5-HIAA Concentrations Research Articles

Monoamine metabolites in successive samples of spinal fluid

Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were measured in the cerebrospinal fluid from patients with multiple sclerosis and from healthy volunteers. The fluid was withdrawn with the persons in the lateral recumbent position. In the controls and in 4 of the patients 10 successive samples of 2 ml each were analyzed. In the remaining patients the first 2 ml and last 2 ml of a total 20 ml were analysed. The highest values were obtained in the last portion. Patients with multiple sclerosis had significantly lower levels of 5-HIAA than controls in both the first and last CSF samples. Patients with a progressive course of prominent residual symptoms had a lower concentration of 5-HIAA and HVA than those with a relapsing course and little residual symptoms. The difference was significant for 5-HIAA.

Modulation of anxiety by acute blockade and genetic deletion of the CB 1 cannabinoid receptor in mice together with biogenic amine changes in the forebrain

The CB 1 cannabinoid receptor has been implicated in the control of fear and anxiety. We investigated the effects of genetic and pharmacological blockade of the CB 1 cannabinoid receptor on the behaviour of CD1 mice using three different ethological models of fear and anxiety (elevated T-maze and plus-maze and open field test of emotionality). Furthermore, we measured tissue levels of noradrenalin (NA), dopamine (DA), serotonin (5-HT) and their metabolites in several forebrain regions, i.e. prefrontal cortex, hippocampus, septum, dorsal and ventral striatum to examine the relationship between CB 1 receptor manipulation and monoaminergic neurotransmission. The major findings can be summarized as follows: The CB 1 receptor antagonist SR141617A (rimonabant) modulated anxiety in a dose-dependent manner. At a dose of 3 mg/kg i.p., the compound consistently increased anxiety parameters in all of the three different anxiety tests applied, while a lower dosage of 1 mg/kg had no such effect. The neurochemical evaluation of the mice administered 3 mg/kg SR141617A revealed increases in the concentrations of DOPAC and 5-HIAA in the dorsal striatum, elevated DA levels in the hippocampus and reduced dopamine turnover in the septum. Furthermore, these animals had a higher HVA/DA turnover in the frontal cortex. CB 1 receptor knockout mice as well as mice treated with the selective CB 1 receptor antagonist AM251 (3 mg/kg; i.p.) did not display any significant alterations in anxiety-related behaviour as measured with the elevated plus-maze and open field test of emotionality, respectively. Our findings support the general idea of a SR141617A-sensitive receptive site that is different from the ‘classical’ CB 1 receptor and that has a pivotal role in the regulation of different psychological functions. However, with regard to its functional significance in terms of anxiety our findings suggest that under physiological conditions this receptive site seems to be involved in the control of anxiolysis rather than anxiogenesis as suggested previously.

Sepiapterin reductase deficiency in a 2‐year‐old girl with incomplete response to treatment during short‐term follow‐up

Sepiapterin reductase (SR) catalyses the last step in the tetrahydrobiopterin biosynthesis pathway; it converts 6-pyruvoyl-tetrahydropterin (6-PTP) to BH(4) in an NADPH-dependent reaction. SR deficiency is a very rare autosomal recessive disorder with normal phenylalanine (Phe) concentration in blood and diagnostic abnormalities are detected in CSF. We present a 16-month-old girl with SR deficiency. From the newborn period she presented with an adaptation regulatory disorder. At the age of 3 months, abnormal eye movements with dystonic signs and at 4.5 months psychomotor retardation were noticed. Since that time axial hypotonia with limb spasticity (or rather delayed reflex development), gastro-oesophageal reflux and fatigue at the end of the day has been observed. Brain MRI was normal; EEG was without epileptiform discharges. Analysis of biogenic amine metabolites in CSF at the age of 16 months showed very low HVA and 5-HIAA concentrations. Analysis of CSF pterins revealed strongly elevated dihydrobiopterin (BH(2)), slightly elevated neopterin and elevated sepiapterin levels. Plasma and CSF amino acids concentrations were normal. A phenylalanine loading test showed increased Phe after 1 h, 2 h and 4 h and very high Phe/Tyr ratios. SR deficiency was confirmed in fibroblasts and a novel homozygous g.1330C>G (p.N127K) SPR mutation was identified. On L-dopa and then additionally 5-hydroxytryptophan, the girl showed slow but remarkable progress in motor and intellectual ability. Now, at the age of 3 years, she is able to sit; expressive speech is delayed (to 1 1/2 years), passive speech is well developed. Her visual-motor skills, eye-hand coordination and social development correspond to the age of 2 1/2 years.

