5-hydroxyindoleacetic Acid Concentrations Research Articles

Self-rated childhood emotional neglect and CSF monoamine indices in abstinent cocaine-abusing adults: possible implications for suicidal behavior

Non-human primate studies suggest that early environmental influences may have an enduring effect on central serotonin function. Therefore, it was decided to examine in humans whether childhood trauma might be related to cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) as an adult. A total of 29 withdrawn cocaine-dependent patients completed the Childhood Trauma Questionnaire. They also had a lumbar puncture for determination of CSF concentrations of 5-HIAA. CSF concentrations of the dopamine metabolite homovanillic acid (HVA) were also determined. Childhood emotional neglect scores showed significant negative correlations with CSF levels of 5-HIAA and HVA, and patients with emotional neglect scores above the median had significantly lower CSF 5-HIAA and HVA levels than patients with emotional neglect scores at or below the median. These findings suggest the possibility that childhood trauma may have an effect on central monoamine function as an adult.

Vasopressin in CSF and plasma in depressed suicide attempters: preliminary results

Increased plasma arginine vasopressin (AVP) concentrations have been reported in depressed suicide attempters. Plasma AVP is primarily produced by the magnocellular system in response to increased plasma osmolality, and central AVP may be independently regulated. In the present study we investigated cerebrospinal fluid (CSF) and plasma AVP concentrations in depressed patients and controls. Nineteen drug-free depressed psychiatric inpatients (nine suicide attempters) and nine neurological control subjects underwent lumbar puncture and psychiatric evaluation. CSF and plasma concentrations of AVP, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol were assayed. In 15 depressed patients (eight suicide attempters), the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed to examine the hypothalamic–pituitary–adrenocortical (HPA) system. There were no differences between depressed subjects and controls in all parameters measured. Suicide attempters did not differ from nonattempters. In depressed patients, plasma AVP correlated positively with cortisol. There was no relationship between CSF AVP and monoamine metabolites in CSF.

Effects of pentylenetetrazol-induced kindling of seizures on rat emotional behavior and brain monoaminergic systems

The influence of pentylenetetrazol (PTZ)-induced kindling of seizures on the rat emotional behavior, the brain monoamine turnover rate measured in vitro, and correlation between behavioral and biochemical parameters, were examined in rats. The repeated administration of PTZ (35 mg/kg, ip) evoked kindled seizures in rats (Stage 4 or 5 of clonic–tonic convulsions—maximum). PTZ kindling caused selective changes in the rat emotional behavior, present in some models of anxiety only (a decreased freezing time in the conditioned freezing test and a decreased spontaneous and aversively conditioned ultrasonic vocalization). Simultaneously, PTZ kindling decreased the concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the prefrontal cortex, decreased the DA (HVA/DA ratio) turnover rate in the striatum, and inhibited the serotonin (5-HT) metabolism (5-HIAA/5-HT ratio) in the hippocampus and the prefrontal cortex. Correlations between dopamine (DA) or 5-HT regional metabolic rates in brain structures and animal behavior were either abolished or reversed in PTZ-kindled animals. It is concluded that both DA and 5-HT systems contribute to the emotional effects of PTZ-induced kindling of seizures. The hypothesis is put forward that PTZ kindling-induced inhibition of the serotonergic innervation may lead to the compensatory increase in 5-HT 1A receptors in the dentate gyrus of the hippocampus, thus evoking the anxiolytic-like changes in animal behavior.

Suicide.

Suicide is a multidimensional concomitant of psychiatric diagnoses, especially mood disorders, and is complex in both its causation and in the treatment of those at risk. It has known risk and protective factors that tend to be fairly consistent worldwide, with some cultural variation. Even with standardised assessment and prediction scales (such as the Hamilton or Beck depression inventories), suicide prediction results in about 30% false positives. The most common biological marker of suicide is reduced concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid in the CSF of suicide cases versus controls. Although suicide prevention is ideally primary, in fact most treatment is secondary or tertiary. Dependent on the individual characteristics present, suicide prevention usually includes a pharmacological cocktail (especially one of the selective serotonin reuptake inhibitors, to raise serotonin concentrations, perhaps combined with an anxiolytic, mood stabilising, or antipsychotic agent), supportive psychotherapy (often cognitive or behavioural therapy), and sometimes electroconvulsive therapy. Perceived danger to self can necessitate treatment in hospital.

