CSF 5-HIAA Concentrations Research Articles

In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates.

Studies on brain serotonin metabolism in human and nonhuman primates have indicated that dysfunction of serotonin transmission may play a role in the biological vulnerability to dependence on alcohol. Among young men, low sensitivity to alcohol intoxication predicts subsequent alcohol abuse and dependence. The authors used single photon emission computed tomography and the radioligand [(I)123]beta-CIT ([(I)123]methyl 3beta-(4-iodophenyl) tropane-2-carboxylate) to measure the availability of serotonin transporters in 11 male rhesus monkeys, and the monkeys were genotyped for a functional polymorphism of the serotonin transporter gene. The 11 monkeys had experienced parental separation after birth; their behavior and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in CSF had been assessed regularly. In the 5-year-old monkeys, there was a significant negative correlation between beta-CIT binding to serotonin transporters in the brainstem and 5-HIAA concentrations in CSF. Animals with greater beta-CIT binding and low CSF 5-HIAA concentrations displayed greater aggressiveness and were less sensitive to alcohol-induced intoxication. The genetic constitution of the serotonin transporter promoter gene did not significantly contribute to the availability of brainstem serotonin transporters as measured by beta-CIT binding. In adult nonhuman primates who underwent early developmental stress, variables indicating a low serotonin turnover rate were associated with behavior patterns similar to those predisposing to early-onset alcoholism among humans.

Central serotonin activity and aggression: inverse relationship with prolactin response to d-fenfluramine, but not CSF 5-HIAA concentration, in human subjects.

This study compared the nature and magnitude of the relationship between aggression and CSF 5-hydroxyindoleacetic acid (5-HIAA) concentration with that between aggression and the prolactin response to d-fenfluramine challenge in human subjects. The Life History of Aggression assessment scores of 24 subjects with personality disorders were compared with their lumbar CSF 5-HIAA concentrations and with their prolactin responses to d-fenfluramine challenge. Aggression was significantly and inversely correlated with prolactin responses to d-fenfluramine challenge but not with lumbar CSF 5-HIAA concentrations in these subjects. Prolactin response to d-fenfluramine may be more sensitive than lumbar CSF 5-HIAA concentration in detecting a relationship between aggression and central serotonin activity in noncriminally violent human subjects.

CSF testosterone and 5-HIAA correlate with different types of aggressive behaviors

We studied the potential roles of testosterone and serotonin in various forms of aggressive and violent behaviors by measuring each biochemical and behaviour in free-ranging adolescent male nonhuman primates. Our results showed that (1) CSF free testosterone concentrations were positively correlated with overall aggressiveness, but not with measures of impulsivity. (2) CSF 5-HIAA concentrations were negatively correlated with impulsive behavior, and severe, unrestrained aggression, but not with overall rates of aggression. High rates of impulsive behavior were positively correlated with severe, unrestrained aggression, but not overall rates of aggression. (3) Dimensional analyses showed that while subjects with low CSF 5-HIAA exhibited high rates of aggression, high CSF testosterone further augmented rates and intensity of aggression in subjects with low CSF 5-HIAA. We conclude that high CSF free testosterone concentrations are associated with competitive aggression, while low CSF 5-HIAA concentrations are associated with severe aggression which results from impaired impulse control, and perseverance.

Temperamental vulnerability and suicide risk after attempted suicide.

The aim was to extend recent findings of suggested temperamental features in attempted suicide and to explore possible domains of vulnerability to suicide risk after attempted suicide. Fifty-four psychiatric inpatients hospitalized after a suicide attempt underwent lumbar puncture for analysis of CSF 5-HIAA concentration and also completed the Karolinska Scales of Personality (KSP) before discharge from the hospital. Suicide attempters scored high on Somatic Anxiety, Psychic Anxiety, and Muscular Tension, and low on Socialization, findings that support recent findings in suicide attempters followed up after an emergency room visit. Five patients committed early suicide, i.e., within 3 years, and the overall long-term suicide mortality after attempted suicide was 13%. There were significant correlations between survival time among early suicides and CSF 5-HIAA (r = .87; p = .054), and the following KSP scale t scores: Somatic Anxiety (r = -.96; p < .05), Impulsivity ( r = -.88; p < .05), and Socialization (r = 90; p < .05). KSP Socialization showed correlations with CSF 5-HIAA (r = .89; p = .046) among the early suicides. Features of temperamental vulnerability to suicide risk after attempted suicide might involve anxiety proneness, impulsivity, low socialization, and low CSF 5-HIAA.

