Decrease In 5-HIAA Research Articles

Effects of food quantity on aggression and monoamine levels of juvenile pufferfish (Takifugu rubripes).

Aggressive behavior is important for animals to obtain limited resources. Understanding fish behavior and physiological response is of great significance to evaluate aquaculture production and fish welfare. Food is an important trigger of aggressive behavior in juvenile fish under high-density aquaculture conditions. The aim of this study was to investigate the aggressive behavior and monoamine levels of juvenile pufferfish (mean body mass of 6.29 ± 0.33 g) under normal feeding and restricted feeding. Our main results included the following: (1) The mortality and fin damage were higher and aggression was more intense of juvenile pufferfish at the 1% ration than those of the 3% ration; (2) during feeding, the velocity, body contact, and activity at the 1% ration were significantly higher than that of the 3% ration; (3) the concentrations of brain 5-hydroxyindoleacetic acid (5-HIAA) and monoamine oxidase A (MAOA) at the 1% ration were significantly lower, and dopamine (DA) concentrations were significantly higher. These results suggest that juvenile pufferfish shows serious aggressive behavior at the low ration, which may be related to the decrease of 5-HIAA and MAOA concentrations, and the increase of DA concentrations.

Cerebrospinal fluid biogenic amines depletion and brain atrophy in adult patients with phenylketonuria.

Biogenic amines synthesis in phenylketonuria (PKU) patients with high phenylalanine (Phe) concentration is thought to be impaired due to inhibition of tyrosine and tryptophan hydroxylases and competition with amino acids at the blood-brain barrier. Dopamine and serotonin deficits might explain brain damage and progressive neuropsychiatric impairment in adult PKU patients. Ten early treated adult PKU patients (mean age 38.2 years) and 15 age-matched controls entered the study. Plasma and cerebrospinal fluid (CSF) Phe, 5-hydroxyindoleacetic acid (5-HIAA), 5-hydroxytryptophan (5-HTP), 3,4-dihydroxy-l-phenylalanine (l-DOPA) and homovanillic acid (HVA) were analyzed. Voxel-based morphometry statistical nonparametric mapping was used to test the age-corrected correlation between gray matter atrophy and CSF biogenic amines levels. 5-HIAA and 5-HTP were significantly reduced in PKU patients compared to controls. Significant negative correlations were found between CSF 5-HIAA, HVA, and 5-HTP and Phe levels. A decrease in 5-HIAA and 5-HTP concentrations correlated with precuneus and frontal atrophy, respectively. Lower HVA levels correlated with occipital atrophy. Biogenic amines deficits correlate with specific brain atrophy patterns in adult PKU patients, in line with serotonin and dopamine projections. These findings may support a more rigorous Phe control in adult PKU to prevent neurotransmitter depletion and accelerated brain damage due to aging.

Gastroenteropatic neuroendocrine tumors: Multidisciplinary approach in therapy and influence of tailored therapy for prognosis of patients

