CSF 5-HIAA could not be explained by variability in sperm quantity or quality as we did not find evidence of a relationship between CSF 5-HIAA and either sperm measure. The results of this study suggest that as serotonergic function affects many aspects of behavior and survivorship, it might also be associated with reproductive outcome and different life-history strategies for males differing in concentrations of CSF 5-HIAA.

Oral Ethanol Self‐Administration in Rhesus Monkeys: Behavioral and Neurochemical Correlates

Previous research has revealed that orally administered ethanol serves as a reinforcer in nonhuman primates. The purposes of the present study were to examine the relationship between ethanol preferences and intakes in two distinct self-administration contexts and to reveal some of the behavioral and neurochemical correlates of oral ethanol self-administration in monkeys. Three cohorts of 13 to 29 rhesus monkeys (Macaca mulatta) were socially housed and given daily, 1-hr, one-spout access to an ethanol solution (8.4%, w/v) sweetened with aspartame. Twelve of these monkeys were subsequently selected, individually housed, and given daily, 2-hr, two-spout access to a range of ethanol concentrations (0.25-16%, w/v) concurrently with water. These monkeys (National Institute on Alcohol Abuse and Alcoholism group) showed a marked preference for ethanol (0.5-4%, w/v) over water, and ethanol preferences were 3-fold greater than those of a second group of 12 monkeys (University of Michigan group) purchased from a commercial vendor. Ethanol consumption was consistent across the self-administration paradigms. Monkeys that consumed large quantities of ethanol under the one-spout, social-housing conditions continued to drink large quantities of ethanol under the two-spout, individual-housing conditions (r = 0.86). An association between ethanol preferences and intakes was also demonstrated. Monkeys with the greatest preferences for ethanol over water under the two-spout choice conditions consumed the largest quantities of ethanol (r = 0.82). Finally, cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations were inversely related to ethanol preference but not to ethanol intake. These results indicate that ethanol consumption is stable across contexts and is positively correlated with the preference for ethanol over water.

A nonhuman primate model of type II excessive alcohol consumption? Part 1. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and diminished social competence correlate with excessive alcohol consumption.

Developmental, biochemical, and behavioral concomitants of excessive alcohol consumption were investigated using a nonhuman primate model. The variables of interest were: (1) interindividual stability of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) from infancy to adulthood, (2) effect of parental deprivation early in life on adult CSF 5-HIAA concentrations; (3) correlations between CSF 5-HIAA and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations and alcohol consumption; and (4) correlation between the frequency of competent social behaviors and alcohol consumption. Twenty-nine rhesus macaques were reared for their first 6 months either with their mothers or without adults in peer-only conditions. At 6 and 50 months of age, each subject underwent a series of four, 4-day social separations. Cisternal CSF was sampled before and during the first and last separations; concomitantly, observational data were collected on social dominance behavior in the home-cage. When they reached 50 months of age, the monkeys were provided free access to a palatable alcohol solution daily for 1-hr periods before, during, and after the social separations. Before and after the 50-month separations, data were collected on all types of social behavior in the home-cage. Results showed that peer-reared subjects consumed more alcohol than mother-reared subjects during baseline conditions. Mother-reared subjects, however, increased their rates of consumption to equal peer-reared subjects' rates of consumption during the conditions of a social separation stressor. Peer-reared subjects also exhibited lower CSF 5-HIAA concentrations in infancy and adulthood than their mother-reared counterparts. With rearing condition held constant, interindividual differences in CSF 5-HIAA, MHPG, and homovanillic acid were stable from infancy to adulthood, and high rates of alcohol were consumed by the young adult monkeys with low CSF 5-HIAA and MHPG concentrations, particularly when the CSF was obtained during the social separations. High rates of alcohol consumption were also observed in subjects with infrequent social interactions and less competent social behaviors. In contrast to the human data, we found no gender differences in rates of alcohol consumption, nor in the correlations between alcohol consumption and the other variables. With some exceptions, findings from the study are generally consistent with predictions from Cloninger's type II model of excessive alcohol consumption in men with low CSF 5-HIAA, who also exhibit impaired impulse control and violent and antisocial behaviors.