A delphi method approach to describing mental health practice

Lumbar puncture was performed on 12 healthy female volunteers at the L4-5 level. CSF concentrations of 5-HIAA, HVA and HMPG were included in turn as dependent variables in repeated analyses of covariance with age, height, tapping-time, atmospheric pressure and the distance on the spine in the lying position as regressors. Use or non-use of oral contraceptives was included as a nominal variable. Results obtained were confirmed by nonparametric statistics. We found significant relationships between 5-HIAA and HVA, respectively, and height when the concentrations per minute of tapping-time (nM/min) were used as dependent variables. Hypothetically, the tapping-time mirrors the transport of concentrated CSF from the cranial to the caudal region when sitting up. We also found significant influences of atmospheric pressure and the use or non-use of oral contraceptives on HMPG. The role of atmospheric pressure is not clear but it might contribute to the transport of HMPG from the periphery to the CSF or affect the outflow of HMPG from the lumbar CSF compartment. The contribution of oral contraceptives might reflect interactions in the cerebral catecholamine metabolism.

An investigation of ‘early’ psychiatric readmissions

Lumbar puncture was performed on 12 healthy female volunteers at the L4-5 level. CSF concentrations of 5-HIAA, HVA and HMPG were included in turn as dependent variables in repeated analyses of covariance with age, height, tapping-time, atmospheric pressure and the distance on the spine in the lying position as regressors. Use or non-use of oral contraceptives was included as a nominal variable. Results obtained were confirmed by nonparametric statistics. We found significant relationships between 5-HIAA and HVA, respectively, and height when the concentrations per minute of tapping-time (nM/min) were used as dependent variables. Hypothetically, the tapping-time mirrors the transport of concentrated CSF from the cranial to the caudal region when sitting up. We also found significant influences of atmospheric pressure and the use or non-use of oral contraceptives on HMPG. The role of atmospheric pressure is not clear but it might contribute to the transport of HMPG from the periphery to the CSF or affect the outflow of HMPG from the lumbar CSF compartment. The contribution of oral contraceptives might reflect interactions in the cerebral catecholamine metabolism.

Cerebral glucose metabolism, CSF 5-HIAA levels, and aggressive behavior in rhesus monkeys

Considerable evidence suggests that low concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in CSF are associated with a history of aggressive behavior in both human and nonhuman primates. The purpose of this investigation was to examine the relationships among CSF 5-HIAA concentration, history of aggressive behavior, and cerebral glucose metabolism in a group of nonhuman primates whose CSF 5-HIAA had been sampled several times over the preceding 2 years and whose social behavior had been observed since birth. The subjects were nine adult male rhesus monkeys studied under isoflurane anesthesia. Cerebral glucose utilization was measured by [18F]fluorodeoxyglucose positron emission tomography. Aggressiveness ratings were made by a primatologist who had had frequent contact with the animals over several years. There was a significant negative correlation between ratings of aggressive behavior and CSF 5-HIAA concentrations. There was also a negative correlation between the dose of pentobarbital required to induce anesthesia and level of CSF 5-HIAA. Moreover, there were significant negative correlations between CSF 5-HIAA levels and both whole brain glucose utilization and regional glucose utilization in the orbital-frontal cortex. These results suggest that both increased aggressiveness and low concentrations of CSF 5-HIAA are associated with higher brain glucose metabolism in rhesus monkeys under standardized anesthesia. Aggressive nonhuman primates with low CSF 5-HIAA concentrations may have "innate" tolerance toward functional gamma-aminobutyric acid A receptor agonists such as pentobarbital, isoflurane, and possibly alcohol.