Introduction: Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are classified on the basis of hormonal activity of tumor cells to functional and non-functional tumors. Therapy of well differentiated NETs includes surgical procedures, debulking of tumor mass, biotherapy and peptide receptor radionuclide therapy. Multidisciplinary approach in diagnostic and therapy leads to prolongation of survival. Aim of the study: Analysis of therapeutic modalities in group of patients with well differentiated gastroenteropatic neuroendocrine tumors and influence of tailored therapy for prognosis of patients. Characteristics of patients: In our department we followed up in period from 1.1.2007 to 31.3.2013 65 pts (21 men/44 women) with well differentiated GEP neuroendocrine tumors. Primary localisation was: stomach — 6 times, pancreas — 9×, duodenum — 1×, jejunum — 4×, appendix — 8×, ileum — 26×, rectum — 7×, unknown primary — 4×. On the base of histomorphological diagnosis 47 patients belonged to WHO I. group — very well differentiated neuroendocrine tumors, and 18 pts to WHO II. group — well differentiated neuroendocrine carcinomas. Metastatic disease was affirmed in 36 patients in time of diagnosis. In all patients chromogranin A, urine level of 5-HIAA, hormonal analysis were examined. Besides ultrasound, endoscopy, computer tomography also Octreoscan was performed. Carcinoid syndrome was present in 27 patients: in 23 pts primary tumors were localised in midgut, in 4 pts we did not find the primary tumor. In our group 9 patients had neuroendocrine tumor of pancreas, 4 of them were functional: 2× overproduction of calcitonine, 1× of gastrin,1× of insulin. Therapy: A. Surgical treatment: Resection of primary tumor and debulking of metastases was performed in 56 pts, in 5 pts with pancreatic tumor resection was not possible due to invasion of tumor mass to surrounding tissue and vessels. In 4 patients with unknown primary surgical treatment was not performed. B. Biological treatment with long acting somatostatin analogues was indicated in 37 pts, 4 pts are treated also with m-tor inhibitors. Biotherapy with somatostatin analogues reduced symptoms of hormonal activity (decrease of 5-HIAA in urine) and brought on stabilisation of disease in most of patients. C. Peptide receptor radionuclide therapy (PRRT) was indicated in 8 pts, 4 of them with nonresectable neuroendocrine carcinoma of pancreas. In 6 of patients PRRT with 90 Ytrium–DOTA-octreotid and in 2 patients with 123 I-MIBG. Reduction of tumor volume was noticed. In period of follow up 8 patients died. Reasons of death: in 2 pts right side heart failure due to fibrosis of endocardium, in 1 patient — small bowel necrosis due to desmoplastic reaction of mesenterium, in 4 patient — malignant cachexia, in 1 patient — carcinoid crisis. Conclusion: Patients with GEP-NETs demand on multidisciplinary approach in therapy. Surgical procedure, biological therapy with somatostatin analogues, m-tor inhibitors and PRRT in patients with well differentiated neuroendocrine tumors markedly contribute to prolongation of survival of patients and also to enhancement quality of their life. We supposed that early combination treatment has high influence for best survival of patients with metastatic disease.

The effects of himantane and cycloprolylglycine on the enzymatic linkage of monoamine synthesis in the rat brain

Using HPLC we studied the effects of new substances with antiparkinsonian activities, viz., himantane and cycloprolylglycine (CPG), on the contents of monoamines and their metabolites in the brain structures of Wistar rats under conditions of the inhibition of tyrosine and tryptophan hydroxylases. It was shown that 70 min after administration himantane induces a significant decrease in the level of noradrenaline in the nucleus accumbens (NA) and striatum. At 70 min after administration of CPG, we observed an increase in the DOPAC/DA ratio in the NA and the level of 5-HIAA in the striatum. At 24 h after CPG administration, we observed an increase in the HVA content and HVA/DA ratio in the hypothalamus and striatum. We found a decrease in 5-HIAA in all brain structures we studied at 24 h after administration of CPG, which was absent at 70 min after injection of the substance; the magnitude of 5-HIAA/5-HT decreased in the hypothalamus, nucleus accumbens, and hippocampus. Our results suggest that both substances we studied influence serotonergic transmission by inhibition of the MAO B enzyme.

Effectiveness of trans-arterial embolisation of liver neuroendocrine tumour metastases

IntroductionNeuroendocrine tumours (NET) with liver metastases have a poor prognosis and are difficult to palliate. Transarterial embolisation (TAE) is increasingly used to improve symptoms and reduce tumour size. We sought...

Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson’s disease and major depression

The biochemical basis of major depression (MD) in Parkinson's disease (PD) is largely unknown. To increase our understanding of MD in PD patients, the levels of monoamine metabolites (HVA, 5-HIAA and MHPG), BDNF, orexin-A, IL-6 and corticosterone were examined in cerebrospinal fluid. The analyses were performed in MD patients with (n = 11) and without (n = 12) PD at baseline and after 12 weeks' of treatment with the antidepressant citalopram, and in patients with solely PD (n = 14) at baseline and after 12 weeks. The major findings were that PD patients with MD had significantly lower baseline levels of MHPG, corticosterone and IL-6 when compared to patients with solely MD. In response to citalopram treatment, patients with solely MD exhibited an expected decrease in 5-HIAA and MHPG levels which was not found in PD patients with MD. Moreover, the levels of BDNF and IL-6 were lower in PD patients with MD compared with patients with solely MD after treatment with citalopram. Thus, the biochemical basis and the response to citalopram differ between PD patients with MD and patients with solely MD.

Alteration of Brain Levels of Neurotransmitters and Amino Acids in Male F344 Rats Induced by Three-week Repeated Inhalation Exposure to 1-Bromopropane

The present study investigated the effects of 1-bromopropane (1BP) on brain neuroactive substances of rats to determine the extent of its toxicity to the central nervous system (CNS). We measured the changes in neurotransmitters (acetylcholine, catecholamine, serotonin and amino acids) and their metabolites or precursors in eight brain regions after inhalation exposure to 1BP at 50 to 1,000 ppm for 8 h per day for 7 d per week for 3 wk. Rats were sacrificed at 2 h (Case 1), or at 19 h (Case 2) after the end of exposure. In Case 1, the level of 5-hydroxyindoleacetic acid (5HIAA) was lowered in some brain regions by 1BP exposure. The decrease of 5HIAA in the frontal cortex was statistically significant at 50 ppm 1BP exposure. In Case 2, gamma-amino butyric acid (GABA) and taurine were decreased in many brain regions of exposed rats, and a significant decrease of taurine in the midbrain occurred at 50 ppm 1BP exposure. In both cases of 2-h and 19-h intervals from the end of exposure to sacrifice, aspartate and glutamine levels were elevated in many brain regions, but the acetylcholine level did not change in any brain region. Three-week repeated exposure to 1BP produced significantly changes in amino acid contents of rat brains, particularly at 1,000 ppm.

An open-label phase II clinical trial of PTK787 in patients with progressive neuroendocrine cancer

14127 Background: PTK787 is an orally active angiogenesis inhibitor blocking all known vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptor (PDGFR)-tyrosine kinases . The majority of metastatic neuroendocrine malignancies express VEGF and PDGF receptors. Since both growth factors have been implicated in tumor-induced angiogenesis, PTK787 offers a novel approach for inhibiting tumor growth. Methods: In a phase II trial, we investigated the safety and antitumor activity of PTK787 in patients who had biopsy-proven metastatic neuroendocrine cancer, such as carcinoid, and had shown evidence of progression on somatostatin analog therapy. Eligible patients had measurable lesions other than bone, a Karnofsky performance status > 60% and normal hematologic, renal and hepatic functions. Patients on octreotide therapy were required to be on a stable dose not exceeding 30 mg monthly of the LAR formulation. Initial dosing of PTK787 was 1,250 mg daily. Results: Eight patients (5 males) were enrolled between 5/20/05 to 9/09/06. Median age was 61 years (range, 48 to 65). There was 1 withdrawal of consent. The median time on study was 6.2 ± 2.1 mos with 1 patient continuing on treatment as of January 2007. Three patients required a 10–28 day discontinuation for rising SGOT/SGPT, alkaline phosphatase and Grade2 proteinuria. Resumption of PTK787 at 1,000 mg daily was well tolerated in 1 patient. One patient developed carcinoid crises with fever, flushing, rising 5-HIAA accompanied by Grade 2 proteinuria. A partial (>50% decrease in 5-HIAA) biochemical response was observed in 25% of the patients. The observed radiographic (CT scans) and scintigraphic (OctreoScan) responses in 6 patients has been stable disease at 3 and 6 mos. Recruitment to this trial continues. Conclusions: PTK787 results in a 25% biochemical partial response rate in neuroendocrine tumor patients with progressive disease following somatostatin analog therapy. Alternative dosing schedules are planned to improve tolerability. [Table: see text]