Behavioral and neurobiological characteristics influencing social hierarchy formation in female cynomolgus monkeys

Socially housed monkeys have been used as a model to study human diseases. The present study examined behavioral, physiological and neurochemical measures as predictors of social rank in 16 experimentally naïve, individually housed female cynomolgus monkeys (Macaca fascicularis). The two behavioral measures examined were novel object reactivity (NOR), as determined by latency to touch an opaque acrylic box placed in the home cage, and locomotor activity assessed in a novel open-field apparatus. Serum cortisol concentrations were evaluated three times per week for four consecutive weeks, and stress reactivity was assessed on one occasion by evaluating the cortisol response to adrenocorticotropic hormone (ACTH) following dexamethasone suppression. Measures of serotonin (5-HT) function included whole blood 5-HT (WBS) concentrations, cerebrospinal fluid (CSF) concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) and brain 5-HT transporter (SERT) availability obtained using positron emission tomography (PET). After baseline measures were obtained, monkeys were assigned to four social groups of four monkeys per group. The two measures that correlated with eventual social rank were CSF 5-HIAA concentrations, which were significantly higher in the animals who eventually became subordinate, and latency to touch the novel object, which was significantly lower in eventual subordinate monkeys. Measures of 5-HT function did not change as a consequence of social rank. These data suggest that levels of central 5-HIAA and measures of novel object reactivity may be trait markers that influence eventual social rank in female macaques.

Omega-3 fatty acid deficiency during perinatal development increases serotonin turnover in the prefrontal cortex and decreases midbrain tryptophan hydroxylase-2 expression in adult female rats: Dissociation from estrogenic effects

A dysregulation in central serotonin neurotransmission and omega-3 fatty acid deficiency have been implicated in the pathophysiology of major depression. To determine the effects of omega-3 fatty acid deficiency on indices of serotonin neurotransmission in the adult rat brain, female rats were fed diets with or without the omega-3 fatty acid precursor α-linolenic acid (ALA) during perinatal (E0-P90), post-weaning (P21-P90), and post-pubescent (P60-130) development. Ovariectomized (OVX) rats and OVX rats with cyclic estrogen treatment were also examined. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content, and fatty acid composition were determined in the prefrontal cortex (PFC), and tryptophan hydroxylase-2 (TPH-2), serotonin transporter, and 5-HT 1A autoreceptor mRNA expression were determined in the midbrain. ALA deficiency during perinatal (−62%, p = 0.0001), post-weaning (−34%, p = 0.0001), and post-pubertal (−10%, p = 0.0001) development resulted in a graded reduction in adult PFC docosahexaenoic acid (DHA, 22:6 n−3) composition. Relative to controls, perinatal DHA-deficient rats exhibited significantly lower PFC 5-HT content (−65%, p = 0.001), significant greater 5-HIAA content (+15%, p = 0.046), and a significant greater 5-HIAA/5-HT ratio (+73%, p = 0.001). Conversely, post-weaning DHA-deficient rats exhibited significantly greater PFC 5-HT content (+12%, p = 0.03), no change in 5-HIAA content, and a significantly smaller 5-HIAA/5-HT ratio (−9%, p = 0.01). Post-pubertal DHA-deficient and OXV rats did not exhibit significant alterations in PFC 5-HT or 5-HIAA content. Only perinatal DHA-deficient rats exhibited a significant reduction in midbrain TPH-2 mRNA expression (−29%, p = 0.03). These preclinical data support a causal link between perinatal omega-3 fatty acid deficiency and reduced central serotonin synthesis in adult female rats that is independent of ovarian hormones including estrogen.