Serotonin, testosterone and alcohol in the etiology of domestic violence

In a previous study we administered the panicogenic agent sodium lactate to a select group of perpetrators of domestic violence and comparison groups. Results of that study showed that perpetrators exhibited exaggerated lactate-induced fear, panic and rage. In this current study, we compared the cerebral spinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and testosterone obtained from perpetrators of domestic violence and a group of healthy comparison subjects. All subjects were assessed for DSM-III-R diagnoses. Perpetrators with alcohol dependence (DV-ALC) ( n=13), perpetrators without alcohol dependence (DV-NALC) ( n=10) and healthy comparison subjects (HCS) ( n=20) were clinically assessed using the Spielberger Trait Anxiety, Brown–Goodwin Aggression Scale, Buss Durkee Hostility Inventory and Straus Conflict Tactics. Following an overnight fast and bed rest, subjects received a lumbar puncture to obtain CSF concentrations of 5-HIAA and testosterone. Perpetrators scored significantly higher on measures of aggression than HCS. DV-NALC had significantly lower concentrations of CSF 5-HIAA and higher Straus Conflict Tactics (CT) physical violence scores than DV-ALC and HCS. DV-ALC had significantly higher concentrations of CSF testosterone than DV-NALC. DV-ALC also had significantly higher Straus CT physical violence scores than HCS. DV-NALC and DV-ALC differed on 5-HIAA concentrations, testosterone concentrations, Straus CT physical violence scores and alcohol dependence. These results suggest that DV-NALC and DV-ALC groups could have different biological mechanisms mediating domestic violence.

Effects of isatin on rotational behavior and DA levels in caudate putamen in Parkinsonian rats

Isatin was a potent endogenous monoamine oxidase (MAO) inhibitor that is more active against MAO-B than MAO-A. The acute effects of isatin on apomorphine (APO)-induced rotations were evaluated in Parkinsonian rats induced by 6-hydroxydopamine (6-OHDA) lesion. Furthermore, the effects of isatin on DA release in caudate putamen (CPu) of model and normal rats were monitored using fast cyclic voltammetry (FCV). The contents of monoamine transmitters and their metabolites in CPu of model and normal rats were also analyzed by high performance liquid chromatography with electrochemical detection after administration of isatin. Here we show that isatin (100 mg/kg, i.p.) apparently inhibited APO-induced rotations of Parkinsonian rats to 39.1±3.7% of the control ( n=12), while it had no apparent effects on electrical stimuli-induced DA release either in normal rats or in model rats. In addition, the content of 5-hydroxytryptamine but not DA was increased in both normal rats and model rats after isatin (100 mg/kg, i.p.) was administered ( P<0.01, n=6). The content of 5-hydroxyindole acetic acid was not changed. These results suggest that isatin cannot increase DA levels in rat CPu. Therefore, the effects of isatin on APO-induced rotations of our Parkinsonian rats could not attribute to its inhibition of DA catabolism as a MAO inhibitor.

Inhibition of K+-Evoked Release of Rat Striatal 5-Hydroxytryptamine by an Atypical Antidepressant: Trazodone

Using microdialysis, extracellular concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the striatum of rats. In rats given trazodone, m-chlorophenylpiperazine dihydrochloride, or imipramine, the concentrations of 5-HT were unchanged. 5-HIAA in trazodone- or imipramine-treated rats, however, was respectively, decreased to 80 or 65% of preinjections levels. When the potassium concentration (K⁺) was increased up to 150 mmol/l in the perfusate, the concentrations of 5-HT increased to about ten times the basal levels in the rats given saline. In rats treated with trazodone, K⁺-evoked elevations of 5-HT were less than five times the basal level. Multiple trazodone administrations prolonged the duration of inhibition of 5-HT release. In rats treated with other drugs, the K⁺-evoked 5-HT release was not affected. These observations suggest that trazodone itself might reduce 5-HT neural transmission.

