CSF 5-HIAA Concentrations Research Articles

CSF P-Tau181 and Other Biomarkers in Patients With Neuronal Intranuclear Inclusion Disease.

CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer disease (AD) and has recently been regarded to reflect β-amyloid and/or p-tau deposition in the AD brain. Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by intranuclear inclusions in neurons, glial cells, and other somatic cells. Symptoms include dementia, neuropathy, and others. CSF biomarkers were not reported. The objective of this study was to investigate whether CSF biomarkers including p-tau181 are altered in patients with NIID. This was a retrospective observational study. CSF concentrations of p-tau181, total tau, amyloid-beta 1-42 (Aβ42), monoamine metabolites homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) were compared between 12 patients with NIID, 120 patients with Alzheimer clinical syndrome biologically confirmed based on CSF biomarker profiles, and patients clinically diagnosed with other neurocognitive disorders (dementia with Lewy bodies [DLB], 24; frontotemporal dementia [FTD], 13; progressive supranuclear palsy [PSP], 21; and corticobasal syndrome [CBS], 13). Amyloid PET using Pittsburgh compound B (PiB) was performed in 6 patients with NIID. The mean age of patients with NIID, AD, DLB, FTD, PSP, and CBS was 71.3, 74.6, 76.8, 70.2, 75.5, and 71.9 years, respectively. CSF p-tau181 was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared with DLB, PSP, and CBS and was comparable between NIID and AD. CSF p-tau181 was above the cutoff value (50.0 pg/mL) in 11 of 12 patients with NIID (91.7%). Within these patients, only 2 patients showed decreased CSF Aβ42, and these patients showed negative or mild local accumulation in PiB PET, respectively. PiB PET scans were negative in the remaining 4 patients tested. The proportion of patients with increased CSF p-tau181 and normal Aβ42 (A-T+) was significantly higher in NIID (75%) compared with DLB, PSP, and CBS (4.2%, 4.8%, and 7.7%, respectively). CSF HVA and 5-HIAA concentrations were significantly higher in patients with NIID compared with disease controls. CSF p-tau181 was increased in patients with NIID without amyloid accumulation. Although the deposition of p-tau has not been reported in NIID brains, the molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID.

Early Rearing Conditions Affect Monoamine Metabolite Levels During Baseline and Periods of Social Separation Stress: A Non-human Primate Model (Macaca mulatta).

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the “experience-expectant brain,” with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study, N = 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR; n = 269) or without adults with 24-h access to same-aged peers (PR; n = 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with the s allele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for the L allele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype.

The effects of fluoxetine on socioemotional behavior in female rhesus monkeys is influenced by social status

BackgroundChronic adverse social experience is a major environmental variable linked to multiple psychiatric disorders. The use of social subordination in nonhuman primates represents a translational model of chronic psychosocial stress. While social dominance is associated with a resistance to a range of stressors and social subordination produces stress‐susceptible phenotypes, the neural mechanisms that underlie status‐induced differences in susceptibility remain unclear. The current study assessed the effects of increasing serotonin (5HT) activity by administering fluoxetine on rates of socioemotional behavior (including agonistic, affiliative, and anxiety‐like behaviors) in female rhesus monkeys. We hypothesized that fluoxetine would increase rates of aggression in dominant but not subordinate animals.MethodsSubjects were gonadally intact adult female rhesus monkeys (n=14) housed in small social groups of four to six females each (6 dominant and 8 subordinate females). Using a counterbalanced design, subjects received both a 14‐day treatment with fluoxetine (SC dose of 2.8 mg/kg/day) and vehicle (50% polyethylene glycol in sterile saline) separated by a three‐week washout period. Behavioral observations were collected every two days using a standard monkey ethogram during each treatment, and CSF samples were collected at the end of each treatment for assessment of central 5‐hydroxyindoleacetic (5HIAA).ResultsThe amount of aggression directed at group mates was influenced by a status by treatment interaction (p=0.05, η2=0.27), with fluoxetine enhancing aggression in dominant females and decreasing aggression in subordinate females. As expected, subordinate females emitted significantly higher rates of submission behavior than did dominant females and this was unaffected by treatment (p=0.001). Affiliation emitted towards others was influenced by a status by treatment interaction (p=0.05, η2=0.27), as fluoxetine treatment decreased affiliation emitted in dominant females and increased it in subordinates. Anxiety‐like behavior was also influenced by a status by treatment interaction (p=0.011), as anxiety‐like behaviors were reduced only in subordinate females by fluoxetine treatment (p=0.012). CSF 5HIAA concentrations were reduced by fluoxetine (p<0.001) regardless of social status.ConclusionThe data show that increased 5HT activity following fluoxetine treatment in female monkeys alters socioemotional behavior in a status‐dependent manner. Notably, subordinate females are less aggressive and more affiliative during fluoxetine treatment. Future studies include determining whether these effects of fluoxetine are sex dependent and whether subordinate males respond similarly to subordinate females.Support or Funding InformationThis research was supported by an NIMH grant MH110212.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dietary tryptophan depletion in humans using a simplified two amino acid formula – a pilot study