Brain-derived neurotrophic factor gene variation influences cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol concentrations in healthy volunteers

Brain-derived neurotrophic factor (BDNF) has been shown to influence monoamine transmitter synthesis, metabolism and release. We investigated possible relationships between four BDNF gene polymorphisms and cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 132). All BDNF polymorphisms (270 C/T, -633 T/A, Val66Met, and 11757 G/C) were associated with MHPG (P < 0.02), but not with 5-HIAA and HVA concentrations. At a second clinical investigation 8-20 years after CSF sampling 30% of the subjects had experienced various psychiatric disorders. Development of a psychiatric disorder was predicted by low 5-HIAA concentrations (P = 0.01). The results suggest that BDNF gene variation participates in regulation of norepinephrine turnover rates in the central nervous system of human subjects.

Exaggerated feedback control decreases brain serotonin concentration and elicits hyperactivity in a rat model of diet-restriction-induced anorexia nervosa

5-Hydroxytryptamine (5-HT; serotonin) system is the major neurotransmitter system of interest in research on anorexia nervosa (AN). The AN patients show extreme dieting weight loss, hyperactivity and low basal levels of 5-hydroxyindoleacetic acid (5-HIAA), a major metabolite of 5-HT in the cerebrospinal fluid (CSF). Studies on animal models show that diet restriction (DR) decreases 5-HT metabolism in the brain and hypothalamus which is not necessarily associated with a decrease in the availability of essential amino acid tryptophan (TRP) the precursor of serotonin. To further investigate the mechanism involved in DR-induced decreases of 5-HT the present study uses 8-hydroxy-(2-di- n-propylamino) tetralin (8-OH-DPAT), a selective 5-HT-1A agonist, as a probe to monitor the responsiveness of negative feedback control over 5-HT metabolism. Effects of DR and of 8-OHDPAT on TRP, 5-HT and 5-HIAA concentrations are determined in the hypothalamus, a region of the brain known to role in the regulation of appetite. Animals of DR group given access to food 2 h daily for 6 days exhibited 21.6% decrease in the body weight compared to freely feeding (FF) controls. The levels of TRP in the plasma and of 5-HT in the hypothalamus decreased. No effect was found on the levels of TRP in the hypothalamus. 8-OH-DPAT-induced decreases of 5-HT and 5-HIAA were greater in DR than FF group. 8-OH-DPAT-induced hyperactivity was also greater in DR than FF group. The results show that DR-induced decreases of 5-HT are due to an increase in the responsiveness of negative feedback control over 5-HT and not due to smaller availability of TRP. DR-induced increase in activity and 8-OH-DPAT-induced greater hyperactivity in DR than FF group may also be due to exaggerated negative feedback control over 5-HT. It is suggested that drugs decreasing the responsiveness of negative feedback control over 5-HT may be of use for the treatment and prevention of AN in under weight patients on restricted diet.

Diagnosis and therapy of carcinoid tumors—current state of the art and future directions

Abstract Carcinoid tumors account for less than 1% of all malignancies and the majority arise in the gastrointestinal system. These tumors are slow growing compared with adenocarcinomas and they differ from the other neuroendocrine malignancies by their protean clinical presentation. Carcinoid tumors were previously considered indolent, but they can manifest malignant characteristics with metastatic spread which often results in a poor prognosis. Although there have been advances in diagnostic and treatment modalities, carcinoid tumors are still often diagnosed late, often when the tumor has metastasized and patients develop carcinoid syndrome. Diagnosis, prognosis and treatment options are based on biochemical markers and imaging investigations. High concentration of urinary 5-HIAA, elevated plasma serotonin and chromogranin A levels help to establish the initial diagnosis of carcinoid tumors. In addition to the CT and MRI, molecular imaging modalities such as OctreoScan, MIBG imaging and more recently PET imaging are vital in detection of primary malignancy and metastatic involvement. Surgery is the mainstay of treatment of nonmetastatic carcinoid tumors. Cytotoxic chemotherapy is not beneficial due to the chemoresistant nature of these tumors. Because carcinoid tumors express somatostatin receptors, somatostatin analogues, which inhibit the release of serotonin and other neuroendocrine peptides, are often used, but their use is limited to symptom control. Treatment using high doses of radionuclides such as radiolabeled somatostatin analogues and MIBG is a more recent option which offers a definite advantage in management. In this article, we review typical features of the carcinoid tumors, examine contemporary methods of detecting and assessing carcinoid tumors and discuss the role of various diagnostic and therapeutic options.