Excessive Mortality in Young Free-Ranging Male Nonhuman Primates With Low Cerebrospinal Fluid 5-Hydroxyindoleacetic Acid Concentrations

The purpose of this study was to assess the impact of central serotonin turnover rate on survival to adulthood among nonhuman primates living in a large, free-ranging colony. The rate of mortality was ascertained over a 4-year period after obtaining blood and cisternal cerebrospinal fluid (CSF) samples from 49 free-ranging, 2-year-old prepubertal male rhesus monkeys. Cerebrospinal fluid was assayed for 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, 3-methoxy-4-hydroxyphenylgycol, and homovanillic acid. Blood plasma was assayed for adrenocorticotropic hormone, cortisol, and testosterone. Following the sampling of body fluids, records of scars and wounds and aggressive encounters were used to rank the subjects from low to high in aggressiveness. Direct observations of aggressive behavior were collected from 27 of the subjects over a 3-month period. Four years later, 6 of the 49 subjects were known to be dead and an additional 5 had been missing for more than 2 years and were presumed dead. The CSF 5-HIAA concentrations were predictive of which subjects died, with 46% of the subjects with low CSF 5-HIAA concentrations dead or presumed dead. None of the subjects from the highest CSF 5-HIAA concentration quartile were dead or missing. Indeed, 91% of the dead subjects came from the 2 lowest quartiles of CSF 5-HIAA concentrations. Direct observations of aggressive behavior showed that dead or missing subjects had initiated escalated aggression, a measure of unrestrained aggression that has a high probability of trauma or injury, at a higher rate than subjects that were known to be alive. The cause of death could be ascertained for 6 of the 11 missing subjects. The 4 subjects that were known to die as a consequence of aggressive encounters came from the lowest quartile of CSF 5-HIAA concentrations and had been rated as more aggressive during their initial capture. Subjects captured more than once possessed lower CSF 5-HIAA concentrations, were rated as more aggressive, and were more likely to suffer early death than those captured only once. These findings suggest that low CSF 5-HIAA concentrations quantified early in life is a powerful biological predictor of future excessive aggression, risk taking, and premature death among nonhuman primate males.

Early-Onset Alcoholics Have Lower Cerebrospinal Fluid 5-Hydroxyindoleacetic Acid Levels Than Late-Onset Alcoholics

We investigated the interrelationships of age at onset of excessive alcohol consumption, family history of alcoholism, psychiatric comorbidity, and cerebrospinal fluid monoamine metabolite concentrations in abstinent, treatment-seeking alcoholics. We studied 131 recently abstinent alcoholics. Supervised abstinence was maintained on a research ward at the National Institutes of Health Clinical Center for a minimum of 3 weeks. All alcoholics received a low-monoamine diet for a minimum of 3 days before lumbar puncture. Lumbar punctures were performed in the morning after an overnight fast. Monamine metabolites and tryptophan in cerebrospinal fluid were quantified with liquid chromatography by means of electrochemical detection. Psychiatric diagnoses were established from blind-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews administered by a research social worker. Severity and age at onset of excessive alcohol consumption were documented with a structured lifetime drinking history questionnaire and with selected alcoholism screening questionnaires (CAGE and Michigan Alcoholism Screening Test). Family history of alcoholism was obtained from the probands. A majority of the treatment-seeking, primarily white male alcoholics had a lifetime history of psychiatric disorders other than alcoholism. None fulfilled criteria for antisocial personality disorder. Early-onset alcoholics (onset of excessive consumption before 25 years of age) had a more severe course of alcoholism and lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration than late-onset alcoholics. Patients who reported both parents to be alcoholics had particularly low mean cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan concentrations. Among treatment-seeking alcoholics, early age at onset is generally associated with a more severe course of alcoholism and lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.

Neurochemical correlates of sympathetic activation during severe alcohol withdrawal.

Cerebrospinal fluid (CSF) was obtained from 17 patients during acute alcohol withdrawal. Eight of these 17 patients had a second lumbar puncture a mean of 11.9 +/- 8.1 (SD) days later, when the clinical signs of alcohol withdrawal had subsided. CSF 3-methoxy-4-hydroxyphenylglycol concentrations declined significantly (p < 0.05) during the course of alcohol withdrawal from 52.0 +/- 22.1 (SD) to 39.6 +/- 12.6 pM/ml. In early withdrawal, there was a significant positive correlation between CSF norepinephrine (NE) and corticotropin releasing hormone (CRH) concentrations (r = 0.95, p < 0.001). Both NE and CRH concentrations correlated positively with diastolic blood pressure (r = 0.88, p < 0.001 and r = 0.62, p < 0.05, respectively). In all samples, CSF 5-hydroxyindole acetic acid concentrations correlated positively with CSF-homovanillic acid concentrations (r = 0.83, p < 0.001). These findings indicate significant perturbations of the noradrenergic neuronal system and a change in CRH-NE interactions during acute alcohol withdrawal.