Effect of probenecid on 5-hydroxyindoleacetic acid in cisternal cerebrospinal fluid of rats with portacaval anastomosis

Portal-systemic encephalopathy (PSE) is characterized by a neuropsychiatric disorder progressing through personality changes, to stupor and coma. Previous studies have revealed alterations of serotonin and of its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in brain tissue and CSF in experimental (rat) and human PSE. Increased brain 5-HIAA concentrations could result from its decreased removal rather than to increased serotonin metabolism. In order to evaluate this possibility, CSF 5-HIAA concentrations were measured using an indwelling cisterna magna catheter technique at various times following end-to-side portacaval anastomosis in rats (the most widely used animal model of PSE) treated with probenecid, a competitive inhibitor that blocks the active transport of acid metabolites out of the brain and CSF. Following portacaval anastomosis and probenecid treatment, CSF concentrations of 5-HIAA were increased to a greater extent than in sham-operated controls. When data were expressed as per-cent baseline values, the relative increase of CSF 5-HIAA in portacaval shunted rats following probenecid treatment was not significantly different from sham-operated controls. These findings confirm that increased 5-HIAA in the CNS in experimental PSE results from increased 5HT metabolism or turnover and that the probenecidsensitive acid metabolite carrier is intact in PSE.

Correlation of CSF 5-HIAA concentration with sociality and the timing of emigration in free-ranging primates

The purpose of this study was to examine the relationship between behavior and serotonin in nonhuman primates. During a routine capture and medical examination, 26 adolescent male rhesus macaques (Macaca mulatta) were selected as subjects from a free-ranging population of 4,500 rhesus monkeys inhabiting a 475-acre sea island. Blood samples (N = 23) and CSF samples (N = 22) were obtained, and each subject was fitted with a radio transmitter collar for rapid location. The subjects were released into their social groups, and quantitative behavioral observations were made over a 3-month period. CSF 5-hydroxyindoleacetic acid (5-HIAA) concentration was positively correlated with three measures of sociality: 1) total time spent grooming others, 2) total time spent in close proximity to other group members, and 3) mean number of neighbors within a 5-m radius. In addition, CSF 5-HIAA concentration was positively correlated with age at emigration from the natal group (in months). In adolescent male rhesus macaques living in naturalistic settings, CSF 5-HIAA concentration is positively correlated with affiliative sociality. Rhesus males with low CSF 5-HIAA concentrations exhibit less social competence and emigrate from their social groups at a younger age than do males with higher concentrations of CSF 5-HIAA.

Influence of tapping-time and atmospheric pressure on concentrations of monoamine metabolites in the cerebrospinal fluid: A prospective study in female volunteers

Lumbar puncture was performed on 12 healthy female volunteers at the L4-5 level. CSF concentrations of 5-HIAA, HVA and HMPG were included in turn as dependent variables in repeated analyses of covariance with age, height, tapping-time, atmospheric pressure and the distance on the spine in the lying position as regressors. Use or non-use of oral contraceptives was included as a nominal variable. Results obtained were confirmed by nonparametric statistics. We found significant relationships between 5-HIAA and HVA, respectively, and height when the concentrations per minute of tapping-time (nM/min) were used as dependent variables. Hypothetically, the tapping-time mirrors the transport of concentrated CSF from the cranial to the caudal region when sitting up. We also found significant influences of atmospheric pressure and the use or non-use of oral contraceptives on HMPG. The role of atmospheric pressure is not clear but it might contribute to the transport of HMPG from the periphery to the CSF or affect the outflow of HMPG from the lumbar CSF compartment. The contribution of oral contraceptives might reflect interactions in the cerebral catecholamine metabolism.

Low CSF 5-HIAA concentrations and severe aggression and impaired impulse control in nonhuman primates.

The purpose of this study was to examine the relationship between behavior and serotonin by using a nonhuman primate model of aggression and impulse control. During a routine capture and medical examination, 26 adolescent male rhesus macaques (Macaca mulatta) were selected as subjects from a free-ranging population of 4,500 rhesus monkeys inhabiting a 475-acre sea island. Physiological data were obtained from 22-23 of the subjects. Blood and CSF samples were obtained, and each subject was fitted with a radio transmitter collar for rapid location. The subjects were released into their social groups, and quantitative behavioral observations were made over a 3-month period. CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were inversely correlated with "escalated" aggression, i.e., a measure of more intense or severe aggression as defined by the ratio of chases and physical assaults to all aggressive acts. CSF 5-HIAA concentrations were significantly lower in those subjects who showed evidence of physical wounding than in subjects with no wounds. Low CSF 5-HIAA concentrations were also correlated with greater risk-taking as determined by an analysis of leaping behaviors in the forest canopy. The ratio of long leaps (leaps that traversed the longest distances at dangerous heights) to all leaps was negatively correlated with CSF 5-HIAA concentrations. Adolescent male rhesus macaques with low CSF 5-HIAA concentrations are at risk for 1) exhibiting more violent forms of aggressive behavior and 2) loss of impulse control as evidenced by greater risk taking during movement through the forest canopy.