Effects of Feedborne Fusarium Mycotoxins on Brain Regional Neurochemistry of Turkeys

An experiment was conducted to investigate the effects of feeding grains naturally contaminated with Fusarium mycotoxins on brain regional neurochemistry of turkeys. The possible preventative effect of a poly-meric glucomannan mycotoxin adsorbent (GMA) was also determined. Forty-five 1-d-old male turkey poults were fed wheat-, corn-, and soybean meal-based diets up to wk 6, formulated with control grains, contaminated grains, or contaminated grains + 0.2% GMA. Deoxynivalenol was the major contaminant, and the concentrations were 2.2 and 3.3 mg/kg of feed during starter and grower phases, respectively. Concentrations of brain monoamine neurotransmitters and metabolites were measured in discrete regions of the brain including the pons, hypothalamus, and cortex by HPLC with electrochemical detection. Neurotransmitters and metabolites analyzed included norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin (5-hydroxytryptamine, 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). The concentration of 5-HIAA and the 5-HIAA:5-HT-ratio were significantly decreased in pons after feeding contaminated grains. Dietary supplementation with GMA prevented these effects. In the pons, a significant positive correlation (r = 0.52, P < 0.05) was observed between the concentration of 5-HT and BW gain after feeding contaminated diets. The feeding of contaminated diet had no significant effects on the concentrations of neurotransmitters and metabolites in hypothalamus and cortex. It was concluded that consumption of grains naturally contaminated with Fusarium mycotoxins adversely altered the pons serotonergic system of turkeys. Supplementation with GMA partially inhibited these effects.

Effect of neonatal nociceptin or nocistatin imprinting on the brain concentration of biogenic amines and their metabolites

Noradrenaline (NA), dopamine (DA), homovanillic acid (HA), serotonin (5HT) and 5-hydroxyindole acetic acid (5HIAA) content of five brain regions (hypothalamus, hippocampus, brainstem, striatum and frontal cortex) and the cerebrospinal fluid (CSF) was measured in adult (three months old) male and female rats treated neonatally with a single dose of 10 μg nociceptin (NC) or 10 μg nocistatin (NS) for hormonal imprinting. The biogenic amine and metabolite content of cerebrospinal fluid was also determined. In NC treated animals the serotonergic, dopaminergic as well as noradrenergic systems were influenced by the imprinting. The 5HT level increased in hypothalamus, the 5HIAA tissue levels were found increased in hypothalamus. Hippocampus and striatum and the HVA levels increased highly significantly in brainstem. Dopamine level decreased significantly in striatum, however in frontal cortex both noradrenalin and 5HIAA level decreased. Nevertheless, in NS-treated rats decreased NA tissue levels were found in hypothalamus, brainstem and frontal cortex. Decreased DA levels were found in the hypothalamus, brainstem and striatum. NS imprinting resulted in decreased HVA level, but increased one in the brainstem. The 5HT levels decreased in the hypothalamus, brainstem, striatum and frontal cortex, while 5HIAA content of CSF, and frontal cortex decreased, and that of hypothalamus, hippocampus and striatum increased. There was no significant difference between genders except in the 5HT tissue levels of NC treated rats. Data presented show that neonatal imprinting both by NC and NS have long-lasting and brain area specific effects. In earlier experiments endorphin imprinting also influenced the serotonergic system suggesting that during labour release of pain-related substances may durably affect the serotonergic (dopaminergic, adrenergic) system which can impress the animals’ later behavior.