BackgroundAcute tryptophan depletion (ATD) is a well-established dietary method in translational brain research used to briefly lower central nervous serotonin (5-hydroxytryptamine (5-HT)) synthesis. A simplified two amino acid ATD formula (ATDPHE/LEU) was developed while reducing the overall amount of amino acids (AAs), with the objective of administration especially in children and adolescents in future studies.ObjectiveThis study investigated tryptophan (TRP) influx rates across the blood-brain barrier (BBB) after dietary ATDPHE/LEU administration relative to the ATD Moja-De protocol that has been established for use in children and adolescents.DesignSeventy-two healthy adults (50% females) were randomized into four groups and administered ATD Moja-De, its TRP-balanced control condition (BAL), ATDPHE/LEU, or its respective control mixture (BALPHE/LEU) in a counterbalanced, double-blind, between-subjects design. Blood samples were collected at baseline and at hourly intervals for 6 h after AA intake. Questionnaires about mood, taste, and challenge tolerance were completed at fixed time points.ResultsBoth challenge mixtures significantly reduced central nervous TRP influx as calculated by Michaelis–Menten kinetics relative to baseline and the respective control conditions with only mild and comparable side effects. A greater decline in TRP influx over the BBB after ATDPHE/LEU administration when compared with ATD Moja-De was detected without group effects for taste, challenge tolerance, and mood. There was unintended initial short increase in plasma TRP concentrations observed after ATDPHE/LEU intake, and a possible redistribution between free and protein-bound TRP triggered by protein synthesis stimulated by the ingested AAs may account for this finding. Moreover, a decline in TRP influx after BALPHE/LEU administration over a 6-h period was observed, and the large amount of PHE in the BALPHE/LEU mixture may be a possible explanation for this particular phenomenon, which could have led to an unexpected increase in displacement of TRP at the BBB in this control condition.ConclusionsThis pilot study provides preliminary evidence for the possibility of lowering TRP influx as calculated by Michaelis–Menten kinetics into the brain by using a simplified ATD protocol in humans. The simplified composition of only two AAs, the lower overall AA amount, and the appropriate tolerance are characteristics of the newly developed ATDPHE/LEU protocol. Future studies focusing on the effects of the ATDPHE/LEU protocol and its respective control condition on CSF 5-HIAA concentrations, as well as neurochemical studies in rodents, are needed to further validate this newly developed AA mixture before definite conclusions about its usability in ATD-related research in humans, its specificity, and additional effects can be made.

Cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid: reciprocal relationships with impulsive aggression in human subjects

While the relationship between cerebrospinal fluid 5-HIAA (CSF 5-HIAA) and aggression is typically reported as inverse, studies of some groups of aggressive individuals demonstrate a positive (or no) relationship, between these two variables. It is possible that simultaneous examination of both CSF 5-HIAA and CSF homovanillic acid (HVA), which co-vary in human subjects may clarify differences in reported findings in different groups of aggressive individuals. CSF 5-HIAA and CSF HVA concentrations were simultaneously examined in 60 healthy human subjects (40 with personality disorder and 20 healthy controls) and were correlated with measures of aggression and impulsivity. CSF 5-HIAA concentrations correlated positively, and CSF HVA concentrations correlated inversely, with a composite measure of impulsive aggression in all subjects as well as in the personality disordered subjects. The CSF 5-HIAA findings are consistent with those demonstrating reduced post-synaptic 5-HT receptor responsiveness to 5-HT agent challenge and suggest differences in the pathophysiology between different groups of subjects with aggressive behavior, particularly with regard to severity of aggressive behavior.