CSF concentration gradients of monoamine metabolites in patients with hydrocephalus.

Concentration gradients of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), were assessed in 762 successive CSF fractions (2 ml lumbar CSF) from 15 patients with the adult hydrocephalus syndrome (AHS) and 11 patients with hydrocephalus of other causes (mixed group). A mean volume of 49.6 (SD 11.8) ml CSF was removed in the AHS group and 56.4 (10.2) ml in the mixed group. The CSF was collected with a specially designed carousel fraction collector and the corresponding CSF dynamics were continuously registered by a constant pressure CSF infusion method. Pronounced gradients in CSF HVA and CSF 5-HIAA were seen in both patient groups in the first 25 ml of CSF removed. The concentration curves levelled off, despite the removal of larger amounts of CSF and stabilised at about twice the initial concentrations. This phenomenon has not been described before. Concentrations of HVA and 5-HIAA in the first CSF fraction correlated strongly with concentrations in fractions up to about 40 ml. A positive correlation between the first fraction of CSF HVA and CSF 5-HIAA concentrations and CSF outflow conductance was found in the AHS group. There was no gradient in MHPG. It is suggested that the rostrocaudal gradients in CSF HVA and 5-HIAA may be explained by a downward flow of CSF along the spinal cord with absorption of metabolites occurring during passage. Mixing of CSF from different CSF compartments, extraventricular production sites of CSF, clearance of metabolites to venous blood or extracellular fluid, and CSF outflow conductance are probably important determinants of the plateau phase in patients with hydrocephalus. It is concluded that lumbar CSF does not exclusively reflect the concentrations of HVA, 5-HIAA, or MHPG in the ventricles. It should be noted that these results obtained in patients with hydrocephalus may not be applicable to other groups of patients or normal subjects.

Test-retest reliability of team consensus best-estimate diagnoses of axis I and II disorders in a family study.

The present study examined the test-retest reliability of team consensus best-estimate diagnoses of axis I and II disorders. As part of a series of family studies of outpatients with depressive and personality disorders, best-estimate diagnoses of relatives were derived in team diagnostic conferences held regularly over 4 years. Diagnoses were based on all available information, including direct interviews, family history data, and treatment records, and explicit guidelines were developed to resolve discrepancies between data sources. To evaluate the reliability of the team best-estimate diagnoses, 92 relatives were independently rediagnosed after a 2-year interval. The reliability of both axis I and II disorders was good to excellent. The results were similar for cases in which diagnoses were based on direct interviews plus informant data and cases in which diagnoses were based on informant data alone. These data indicate that the team consensus best-estimate diagnostic method can be applied consistently, even over an interval of several years.

Tapping-time influences concentrations of 5-HIAA in the CSF

Lumbar puncture was performed on 12 healthy male volunteers at the L 4–5 level to investigate the influence of tapping-time on CSF levels of transmitter metabolites. Applying a backward multiple regression model to the data, height, age and tapping-time was found to influence 5-HIAA while HVA correlated only with height. Also HMPG was influenced by height, but the distance from the external occipital protuberance to the site of puncture made a contribution. The present results indicate that tapping-time might be a factor of importance when using CSF concentrations of 5-HIAA as a measure of serotonin turnover.

Brain serotonin, type II alcoholism and impulsive violence.

There is ample evidence that low CSF 5-HIAA concentration is associated with a tendency to exhibit impulsive violent behavior under the influence of alcohol. This is especially true for subjects who fulfill criteria for psychiatric diagnoses often associated with early onset alcoholism such as antisocial personality disorder and intermittent explosive disorder. Brain serotonin turnover as indicated by CSF 5-HIAA concentration does not correlate with CSF free testosterone concentration. The latter is more strongly associated with outward-directed aggressiveness and lack of socialization than impulsiveness. CSF ACTH concentration on the other hand correlates positively with socialization.