Two Greek siblings with sepiapterin reductase deficiency

Background: Sepiapterin reductase (SR) deficiency is a rare inherited disorder of neurotransmitter metabolism; less than 25 cases have been described in the literature so far. Methods: We describe the clinical history and extensive cerebrospinal fluid (CSF) and urine examination of two Greek siblings with the diagnosis of SR deficiency. The diagnosis was confirmed by enzyme activity measurement in cultured fibroblasts and by mutation analysis. Results: Both patients suffered from a progressive and complex l-dopa responsive movement disorder. Very low concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in CSF. CSF neopterin and biopterin concentrations were abnormal in one case only, whereas in both cases sepiapterin concentrations were abnormally high and 5-hydroxytryptophan was undetectable. Urine concentrations of HVA, 5-HIAA and vanillyl mandelic acid (VMA) were decreased in both cases. Both patients had no detectable SR enzyme activity in primary dermal fibroblasts, and upon analysis of genomic DNA revealed the same homozygous point mutation introducing a premature stop codon into the reading frame of the SPR gene (mutant allele K251X). Conclusions: Our cases illustrate that, apart from HVA and 5-HIAA analysis, the specific quantification of sepiapterin in CSF, rather than neopterin and biopterin alone, is crucial to the final diagnosis of SR deficiency. In addition, urinary concentrations of neurotransmitter metabolites may be abnormal in SR deficiency and may provide an initial indication of SR deficiency before CSF analysis is performed. The known, impressive beneficial response of SR deficient patients to treatment with l-dopa, is illustrated again in our cases.

Mitochondrial diseases mimicking neurotransmitter defects

Objectives Mitochondrial disorders are clinically heterogeneous. We aimed to describe 5 patients who presented with a clinical picture suggestive of primary neurotransmitter defects but who finally fulfilled diagnostic criteria for mitochondrial disease. Methods We report detailed clinical features, brain magnetic resonance findings and biochemical studies, including cerebrospinal fluid (CSF) biogenic amine and pterin measurements, respiratory chain enzyme activity, and molecular studies. Results The 5 patients had a very early onset age (from 1 day to 3 months) and a severe clinical course. They all showed a clinical picture suggestive of infantile hypokinetic-rigid syndrome (hypokinesia, hypomimia, slowness of reactions, tremor), other abnormal movements (myoclonus, dystonia), axial hypotonia, limb hypertonia, feeding difficulties, and psychomotor delay. Abnormal CSF findings among the 4 patients without treatment included low levels of homovanillic acid (HVA) in 3 patients, with associated low 5-hydroxyindoleacetic acid (5-HIAA) concentrations in two of them. Absent or mild and transitory improvement was observed after treatment with l-dopa. A diagnosis of mitochondrial disorder was finally made due to the appearance of hyperlactacidemia, diverse respiratory chain defects, and multisystemic involvement. Conclusions Secondary neurotransmitter disturbances may occur in mitochondrial diseases. Differential diagnosis of hypokinetic-rigid syndrome presenting in infancy could also include paediatric mitochondrial disorders.

Anti-inflammatory drugs ameliorate opposite enzymatic changes in ileal 5-hydroxytryptamine metabolism in the delayed phase after cisplatin administration to rats

The effects of anti-inflammatory drugs on ileal 5-hydroxytryptamine (5-HT) metabolic dynamics at 72 h after a single administration of cisplatin were investigated in rats. Cisplatin 5 mg/kg i.p. caused pathological changes, with an inflammatory response occurring 72 h after its administration. The inflammatory response was associated with the induction of cyclooxygenase-2, but not cyclooxygenase-1, in the ileal mucosa at 72 h after the cisplatin administration. Daily treatment with meloxicam 3 mg/kg s.c. ameliorated the cisplatin-induced mucosal damage, whereas dexamethasone 1 mg/kg s.c. did not. Cisplatin administration also caused a significant increase in cyclooxygenase-2 mRNA expression at 72 h after administration, which was blunted by dexamethasone, but not by meloxicam. Cisplatin increased the content of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), but had no effect on 5-HT turnover (5-HIAA/5-HT ratio). Meloxicam and dexamethasone did not significantly decrease 5-HT and 5-HIAA content. Cisplatin significantly decreased monoamine oxidase activity but increased tryptophan hydroxylase (TPH) activity and TPH1 mRNA expression in ileal tissue. Meloxicam and dexamethasone significantly restored the decreased monoamine oxidase activity and inhibited the cisplatin-induced increase in tryptophan hydroxylase activity toward the control levels. These drugs also decreased the cisplatin-induced increase in TPH1 mRNA expression. Neither cisplatin nor the anti-inflammatory drugs had significant effect on mRNA expression of the serotonin re-uptake transporter. These results suggest that the inflammatory response associated with cyclooxygenase-2 induction is involved in the opposite change in ileal tryptophan hydroxylase and monoamine oxidase activities in the delayed phase after single administration of cisplatin to rats.