Abnormalities of Serotonin Metabolism and Nonpsychotic Psychiatric Disorders

Abnormalities of brain serotonin (5-hydroxytryptamine; 5-HT) metabolism have been proposed as the neurobiological basis of a vulnerability to depression and of a long-standing tendency toward impulsivity and aggression. Results from studies that have employed a variety of 5-HT measures, including the assessment of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations, 5-HT uptake site densities, and 5-HT2 receptor densities in brain tissue and on platelets, and prolactin increases following fenfluramine administration, provide support for these two hypotheses. The goal of future research should be to better define the pathophysiological role of 5-HT dysfunction for both mood instability and impulsivity, in the service of developing improved treatments for these psychopathological conditions.

Milacemide effects on the temporal inter-relationship of amino acids and monoamine metabolites in rat cerebrospinal fluid

The temporal inter-relationship of various amino acids and monoamine metabolites in rat cerebrospinal fluid was examined after acute administration of milacemide (100, 200 or 400 mg/kg i.p.), a glycine prodrug. Glycine concentrations rose linearly and dose dependently (20–190%) but were only significantly elevated at the higher milacemide dose (200 and 400 mg/kg). In animals given 400 mg/kg, glycine values were still significantly elevated 8 h later. A concomitant increase (20–25%) in serine and taurine and a decrease in alanine cerebrospinal fluid values were observed at the highest milacemide dose. Other amino acids were unaffected. While cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations were unaffected, the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, exhibited a linear dose-dependent reduction. However, only homovanillic acid values were significantly decreased after 400 mg/kg milacemide. Cerebrospinal fluid analysis may be useful as a first screen in ascertaining putative neurochemical changes associated with drug administration.

A 2-year prospective follow-up study of children and adolescents with disruptive behavior disorders. Prediction by cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and autonomic measures?

A 2-year prospective follow-up study of 100% (N = 29) of a sample of children and adolescents with disruptive behavior disorders found that the baseline lumbar cerebrospinal fluid monoamine metabolite concentration and autonomic nervous system activity predicted some subsequent outcomes. The 5-hydroxyindoleacetic acid concentration significantly predicted severity of physical aggression during follow-up. The skin conductance level significantly predicted institutionalization. Correlations were in predicted directions with lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and autonomic activity correlated with poor outcome. Moreover, in multivariate analyses, which included nonlaboratory measures as predictors, cerebrospinal fluid and autonomic measures still contributed significantly to the prediction. However, hypothesized predictions of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations for suicide attempts and of low autonomic nervous system activity for arrests were not supported thus far. Patients are still at risk; consequently, these results must be considered preliminary. Nonetheless, the results suggest that further investigation of relationships between biological factors and outcome of children with disruptive behavior disorders is warranted.

Cerebrospinal fluid monoamine and adrenal correlates of aggression in free-ranging rhesus monkeys.

Clinical and preclinical studies involving several different mammalian species and research paradigms suggest a negative correlation between aggression and central serotonin activity. To test the generalizability of laboratory findings in rhesus monkeys that show a negative correlation between cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and aggression, we obtained cisternal cerebrospinal fluid and blood plasma samples from monkeys living in naturalistic conditions. During a semiannual trapping, 28 juvenile and adolescent male rhesus monkeys were chosen from a population of 4200 provisioned, free-ranging rhesus monkeys living on Morgan Island, a sea island located off the coast of South Carolina. Based on direct observations of participation or avoidance of aggressive behavior and examinations of apparent fight wounds, 18 monkeys were selected for cerebrospinal fluid taps and blood samples. The remaining 10 monkeys were selected at random. Descriptions of aggressive behavior and the number of old scars and recent wounds were carefully transcribed, and a photograph showing wounds and scars was obtained for each animal. Using the transcriptions and photographs, researchers experienced in rhesus monkey behavior, but blind to the subjects' monoamine and hormone concentrations, were asked to rank the monkeys from the most to the least aggressive. The results showed a significant negative correlation between high rankings for aggression and cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. There was evidence that aggression was associated with stress, in that cerebrospinal fluid, norepinephrine, and plasma corticotropin and cortisol concentrations were positively correlated with high rankings of aggression.