CSF 5-HIAA and HVA concentrations in elderly depressed patients who attempted suicide

CSF findings distinguished 12 elderly depressed patients who attempted suicide from nine depressed patients who did not and from seven normal control subjects. Psychosocial factors and measures of psychopathology did not differentiate suicidal from nonsuicidal patients. Biochemical factors may be important in evaluating suicide risk in the elderly.

5-HIAA in Cerebrospinal Fluid and Deficit Schizophrenic Characteristics

Higher CSF 5-HIAA concentrations and lower CSF HVA concentrations have been associated with various measures of slowed motor behaviour and communication in schizophrenic patients. To derive a single, reliable measure of deficit characteristics in schizophrenic patients, we entered four items of the BPRS reflecting negative symptoms, a work history measure derived from the Strauss-Carpenter scale, and three subscale scores of the WAIS-R into a principal-components analysis to derive a single factor score. The CSF 5-HIAA concentrations were within the normal range of values, and correlated directly with this factor score, but CSF HVA concentrations were not associated with the deficit factor score. These findings add support to the hypothesis that brain serotonin function is associated with deficit schizophrenic characteristics.

Central serotonergic function in parasuicide

1. 1. Central 5-HT is thought to be involved in neuronal inhibition and as such as a modulating influence in restraining the organism from responding to (e.g., especially adverse) stimuli. 2. 2. Evidence for a role of central 5-HT in suicide arises from reduced concentrations of brain 5-HT or 5-HIAA in brain stem, reduced binding of [3-H]-IMI in brain tissue of frontal cortex/hypothalamus, and increased binding of radioligands to 5-HT-2 receptors in the frontal cortex. 3. 3. Evidence for a role of central 5-HT in parasuicide arises from reduced concentrations of lumbar CSF 5-HIAA, reduced PRL responses to d,l-fenfluramine challenge, and increased CORT responses to 5-HTP challenge. 4. 4. Since reduced central 5-HT activity appears to be consistently associated with impulsiv aggression, it is possible that suicidal and parasuicidal acts in individuals with evidence of reduced central 5-HT activity are a manifestation of reduced impulse control. 5. 5. Agents which enhance central 5-HT function and/or diminish the activity of neuronal systems involved in arousal (e.g. norepinephrine or dopamine) should be efficacious in reducing parasuicidal behavior.

Xq28 DNA markers and inheritance of manicdepressive illness: Rejection of linkage

contributions of CNS systems to ID in reactivity, assessed via CSF monoamine metabolites. Twenty Rhesus monkeys were reared for their first six months either with only peers (N = 8) or as controls with their mothers (N = 12). When subjects were six and 18 months of age, they underwent a series of four 4-day social separations. Thereafter, both groups were placed together and received identical treatment. In both years, prior to and during separations, CSF was obtained via cistemal puncture. The more reactive peer-only reared subjects had higher levels of MHPG across both years and in the second year, higher levels of 5-HIAA. Within group ID were remarkably stable: Mean separation levels of MHPG, HVA, and 5-HIAA correlated at r = .47, .71, and .5 1 respectively. When these subjects and an additional 20 were grouped according to their unfamiliar biological sire, CSF 5-HIAA and HVA concentration were heritable.

Biochemical aspects of suicidal behavior

Traskman-Bendz, Lil, Marie Asberg, Peter Nordstrom and Michael Stanley: Biochemical Aspects of Suicidal Behavior. Prog. Neuropsychopharmacol. & Biol. Psychiat. 1989, 13 (Suppl): S35–S44 1. 1. In completed suicides, studies of brain regions and CSF indicate a dysfunction of the serotonergic system. 2. 2. In suicidal patients, regardless of diagnoses, analyses of monoamine metabolites in lumbar CSF reveal decreased concentrations of the serotonin metabolite 5-HIAA. 3. 3. In depressed suicidal patients,both low CSF 5-HIAA and low concentrations of the dopamine metabolite HVA are associated with suicidality.In addition, pathological dexamethasonetests may indicate an increased suicide-risk in these patients. 4. 4. In depressed patients, there is evidence that the association between CSF 5-HIAA and corticosteroids is in contrast to findings in depressed suicidal patients.