β-Naphthoflavone and benzo(a)pyrene alter dopaminergic, noradrenergic, and serotonergic systems in brain and pituitary of rainbow trout (Oncorhynchus mykiss)

In the present study we evaluate for the first time the potential of the flavonoid compound β-naphthoflavone (BNF) and the high molecular weight- Polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BaP) to alter brain neurotransmitter metabolism in fish. Fish of three different groups were intraperitoneally (i.p.) injected (2μlg−1) with vegetable oil alone (control) or containing BNF or BaP (10mgkg−1) and sacrificed 3, 24, and 72h after treatment. Contents of dopamine (DA), noradrenaline (NA) and serotonin (5HT), as well as the amine oxidative metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole-3-acetic acid (5HIAA) were assayed in telencephalon, hypothalamus, preoptic region, optic tectum, and brain stem, as well as the pituitary. Fish treated with PAHs showed after 3h decreases in 5HT content in telencephalon, hypothalamus, preoptic region (with both BNF and BaP), and pituitary (with BaP), resulting in increased 5HIAA/5HT ratio. An increased ratio was also observed in hypothalamus 24h after BaP, and in preoptic region 72h after BNF, in both cases due to an increased 5HIAA content. In other brain regions PAHs effects on 5-HT metabolism were less consistent. With respect to the dopaminergic system, changes induced by PAHs mainly occurred after 24 and 72h of treatment, with increased DOPAC/DA ratio in preoptic region and brain stem. In hypothalamus, tectum, and pituitary, changes in DA metabolism showed strong variability. Finally, a decreased content of NA was evident in preoptic region (3h) and in telencephalon (24h) after both BNF and BaP treatments. Therefore, both BNF and BaP seem to act in rainbow trout brain by impairing 5HT availability at short term (3h) and increasing neuronal metabolic utilization of both 5HT and DA after 24 and 72h. Data collected in the present study suggest that brain monoamine neurotransmitters are potential targets of BNF and BaP, and their alteration could have a role in known effects of PAHs on several neuroendocrine processes that are centrally regulated or modulated by brain monoamines.

The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat

It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-γ, TNF-α and IL-6 cytokines following mitogen stimulation ( p < 0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan ( p < 0.005) and kynurenic acid ( p < 0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted.

Participation of 5-Hydroxytryptamine in Pain-Related Behavior Induced by Nucleus Pulposus Applied on the Nerve Root in Rats

The role of 5-hydroxytryptamine (5-HT) in sciatica in lumbar disc herniation (LDH) in rats was investigated. We evaluated the effects of exogenous 5-HT applied on the nerve root on pain-related behavior, the release of endogenous 5-HT in plasma, and the expression of 5-HT2A receptors in dorsal root ganglion (DRG) in a rat LDH model. In previous studies, 5-HT2A receptor antagonists improved sciatica in patients with LDH and attenuated pain-related behavior induced by nucleus pulposus applied to the nerve root in rats. Adult female Sprague-Dawley rats were divided into four experimental groups [control group; low-dose (10 microg) 5-HT-group; high-dose (30 microg) 5-HT-group; and autologous nucleus pulposus (NP) and saline group] and each drug was applied to the L5 nerve root. Von Frey tests were used for pain-behavior testing. To assess levels of endogenous 5-HT released in capillaries surrounding inflamed nerve roots, we measured 5-hydroxyindole acetic acid (5-HIAA), a metabolite of 5-HT. Expression of 5-HT2A receptors in the left L5 DRG was examined by immunohistochemical and immunoblotting analyses in the control and NP groups. Mechanical withdrawal thresholds of the high-dose 5-HT and the NP groups were significantly decreased after surgery compared with the control group and recovered after 14 days in the high-dose 5-HT group. 5-HIAA in plasma was increased by nucleus pulposus applied on the nerve root for 7 days after surgery. The expression of 5-HT2A receptors was enhanced in a time-dependent manner by nucleus pulposus. Exogenous 5-HT to the nerve root induced pain-related behavior with short-lasting effects compared with the nucleus pulposus application. 5-HIAA content in plasma and expression of 5-HT2A receptors in DRG neurons increased early time points after the nucleus pulposus application. These results suggest that 5-HT plays a role in the early phase of the chemical pathogenesis of sciatica in LDH in rats.