Secondary sexual coloration and CSF 5‐HIAA are correlated in vervet monkeys (Cercopithecus aethiops sabaeus)

Identifying indirect markers of the physiology or neuroendocrinology of a primate can provide a powerful tool to scientists. Anecdotal descriptions and recent experimental evidence suggests that the colorful sexual skin in adult male vervet monkeys (Cercopithecus aethiops sabaeus) might be sensitive to social changes, including dominance relationships, which could be related to serotonergic activity. The present study examined whether individual differences in scrotal coloration were related to cisternal cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (CSF 5-HIAA) in a captive population of vervet monkeys. Darkly colored males had relatively higher CSF 5-HIAA concentrations than paler males, and scrotal color hue was also related CSF 5-HIAA concentrations. These preliminary data are compatible with the hypothesis that scrotal coloration serves as an indirect marker of serotonergic activity. These findings suggest that color assessments might be useful to consider for study design, as well as for animal welfare and captive management.

Maternal Absence and Stability of Individual Differences in CSF 5-HIAA Concentrations in Rhesus Monkey Infants

Maternal Absence and Stability of Individual Differences in CSF 5-HIAA Concentrations in Rhesus Monkey Infants

Maternal Absence and Stability of Individual Differences in CSF 5-HIAA Concentrations in Rhesus Monkey Infants

Early life events often lead to deficits in CNS serotonin function, which underlie a number of reoccurring psychopathological disorders. Studies using rhesus macaques have demonstrated that early maternal deprivation reduces CNS serotonin turnover, as measured by cisternal CSF 5-HIAA concentrations. In addition, individual differences in CSF 5-HIAA remain stable from the first year of life through adulthood. The purpose of this study was to assess 1) the impact of rearing environment on the early development (<6 months of age) of the serotonin system, and 2) at what stage of early development individual differences in CSF 5-HIAA concentrations stabilize. The subjects were 256 infant rhesus macaques reared in three different conditions (mother-reared, peer-reared, and surrogate/peer-reared). Cisternal CSF was obtained at 14, 30, 60, 90, 120, and 150 days of age. No differences in CSF 5-HIAA concentrations were observed between peer only- and surrogate/peer-reared infants, and these groups combined exhibited lower 5-HIAA concentrations than mother-reared infants throughout early development. CSF 5-HIAA concentrations declined with increasing age regardless of rearing condition. Within each rearing condition, individual differences in CSF 5-HIAA concentrations remained stable from 14 to 150 days of age. Early maternal deprivation reduces CNS serotonin turnover, and individual differences in CSF 5-HIAA concentrations are trait-like and appear to stabilize in infancy.

Suicidality, impulsivity and aggression—is there a link to 5HIAA concentration in the cerebrospinal fluid?

In biological suicide research, low cerebrospinal fluid–5-hydroxyindolacetic acid (CSF–5HIAA) concentrations have been associated with suicidality, aggression and impulsivity. However, it frequently appears that the interpretation of existing study results is flawed. The analysis of various published findings suggests that contaminating factors like impulsivity or depressive symptoms in suicide attempters are often not taken into consideration at the time of suicide. The seemingly ‘robust’ association of low CSF–5HIAA concentration with ‘suicidality’ and ‘aggression’ is in fact rather weak. Reported associations of subgroups of suicidal behavior (e.g. violent suicide attempts) with low CSF–5HIAA concentrations are likely to represent somewhat premature translations of findings from studies that have flaws in methodology. Furthermore, the perception of ‘suicidal behavior’ as autoaggressive behavior or inwardly directed aggression in the view of the authors may not be useful in biological suicide research. The construct of aggressivity is insufficiently defined, resulting in difficulties to interpret empirical data. Some evidence exists, however, that reduced CSF–5HIAA concentrations might be related to certain depressive symptoms and changes in impulsivity. More carefully designed studies are required to overcome the existing methodological shortcomings.

Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels

Background:We have proposed a stress-diathesis model for suicidal behavior, in which major depression is a stressor and the diathesis is shared with aggression. Neurotransmitter correlates of the stress or diathesis have not been adequately evaluated by previous studies, because they did not simultaneously examine the relationship of multiple neurotransmitters to all three psychopathologies in the same population. In the present study we investigated the relationship of monoamine metabolites to aggressivity, suicidal behavior, and depression in patients with mood disorders. Methods: Ninety-three drug-free subjects with a major depressive episode underwent lumbar puncture and psychiatric evaluation. Cerebrospinal fluid CSF levels of 5hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and methoxy-hydroxy-phenylglycol (MHPG) were assayed. The relationships between monoamine metabolites and clinical variables were statistically evaluated. Results: Higher lifetime aggressivity correlated significantly with lower CSF 5-HIAA. Lower CSF 5-HIAA and greater suicidal intent were found in high-lethality suicide attempters compared with low-lethality suicide attempters. Low-lethality attempters did not differ biologically from nonattempters. No correlation between CSF HVA and any of the psychopathological variables was found. Only aggression showed a trend statistically in correlating positively with CSF MHPG levels. Conclusions: Lower CSF 5-HIAA concentration was independently associated with severity of lifetime aggressivity and a history of a higher lethality suicide attempt and may be part of the diathesis for these behaviors. The dopamine and norepinephrine systems do not appear to be as significantly involved in suicidal acts, aggression, or depression. The biological correlates of suicide intent warrant further study.

Dr. Stanley Replies

Back to table of contents Previous article Next article Letter to the EditorFull AccessDr. Stanley RepliesBARBARA STANLEY, PH.D., BARBARA STANLEYSearch for more papers by this author, PH.D., New York, N.Y.Published Online:1 Aug 2001https://doi.org/10.1176/appi.ajp.158.8.1336AboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Dr. Brewerton raises an interesting point regarding a potential confound of seasonal variation in serotonin function and aggressive behavior. He suggests that our findings of lower CSF 5-HIAA concentrations in aggressive individuals may be accounted for by seasonal fluctuation. This seems unlikely. Our measure of aggression was a lifetime history of aggressive behavior, not a single incident that occurred at a specific time of the year. It was an accumulation of behaviors across seasons and over many years. Thus, our aggression measure was not seasonal.Furthermore, although there is evidence of seasonality in aggression, the findings are not straightforward. Murder does not show a seasonal change (Michael and Zumpe, 1983); the rates of occurrence for rape (Michael and Zumpe, 1983) and the battering of women (Michael and Zumpe, 1986) are higher in the summer. When all forms of suicide are considered, seasonal variation is not always found (1). However, violent suicides are at their peak in the spring (1).According to Brewerton et al. (1988), CSF 5-HIAA concentrations are at their highest during the summer. When this finding is coupled with the increased rates of battering and rape found during the summer, the results are contrary to the inverse correlation we, as well as others (2, 3), have found between CSF 5-HIAA concentrations and aggression. Dr. Brewerton’s point would be more convincing if CSF 5-HIAA levels were lower, rather than higher, in the summer. Nevertheless, Dr. Brewerton’s point is well taken, and it seems worthwhile to remember to consider the effect of seasonality on both biological and behavioral measures.