β-Amyloid(1-42)-Induced Cholinergic Lesions in Rat Nucleus Basalis Bidirectionally Modulate Serotonergic Innervation of the Basal Forebrain and Cerebral Cortex

Ample experimental evidence suggests that β-amyloid (Aβ), when injected into the rat magnocellular nucleus basalis (MBN), impels excitotoxic injury of cholinergic projection neurons. Whereas learning and memory dysfunction is a hallmark of Aβ-induced cholinergic deficits, anxiety, or hypoactivity under novel conditions cannot be attributed to the loss of cholinergic MBN neurons. As mood-related behavioral parameters are primarily influenced by the central serotonergic system, in the present study we investigated whether Aβ(1-42) toxicity in the rat MBN leads to an altered serotonergic innervation pattern in the rat basal forebrain and cerebral cortex 7 days postsurgery. Aβ infusion into the MBN elicited significant anxiety in the elevated plus maze. Aβ toxicity on cholinergic MBN neurons, expressed as the loss of acetylcholinesterase-positive cortical projections, was accompanied by sprouting of serotonergic projection fibers in the MBN. In contrast, the loss of serotonin-positive fiber projections, decreased concentrations of both serotonin and 5-hydroxyindoleacetic acid, and decline of cortical 5-HT1A receptor binding sites indicated reduced serotonergic activity in the somatosensory cortex. In conclusion, the Aβ-induced primary cholinergic deficit in the MBN and subsequent cortical cholinergic denervation bidirectionally modulate serotonergic parameters in the rat basal forebrain and cerebral cortex. We assume that enhanced serotonin immunoreactivity in the damaged MBN indicates intrinsic processes facilitating neuronal recovery and cellular repair mechanisms, while diminished cortical serotonergic activity correlates with the loss of the subcortical cholinergic input, thereby maintaining the balance of neurotransmitter concentrations in the cerebral cortex.

Effects of the serotonin receptor antagonist cyproheptadine on the activity and pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

DMXAA (5,6-dimethylxanthenone-4-acetic acid) is a new drug synthesized in this laboratory and currently in phase I clinical trial. In mice it acts as an antivascular drug, selectively inhibiting tumour blood flow and inducing tumour haemorrhagic necrosis with resultant tumour regression. It also induces the synthesis of tumour necrosis factor (TNF), nitric oxide and serotonin. Cyproheptadine, a type 2 serotonin receptor antagonist, is known to reduce the degree of tumour necrosis-induced TNF in mice. We investigated the pharmacological interaction between a suboptimal dose of DMXAA (20 mg/kg) and cyproheptadine (20 mg/ kg) using mice with Colon 38 tumours that are sensitive to DMXAA. Mice with or without tumours were treated with DMXAA and/or cyproheptadine. Concentrations of plasma and tissue DMXAA and the serotonin metabolite 5-hydroxyindoleacetic acid were measured by high performance liquid chromatography. TNF concentrations were measured by ELISA. While DMXAA alone (20 mg/kg) showed little or no antitumour activity, coadministration with cyproheptadine was curative in four of five mice. DMXAA half-lives in plasma and tumour tissue were increased 5.1- and 5.6-fold, respectively, and the appearance of DMXAA glucuronides in bile was almost completely inhibited for up to 4 h. Serum TNF was low and unchanged by cyproheptadine, and plasma concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were also not substantially changed. The augmentation by cyproheptadine of the induction of tumour response to DMXAA reflects a pharmacological interaction, leading to increased plasma and tumour half-lives, and to reduced excretion. However, serum TNF concentrations were not increased, suggesting that the increased anti-tumour effects are mediated by an increased local tumour response, arising from the extended tumour DMXAA concentrations.