Population Pharmacokinetic-Pharmacodynamic Model of the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid in Cancer Patients

To develop a population pharmacokinetic-pharmacodynamic (PK-PD) model that defines the dose-concentration-effect relationship of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), using plasma 5-hydroxyindole-3-acetic acid (5-HIAA) as a biomarker for the antivascular effect of DMXAA. The plasma DMXAA and 5-HIAA concentration data were obtained from 124 patients receiving DMXAA monotherapy as a 20-minute i.v. infusion weekly or every 3 weeks at doses of 6 to 4,900 mg/m(2). The PK and PD data were analyzed by nonlinear mixed effects modeling with NONMEM version 5. DMXAA concentration-time profiles were well described by a three-compartment model with saturable elimination (Michaelis-Menten kinetics). Body surface area (BSA) and sex were significant covariates on the volume of distribution of the central compartment (V(1)) and the maximum elimination rate (V(m)), respectively. Population estimates for V(m), K(m) (concentration at which half V(m) is achieved), and V(1) were 112[1 + 0.474(2-sex)] micromol/L/h, 102 micromol/L, and 8.19(BSA/1.8)(0.857) liters, respectively (sex in V(m) is equal to 1 for males and equal to 2 for females). The effect of DMXAA on plasma 5-HIAA was described by the stimulatory E(max) model, where population estimates for baseline, E(max), and EC(50) were 46.3 micromol/L, 2.62-fold increase of the baseline value, and 631 micromol/L, respectively. DMXAA plasma disposition is characterized by a saturable elimination process. BSA-guided dosing is important. The present PK-PD model, with 5-HIAA as a biomarker, supports the use of DMXAA doses of 1,000 to 2,000 mg/m(2) in phase II studies, and provides an example of how PK-PD models can be used to aid in selection of drug doses for phase II evaluation.

A prospective clinical trial evaluating urinary 5-hydroxyindoleacetic acid levels in the diagnosis of acute appendicitis

Background To improve the diagnostic accuracy of identifying acute appendicitis, imaging modalities, such as ultrasound and the computed tomography scan, are used in combination with the history and physical examination. There is no reliable single laboratory marker to assist with this diagnosis. During inflammation, enterochromaffin cells in the appendix secrete serotonin, and 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite excreted in urine, has been found to be elevated in patients presenting with acute appendicitis. Objective The aim of this study was to measure the urinary 5-HIAA concentrations of patients presenting with symptoms of acute appendicitis to determine the sensitivity and specificity of urinary 5-HIAA levels for diagnosing acute appendicitis. Methods 5-HIAA was quantitatively measured by high-performance liquid chromatography in the spot urine of 100 healthy individuals, aged 18 to 70 years, who presented to the emergency medicine department with a clinical picture of acute appendicitis. Urine concentration results were correlated to the gold standard of histopathologic reports of removed appendices. The sensitivity, specificity, and their 95% confidence intervals were derived. Results Of the 100 patients presenting with symptoms consistent with acute appendicitis, 72 had appendectomies and 2 had cholecystectomies. The remaining 26 patients were discharged after hospital observation. A total of 64 patients were found to have appendicitis: 52 had acute appendicitis, whereas 12 had perforated and/or gangrenous (nonacute) appendices. The acute appendicitis group had a mean urinary 5-HIAA level of 19.31 μmol/L, slightly lower than the 23.10 μmol/L of the patients with gangrenous/perforated appendicitis. The group without appendicitis had a urinary 5-HIAA value of 17.27 μmol/L. Using the lowest of previously reported cutoffs, we calculated the sensitivity and specificity of this test for acute appendicitis as 63% and 33%, respectively. Conclusion Urinary 5-HIAA level is not a good diagnostic tool for determining acute appendicitis.