479. CSF 5-HIAA and aggression in primates: species and interindividual differences

While the relationship among CSF 5-HIAA, impulsivity, and aggression is well-characterized in males, its investigation in females is limited, and no studies have assessed its generalizability by making simultaneous comparisons between and within closely-related species. In this research we tested hypotheses that (1) female rhesus macaques would have lower CSF 5-HIAA concentrations and be more aggressive than would female pigtailed macaques; (2) females of both macaque species would exhibit an inverse relationship between interindividual differences in CSF 5-HIAA concentrations and rates of severe aggression; and (3) subjects with high CSF 5-HIAA concentrations would be higher in social dominance than would subjects with low CSF 5-HIAA concentrations. We obtained CSF samples from 61 female rhesus and pigtailed macaques and then correlated interindividual differences in CSF 5-HIAA with aggression, wounding, and social dominance rank. Between-species analyses indicated higher CSF 5-HIAA concentrations in pigtailed macaques, and higher rates of high-intensity aggression, escalated aggression, and wounds requiring medical treatment in rhesus macaques. Within-species analyses indicated that interindividual differences in CSF 5-HIAA concentrations were inversely correlated with escalated aggression and positively correlated with social dominance rank. These findings show that agonistic and social differences between closely-related species are correlated with CNS serotonin activity. We conclude that serotonergic functioning plays an important role in controlling impulses that regulate severe aggression and social dominance relationships in both male and female primates, and that between-species differences in agonistic temperament can be predicted by species typical CNS serotonin functioning.

35. Early rearing & genotypic influences on CNS serotonin & behavior in nonhuman primates

Length variation in the serotonin transporter gene-linked promoter region (5-HTTLPR), first described by Lesch et al., are related to serotonin functioning, serotonin-related behaviors, and psychopathological disorders. A similar polymorphism, believed to be homologous, also exists in nonhuman primates. We have recently analyzed the relationship between the rhesus macaque serotonin transporter (rh5-HTTLPR) genotypes, CSF 5-HIAA concentrations, and aggression. Our results show that rhesus macaques with the short rh5-HTTLPR allele have low CSF 5-HIAA concentrations, and are highly aggressive. However, the phenotypic expression of this short allele is environmentally-dependent, with the short allele associated with low CSF 5-HIAA concentrations only in subjects reared in age-matched peer groups that lack adult influence. Aggression was shown to be higher in subjects with the short allele than in subjects with the long allele regardless of early rearing experiences. In humans, the 5-HTTLPR is associated with early infant temperament. Similar data for neonatal rhesus monkeys were collected during assessments on days of life 7, 14, 21 and 30. Subjects with the short rh5-HTTLPR variant exhibit diminished orientation, attention, and increased emotional responses. Consistent with our earlier findings, these differences were generally exaggerated by parental deprivation. These findings illustrate the interacting influence of genotype and early rearing experiences on the developing phenotype.

CSF 5-HIAA and Nighttime Activity in Free-Ranging Primates

Men with low CNS serotonin turnover, as measured by cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations, exhibit aberrant circadian activity patterns characterized by disrupted sleep rhythms and daytime hyperactivity. To assess whether similar patterns are found in nonhuman primates we examined the relationship between CSF 5-HIAA and nighttime activity in free-ranging monkeys. CSF samples were obtained from 16 adult male rhesus macaques living on a 475 acre, heavily forested sea island. Each subject was captured, fitted with a radio-telemetry motion-detector collar, and then released back into its group. A receiver placed near the sleeping trees of the study subjects recorded activity between 2100 hrs and 0600 hrs. Trained observers recorded behavioral data during the day. The animals followed a typical diurnal activity pattern, as they were active 74% of the sampled time during the day and 37% of the sampled time during the night. CSF 5-HIAA concentrations were inversely correlated with total duration of nighttime activity as well as mean duration of all active events. Nighttime activity was inversely correlated with daytime activity. CSF 3-methoxy-hydroxyphenylglycol (MHPG) concentrations were positively correlated with total nighttime activity, and inversely correlated with daytime sleep frequency. We conclude that male rhesus with low CSF 5-HIAA concentrations have higher total nighttime activity, longer mean periods of nighttime activity, and sleep more during the day than do males with high CSF 5-HIAA concentrations. This suggests that low serotonergic neurotransmission is associated with aberrant diurnal activity, as evidenced by a disruption of nighttime sleep patterns and a compensatory higher rate of inactivity during the day.