Prediction of Suicidal Behavior from Biologic Tests

Biochemical studies related with suicidal behavior have mainly dealt with monoaminergic and corticosteroidal measures. We used some of these measures in a study of 61 suicide attempters who, except for occasional doses of benzodiazepines, had been medication free for a mean of 16 days. The monoamine metabolites 5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol were measured in lumbar cerebrospinal fluid (CSF). We found that violent suicide attempters (N = 18) had 5-hydroxyindoleacetic acid concentrations below the median of all patients, whereas the concentrations of 3-methoxy-4-hydroxyphenylglycol were mainly above the median. We found no significant differences between violent and nonviolent (N = 43) attempters concerning CSF homovanillic acid, 24-hour urinary norepinephrine-epinephrine and cortisol, activity of monoamine oxidase in platelets, or post-dexamethasone plasma cortisol. Four patients completed suicide, and 3 of them had CSF 5-hydroxyindoleacetic acid concentrations at or below the median. All completed suicides had CSF 3-methoxy-4-hydroxyphenylglycol concentrations above the median. Urinary measures and platelet monoamine oxidase activity of completed suicides were in the higher concentration ranges. Patients who repeated suicidal behavior after the index investigation had low 24-hour urinary cortisol levels more often than those who did not repeat. Because our subgroups of patients are small, we cannot draw any firm conclusions about the value of our CSF and urinary biochemical findings predicting suicidal behavior. However, our CSF findings in violent suicide attempters are similar to those observed in other studies.

Cerebrospinal Fluid Monoamine Metabolites, Aggression, and Impulsivity in Disruptive Behavior Disorders of Children and Adolescents

Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin, were measured in relation to aggression, impulsivity, and social functioning in 29 children and adolescents with disruptive behavior disorders. The cerebrospinal fluid 5-hydroxyindoleacetic acid level was low compared with that of age-, sex-, and race-matched patients with obsessive-compulsive disorder. Within the disruptive group, significant negative correlations with age-corrected 5-hydroxyindoleacetic acid level were seen for the child's report of aggression toward people and the expressed emotionality of the child toward his or her mother; other correlations of age-corrected 5-hydroxyindoleacetic acid level with measures of aggression were in the expected negative direction but did not reach statistical significance. Impulsivity per se and socioenvironmental factors were not significantly related to cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.

Coexisting Dementia and Depression in Parkinson's Disease

Dementia and depression in patients with Parkinson's disease have been reported separately, but their prevalence is controversial. This study examines the coexistence of these two problems and suggests a common underlying biochemical system. We examined these two entities by retrospective chart review and cerebrospinal fluid biochemistry. We found a prevalence of 10.9% for dementia, 51% for depression, and 5.4% for coincident depression and dementia. In a prospective study of patients with Parkinson's disease we found a continuum of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. Patients who were either depressed or demented had lower concentrations of this metabolite than other patients with Parkinson's disease, but patients who were depressed and demented had the lowest levels. These results suggest that the coexistence of dementia and depression represents a unique clinical entity in Parkinson's disease. The serotonergic system may be involved in depression and dementia because evidence of a cumulative effect on this biochemical system is present.

Relationship of Psychobiological Variables to Recidivism in Violent Offenders and Impulsive Fire Setters

Fifty-eight violent offenders and impulsive fire setters were followed up for an average of 3 years after release from prison. Recidivists who committed a new violent offense or arson had significantly lower cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid concentrations and blood glucose nadirs after oral glucose challenge than did nonrecidivists. A discriminant analysis, based on the blood glucose nadir and cerebrospinal fluid 5-hydroxyindoleacetic acid concentration, correctly classified 84.2% of the subjects.

Family History of Alcoholism in Violent Offenders and Impulsive Fire Setters

Fifty-six of 58 violent offenders and impulsive fire setters fulfilled the DSM-III criteria for alcohol abuse. Information necessary for evaluation of family history of alcoholism was obtained on 54 subjects. Forty-four of the 54 subjects had first- or second-degree blood relatives with alcoholism. Thirty-five had alcoholic fathers. Subjects with alcoholic fathers had a lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration and were more often impulsive than subjects without alcoholic fathers.

Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior

Relationships of impulsive and nonimpulsive violent behavior to cerebrospinal fluid (CSF) monoamines and their metabolite concentrations were studied in thirty-six violent offenders. A relatively low 5-hydroxyindoleacetic acid (5HIAA) concentration was found in the CSF of impulsive violent offenders. This was not true for the offenders who had premiditated their acts. Other CSF monoamine or metabolite concentrations were not significantly different between the two groups. Of the groups studied, impulsive violent offenders who had attempted suicide had the lowest 5HIAA levels. A low CSF 5HIAA concentration may be a marker of impulsivity rather than violence.