Reduced sensitivity to MDMA-induced facilitation of social behaviour in MDMA pre-exposed rats

The acute effects of the party drug 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) in humans include feelings of love, closeness towards other people and an increased acceptance of others views and feelings. Some evidence suggests that regular MDMA users develop a subsensitivity to the positive effects of the drug and escalate their intake of the drug over time as a result. The current study investigated whether brief exposure to relatively high doses of MDMA in rats produces a subsequent attenuation in the ability of MDMA to enhance social interaction. Male Wistar rats were exposed to either MDMA (4 × 5 mg/kg over 4 h) or vehicle on two consecutive days. Twelve weeks later, MDMA pre-exposed rats displayed a significantly shorter period of time spent in social interaction than controls when tested in the drug-free state. MDMA pre-exposed rats also showed a blunted prosocial response to MDMA (2.5 mg/kg) relative to controls. This difference was overcome by increasing the MDMA dose to 5 mg/kg. The 5-HT 1A agonist 8-OH-DPAT (250 µg/kg but not 125 µg/kg) increased social interaction and this effect did not differ in MDMA and vehicle pre-exposed rats. HPLC analysis showed a small but significant depletion of prefrontal 5-HT and 5-HIAA in MDMA pre-exposed rats. Prefrontal 5-HIAA concentrations were also reduced in the subset of vehicle and MDMA pre-exposed rats that received additional testing with MDMA. These results indicate that treatment with MDMA not only causes lasting reductions in social interaction in rats but causes an attenuation of the prosocial effects of subsequent MDMA administration. The lack of a differential response to 8-OH-DPAT agrees with other findings that the 5-HT 1A receptor system remains functionally intact following MDMA pre-exposure and suggests that other neuroadaptations may underlie the lasting social deficits caused by MDMA.

Mechanistic model for the acute effect of fluvoxamine on 5-HT and 5-HIAA concentrations in rat frontal cortex

A mechanistic model is proposed to predict the time course of the concentrations of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in rat frontal cortex following acute administration of SSRIs. In the model, SSRIs increase synaptic 5-HT concentrations by reversible blockade of the SERT in a direct concentration-dependent manner, while the 5-HT response is attenuated by negative feedback via 5-HT autoreceptors. In principle, the model allows for the description of oscillatory patterns in the time course of 5-HT and 5-HIAA concentrations in brain extracellular fluid. The model was applied in a pharmacokinetic–pharmacodynamic (PK/PD) investigation on the time course of the microdialysate 5-HT and 5-HIAA response in rat frontal cortex following a 30-min intravenous infusion of 3.7 and 7.3 mg/kg fluvoxamine. Directly after administration of fluvoxamine, concentrations of 5-HT were increased to approximately 450–600% of baseline values while 5-HIAA concentrations were decreased. Thereafter 5-HT and 5-HIAA concentrations gradually returned to baseline values in 6–10 h, respectively. The PK/PD analysis revealed that inhibition of 5-HT reuptake was directly related to the fluvoxamine concentration in plasma, with 50% inhibition of 5-HT reuptake occurring at a plasma concentration of 1.1 ng/ml (EC 50). The levels of 5-HT at which 50% of the inhibition of the 5-HT response was reached (IC 50) amounted to 272% of baseline. The model was unable to capture the oscillatory patterns in the individual concentration time curves, which appeared to occur randomly. The proposed mechanistic model is the first step in modeling of complex neurotransmission processes. The model constitutes a useful basis for prediction of the time course of median 5-HT and 5-HIAA concentrations in the frontal cortex in behavioral pharmacology studies in vivo.