Severity of depression in abstinent alcoholics is associated with monoamine metabolites and dehydroepiandrosterone-sulfate concentrations

Depressed mood increases the relapse risk of abstinent alcoholics; its neurobiological correlates may include reduced serotonin and norepinephrine turnover rates and increased cortisol concentrations during detoxification stress. Neurosteroids such as dehydroepiandrosterone and its sulfate (DHEA and DHEA-S) may antagonize cortisol action and may have mood-elevating effects on their own. We measured severity of depression with Beck’s Depression Inventory (BDI) and Hamilton’s Depression Rating Scale (HDRS), plasma concentrations of cortisol, DHEA and DHEA-S, and CSF concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and the dopamine metabolite homovanillic acid (HVA) in 21 abstinent alcoholics after 4 weeks of abstinence and in 11 age-matched healthy control subjects. Only CSF MHPG concentrations were reduced in alcoholics compared to control subjects (41.4±6.6 vs. 53.3±8.6 pmol/ml). Self-rated depression was significantly correlated with CSF MHPG (Spearman’s R=+0.57, P<0.01), CSF 5-HIAA ( R=+0.51, P<0.05) and plasma cortisol concentrations ( R=+0.50, P<0.05). Negative correlations were found between DHEA-S concentrations and both self-rated depression ( R=−0.45, P<0.05) and observer-rated depression ( R=−0.55, P<0.05). The ratio of DHEA-S to cortisol serum concentrations was also negatively correlated with depression (BDI: R=−0.55, P<0.01; HDRS: R=−0.63, P<0.005). Anxiety (Spielberger’s State Anxiety Scale) was only associated with CSF MHPG concentrations ( R=+0.58, P<0.01). Our findings point to the importance of noradrenergic dysfunction in the pathogenesis of depression among abstinent alcoholics and indicate that their mood states may also be modulated by a low DHEA-S to cortisol ratio, hypothetically indicative of low stress protection capacities.

CSF 5-HIAA and aggression in female macaque monkeys: species and interindividual differences.

While the relationship among CSF 5-HIAA, impulsivity, and aggression is well characterized in males, its investigation in females is limited, and no studies have assessed its generalizability across primates by making simultaneous comparisons between and within closely-related species. We tested three hypotheses. First, that female rhesus macaques would have lower CSF 5-HIAA concentrations and be more aggressive than would female pigtailed macaques. Second, that females of both macaque species would exhibit an inverse relationship between interindividual differences in CSF 5-HIAA concentrations and rates of severe aggression. Third, that subjects with high CSF 5-HIAA concentrations would be higher in social dominance within their respective groups than would subjects with low CSF 5-HIAA concentrations. We obtained CSF samples from 61 individually housed female primates of two closely related species: rhesus macaques (Macaca mulatta) and pigtailed macaques (Macaca nemestrina). We later placed subjects in unisex social groups, and correlated interindividual differences in CSF 5-HIAA with aggression, wounding, and acquisition of social dominance rank. Between-species analyses indicated higher CSF 5-HIAA concentrations in pigtailed macaques, and higher rates of high-intensity aggression, escalated aggression, and wounds requiring medical treatment in rhesus macaques. Within-species analyses indicated that interindividual differences in CSF 5-HIAA concentrations were inversely correlated with escalated aggression and positively correlated with social dominance rank. These findings show that agonistic and social differences between closely-related species are correlated with CNS serotonin activity, as species that show relatively high rates of severe aggression also tend to have low concentrations of CSF 5-HIAA. We conclude that serotonergic functioning plays an important role in controlling impulses that regulate severe aggression and social dominance relationships in both male and female primates, and that between-species differences in agonistic temperament can be predicted by species typical CNS serotonin functioning.

CSF 5-HIAA levels are lower in impulsive as compared to nonimpulsive violent suicide attempters and control subjects

Background: We studied CSF 5-HIAA and HVA concentrations in violent suicide attempters and examined their relationship with depression, anxiety, and impulsivity.Methods: CSF 5-HIAA and HVA concentrations were determined very shortly after hospital admission and compared to those of a matched control population. Clinical evaluation was performed concomitantly; the level impulsivity was evaluated by the Impulsivity Rating Scale (IRS).Results: Twenty-three patients and 23 control subjects were included. According to the IRS, 14 patients were classified as impulsive, including all patients suffering from personality disorders, and 9 as nonimpulsive, with a main DSM-IIIR diagnosis of melancholia. CSF 5-HIAA concentrations in the suicide group were significantly lower than in control subjects. This difference was entirely due to the impulsive suicide attempters. There was an inverse correlation between the IRS score and CSF 5-HIAA (r = −.47, p = .02) and only a trend for HVA (r = −.41, p = .078) levels in the suicide group.Conclusions: This study of a group of violent suicide attempters distinguished a subgroup of patients diagnosed with personality disorder with high impulsivity scores and a subgroup of patients with the main diagnosis of severe depression. CSF 5-HIAA was significantly lower in impulsive violent attempters than in nonimpulsive violent attempters, therefore desintangling violence from impulsivity and linking this biologic abnormality to impulsivity.