Rapid Changes in Monoamine Levels Following Administration of Corticotropin-Releasing Factor or Corticosterone Are Localized in the Dorsomedial Hypothalamus

Monoaminergic systems are important modulators of the neuroendocrine, autonomic, and behavioral responses to stress-related stimuli. The male roughskin newt (Taricha granulosa) was used as a model system to investigate the effects of corticotropin-releasing factor (CRF) or corticosterone administration on tissue concentrations of norepinephrine, epinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) in microdissected brain areas. Intracerebroventricular infusion of 25 or 50 ng of CRF increased locomotor activity and site-specifically increased dopamine concentrations within the dorsomedial hypothalamus 30 min after treatment when compared to vehicle-treated controls. In further studies, male newts were treated as follows: (1) no injection, no handling, (2) saline injection, or (3) 10 μg corticosterone and then placed in a novel environment. Monoamine and monoamine metabolite concentrations were similar in the unhandled and saline-injected controls 20 min after treatment. In contrast, corticosterone-injected newts had elevated concentrations of dopamine, serotonin, and 5-HIAA in the dorsomedial hypothalamus (a region that contains dopamine- and serotonin-accumulating neuronal cell bodies in representatives of all vertebrate classes) but not in several other regions studied. These site-specific neurochemical effects parallel neurochemical changes observed in the dorsomedial hypothalamic nucleus of mammals following exposure to a variety of physical and psychological stress-related stimuli. Therefore, these changes may reflect highly conserved, site-specific neurochemical responses to stress and stress-related neurochemicals in vertebrates. Given the important role of the dorsomedial hypothalamus in neuroendocrine, autonomic, and behavioral responses to stress, and a proposed role for this region in fast-feedback effects of glucocorticoids on the hypothalamo–pituitary–adrenal axis, these stress-related monoaminergic changes are likely to have important physiological or behavioral consequences.

Striatal Dopaminergic and Serotonergic Markers in Human Heroin Users

To establish whether chronic opiate exposure might impair brain dopaminergic or serotonergic function in humans, we assessed biochemical indices of monoaminergic neurotransmitter activity and integrity in post mortem striatum of nine chronic heroin users and 14 control subjects. Striatal levels of the vesicular monoamine transporter were normal, suggesting that the density of dopamine nerve terminals is not reduced in heroin users. In nucleus accumbens, levels of tyrosine hydroxylase protein (-25%) and those of the dopamine metabolite homovanillic acid (-33%) were reduced significantly together with a trend for decreased dopamine (-32%) concentration. These changes could reflect either a compensatory downregulation of dopamine biosynthesis in response to prolonged dopaminergic stimulation caused by heroin, or reduced axoplasmic transport of tyrosine hydroxylase. Striatal levels of serotonin were either normal or elevated whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were decreased by 27-38%. Our data suggest that chronic heroin exposure might produce a modest reduction in dopaminergic and serotonergic activity that could affect motivational state and impulse control, respectively.

Functional Consequences of Repeated (±)3,4-Methylenedioxymethamphetamine (MDMA) Treatment in Rhesus Monkeys

Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of (±)3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by ∼50% in the treated animals, and this effect persisted for approximately three months post-MDMA. Behavioral performance was disrupted during acute MDMA treatment but returned to baseline within one week following treatment. MDMA also produced persistent alterations in late peak latencies of brainstem auditory evoked potentials (BSAEP), lasting three months post-MDMA. Both CSF 5-HIAA concentrations and evoked potential latencies were normalized four months after treatment. These findings indicate that serotonergic alterations associated with MDMA use may result in persisting changes in brain function.

Catecholamines in the Heart and Adrenal Gland of the STZ-Diabetic Rat

The concentrations of noradrenaline (NA), adrenaline (ADR), 5-hydroxyindoleacetic acid (5-HIAA), serotonin (5-HT) and dopamine (DOP) have been studied in the left ventricle and the left adrenal gland of control and streptozotocin (STZ) – treated rats at various intervals (12, 24, 30, 34, 38 and 42 weeks) after the induction of diabetes. The only amines detected in the heart were NA, 5-HIAA and DOP, whereas those detected in the adrenal gland were NA and ADR. Differential changes in the catecholamine concentrations occurred in the heart and the adrenal gland at different stages of the metabolic disorder. In the heart the initial changes in short-term diabetes included an increase in NA concentration but this did not persist in the longer term diabetic animals (30–38 weeks following STZ injection). In the adrenal gland there was an initial reduction followed by a steady increase in the concentration of NA and ADR throughout the period of the study.

Peripheral interleukin-6 administration increases extracellular concentrations of serotonin and the evoked release of serotonin in the rat striatum

Previous studies have indicated that peripheral administration of interleukin-6 (IL-6) increases brain concentrations of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA), the major catabolite of serotonin (5-HT). To determine whether these changes were related to increased synaptic release of 5-HT, we studied the responses to peripheral administration of IL-6 by in vivo microdialysis and in vivo amperometry. Intraperitoneal injection of recombinant IL-6 resulted in an elevation of microdialysate concentrations of 5-HT in the rat striatum. Also, amperometric measurements indicated that i.p. IL-6 enhanced the 5-HT-like signal obtained from the striatum following electrical stimulation of the dorsal raphe nucleus. These results indicate that the increases in brain concentrations of 5-HIAA observed in earlier studies indeed reflect increased synaptic release of 5-HT.

Brain content of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid and immune response in aggressive C57Bl/6J mice

Catabolism of 5-hydroxytryptamine in the midbrain raphe nuclei of aggressive C57Bl/6J mice increased after 10 and 20 days of confrontations. Both catabolism and concentration of 5-hydroxytryptamine increased in the dopaminergic nuclei A11, A10, A9, and in the amygdala. The level of 5-hydroxyindoleacetic acid in the A9 and raphe nuclei decreased after 20 days of confrontations, which coincided with manifestation of the immune response.

Pharmacological modification of the serotonergic transmitter system and β-N-acetylhexosaminidase activity in rats

The enzyme activity and activation energy of plasma β-N-acetylhexosaminidase (Hex) was determined in rats whose serotonergic system had been pharmacologically altered. In the group of animals treated with 5-hydroxytryptophan, in the different dissected brain regions (brain stem, cortex and hippocampus) significantly higher levels of serotonin and 5-hydroxyindolacetic acid were found, and significantly lower in the group treated with p-chlorophenylalanine, than in the control group. In the total number of animals studied (n = 21), a statistically significant correlation was found between the plasma concentration of 5-hydroxyindolacetic acid and the levels of this metabolite in the different brain regions (p < 0.001). No significant differences were found for the activity of Hex in the plasma, or for its activation energy, which is a marker of its isoenzyme composition, among the three groups of animals. The results obtained using our experimental model in rats do not confirm the hypothesis of other authors who suggest that the Hex responds secondary to increases or decreases of serotonin turnover, and could be a biological test to monitor the serotonin status in psychiatric patients.

Increase in dopamine metabolites in murine striatum after oral exposure to inorganic but not organic form of selenium.

Selenium (Se) is an essential as well as a toxic trace element. Se intoxication has been reported in both livestock and humans. The central nervous system is sensitive to Se poisoning; exposure to Se causes blind staggers in cattle, poliomyelomalacia in pigs, and nervous system disorders in humans. Differences in neurotoxicity between inorganic and organic Se have been demonstrated. In this study, groups of five male BALB/c mice each were administered sodium selenite or selenomethionine in drinking water ad libitum at 0, 1, 3, and 9 ppm as Se for 14 days. At the end of Se exposure, their brains were removed and dissected into different regions. The concentration of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindolacetic acid (5-HIAA) were determined in each brain region. Food and water consumption and body weight gain were significantly decreased in the group treated with the highest concentration of sodium selenite. In mice administered sodium selenite at 3 and 9 ppm, DOPAC was significantly higher in the striatum than in the control group. The striatal HVA was also increased in the group treated with 3 ppm Se; the DA showed a similar pattern, but the increase was not statistically significant. No alterations of NE, 5-HT, or 5-HIAA levels were detected in any brain region of mice treated with sodium selenite. No significant differences in any parameter among the groups treated with selenomethionine were observed indicating that inorganic Se was more neurotoxic than organic Se via drinking water. The alterations of DA metabolites by inorganic Se in DA-rich striatum suggested a Se-specific increased neural activity of dopaminergic pathways. Results may be useful in further elucidation of neurotoxicity of Se and in establishing a safe level of intake for this element.