Memory impairment in abstinent MDMA ("Ecstasy") users.

Methylenedioxymethamphetamine (MDMA, or "Ecstasy") is a popular recreational drug of abuse that is known to damage brain serotonergic neurons in animals and possibly humans. Few functional consequences of MDMA-induced serotonin (5-HT) neurotoxicity have been identified, either in animals or humans. This study sought to determine whether individuals with a history of extensive MDMA use showed evidence of memory impairment, because brain serotonin has been implicated in mnemonic function. The authors compared 24 abstinent MDMA users and 24 control subjects on several standardized tests of memory, after matching subjects for age, gender, educational level, and vocabulary score (a surrogate of verbal intelligence). The authors also explored correlations between changes in memory function and decrements in CSF 5-hydroxyindoleacetic acid (5-HIAA), which serves as a marker of central 5-HT neural function. Greater use of MDMA (total milligrams per month) was associated with greater impairment in immediate verbal memory (p < 0.02) and delayed visual memory (p < 0.06). Furthermore, lower vocabulary scores were associated with stronger dose-related effects, with men having greater dose-related deficits than women. Lastly, lower concentrations of CSF 5-HIAA were associated with poorer memory performance. Abstinent MDMA users have impairment in verbal and visual memory. The extent of memory impairment correlates with the degree of MDMA exposure and the reduction in brain 5-HT, as indexed by CSF 5-HIAA.

A replication study of violent and nonviolent subjects: cerebrospinal fluid metabolites of serotonin and dopamine are predicted by plasma essential fatty acids

Background: Among an independent group of subjects selected for their history of violent, impulsive behaviors and nonviolent control subjects, we attempted to replicate the finding that plasma docosahexaenoic acid concentrations were negatively correlated with cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations. Methods: CSF 5-HIAA and homovanillic acid (HVA), fasting total cholesterol, and plasma fatty acid concentrations were examined in violent and nonviolent subjects matched for their severity of alcohol dependence. Results: Violent subjects had significantly higher lifetime violence and hostility ratings and lower concentrations of CSF 5-HIAA than nonviolent subjects. Plasma docosahexaenoic acid was negatively correlated with CSF 5-HIAA only among violent subjects. Conclusions: This observational study suggests that dietary essential fatty acids may change neurotransmitter concentrations. Prospective dietary intervention trials will be required to determine if increasing dietary intake of docosahexaenoic acid will increase or decrease either CSF 5-HIAA concentrations or impulsive and violent behaviors.

Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics

Background: Impulsive violence, suicide, and depression are strongly associated with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA). Increased suicide and trauma reported in some cholesterol-lowering trials may be related to altered concentrations of polyunsaturated fatty acids rather than cholesterol, a possible surrogate marker. Methods: CSF 5-HIAA and homovanillic acid (HVA), total cholesterol, and plasma fatty acid concentrations were examined in 176 subjects, including 49 healthy volunteers, and 88 early- and 39 late-onset alcoholics. Results: Among each group, polyunsaturated fatty acids predicted both CSF 5-HIAA and CSF HVA concentrations, but total cholesterol was unrelated to either neurotransmitter metabolite. The relationships between plasma 22:6n3 and CSF 5-HIAA were significantly different when healthy volunteers ( r = .35) were compared to early-onset alcoholics ( r = −.38) ( p < .0002). Conclusions: Dietary studies are indicated to determine if essential fatty acid supplementation can influence central nervous system serotonin and dopamine metabolism and modify impulsive behaviors related to these neurotransmitters.