Effect of Fluoxetine on Intraocular Pressure in the Rabbit

The effects of fluoxetine, which is a selective inhibitor of serotonin reuptake (SSRI) have been studied on the intraocular pressure (IOP) in the rabbit. IOP was measured using a Perkins tonometer. Intravenous administration of fluoxetine (6.0mg kg−1) significantly increased IOP by 7.2±1.3mmHg (P<0.001). Fluoxetine administration also reduced the amount of urine excreted during the 24hr, and increased the urine concentration of 5-hydroxyindole acetic acid (5-HIAA). Topical preadministration of ketanserin prevented a rise in IOP, without there being any effects on the other parameters examined.These findings indicate that intravenous administration of fluoxetine is able to raise IOP, through increased plasma levels of serotonin, which is confirmed by elevated 5-HIAA urine excretion and reduction in diuresis. Ketanserin, a specific 5-HT2Aantagonist, counteracts the IOP increase brought about by fluoxetine, thus emphasizing the role of serotonin in the regulation of IOP and stressing the importance of including ophthalmological examination in the protocol of depressed patients undergoing SSRI therapy.

Suicide attempts and impulse control disorder are related to low cerebrospinal fluid 5-HIAA in mentally disordered violent offenders.

The aim of this study was to investigate the relationship between low cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and aggressive acts in mentally disordered violent offenders. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid and 4-hydroxy-3-methoxyphenyl glycol were measured in 35 drug-free men convicted of homicide and currently undergoing forensic psychiatric investigation in a high security hospital. The mean metabolite concentrations in the homicide offenders did not differ from those of age- and body-height matched male control subjects. One-third of the murderers had made one or several suicide attempts, and their mean concentration of spinal fluid 5-HIAA was significantly lower than that of the remaining murderers. Subjects with impulse control disorder also had lower mean CSF 5-HIAA. A consistent pattern of higher CSF 5-HIAA in subjects with more self-reported anxiety traits was observed. The association between serotonin and suicidal behaviour holds for yet another subject group. Determining CSF 5-HIAA might be worth while in the routine assessment of psychiatrically ill homicide offenders.

Cerebrospinal fluid concentrations of tryptophan and 5-hydroxyindoleacetic acid in Macaca mulatta: diurnal variations and response to chronic changes in dietary protein intake.

In rats, dietary protein is known to influence brain tryptophan (TRP) concentrations and serotonin (5HT) synthesis. However, few studies have examined this relationship in primates (including humans). We therefore studied the effect in monkeys of changes in chronic protein intake on plasma and cerebrospinal fluid (CSF) concentrations of TRP and 5-hydroxyindoleacetic acid (5HIAA), the principal 5HT metabolite. Juvenile male monkeys (Macacca mulatta) consumed for sequential 4-week periods diets differing in protein content (approximately 23%-->approximately 16%--> approximately 10%-->approximately 6% protein [%-energy/day]). Each day, food was presented as a morning meal of fruit, and an afternoon meal consisting of a pelleted, commercial diet and fruit. During week 4 on each diet, blood and CSF were sampled diurnally via indwelling catheters. Plasma and CSF TRP varied diurnally and with dietary protein content. On all diets, CSF TRP declined modestly in the morning, and increased in the afternoon; the magnitude of the increments varied directly with dietary protein content. Diurnal variations were absent for CSF 5HIAA; however, CSF 5HIAA varied directly with chronic dietary protein content. We conclude that dietary protein content can chronically influence CSF TRP concentrations in monkeys. The variation in CSF 5HIAA suggests chronic protein intake may influence serotonin synthesis and turnover, perhaps via changes in TRP concentrations.