Age-related deficit in behavioural extinction is counteracted by long-term ethanol consumption: Correlation between 5-HIAA/5HT ratio in dorsal raphe nucleus and cognitive parameters

We investigated age-related changes in learning and memory performance and behavioural extinction in the water maze; and in endogenous levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the neocortex, hippocampus, thalamus and dorsal raphe nucleus of Wistar rats. Another aim was to assess the correlation between behavioural and biochemical parameters, which were measured in rodents of two different ages: 5 months (adults) and 16 months (middle-aged). The middle-aged subjects succeeded in learning the behavioural task, albeit with significantly worse performance when compared to adult animals. Aging also had significant main effects on memory and extinction. An age-dependent decrease in 5-HIAA levels was observed in both hippocampus and dorsal raphe nucleus (DRN). The decrease in DRN 5-HIAA was paralleled by a decrease in 5-HIAA/5-HT ratio in this brain area, which was significantly correlated to the animals’ spatial memory performance and behavioural extinction. In addition, using middle-aged rats, a 2 × 2 factorial study was carried out to examine the effects of food restriction and chronic ethanol consumption on rat's performance in a spatial behavioural task and on central serotonergic parameters. None of these two treatments had a significant effect on the behavioural and biochemical parameters assessed, with the exception of extinction index, which was significantly affected by ethanol consumption. Long-term ethanol ameliorated the impairment in behavioural flexibility caused by aging. In conclusion, long-term ethanol consumption may have a role in protecting against age-related deficit in behavioural extinction. Moreover, the present results also indicate that DRN serotonergic system is involved in spatial memory and behavioural extinction.

Clinical Relevance of Citalopram (CIT) Plasma and Cerebrospinal Fluid (CSF) Concentrations: Impact with CSF Monoamine Metabolites

Therapeutic drug monitoring (TDM) of new generation antidepressants is part of a controversial discussion, since most of the cited studies found no proof for the existence of a therapeutic window for these drugs. Plasma and CSF concentrations of the enantiomers of CIT, its N-demethylated metabolite demethylcitalopram (DCIT) and its deaminated metabolite citalopram propionic acid derivative (CIT-PROP) were measured in plasma and CSF in twenty-two depressed patients after a 4-week treatment with 40mg/day citalopram. CSF 5-HIAA and HVA were measured at baseline and after the 4-week CIT medication period. Patients were assessed clinically, using the 21-item HAM-D scale: at baseline and then at weekly intervals. CSF concentrations of S-CIT and R-CIT were 10.6±4.3 ng/ml and 20.9±6 ng/ml, respectively and their CSF/plasma ratios were 52%±9% and 48%±6%, respectively. The CIT treatment resulted in a significant decrease of 5-HIAA and a increase of HVA in CSF. A frequently reported correlation between 5-HIAA and HVA was also found. ΔHAM-D correlated significantly with CSF S-CIT, CSF S-CIT-PROP and Δ5-HIAA. The demonstrated correlations between pharmacokinetic parameters and the clinical outcome as well as 5-HIAA changes indicate that monitoring of plasma S-CIT, CSF S-CIT- and CSF S-CIT-PROP may be of clinical relevance.

Liquid chromatographic and tandem mass spectrometric assay for evaluation of in vivo inhibition of rat brain monoamine oxidases (MAO) A and B following a single dose of MAO inhibitors: application of biomarkers in drug discovery

A simple and selective assay for the evaluation of in vivo inhibition of rat brain monoamine oxidases (MAO) A and B following a single dose of MAO inhibitors was developed through the simultaneous determination of endogenous 5-hydroxy tryptamine, 5-hydroxyindole-3-acetic acid (5-HIAA), tryptophane, and 2-phenethylamine (PEA) in rat brain using liquid chromatography–tandem mass spectrometry (LC/MS/MS). These analytes were separated on a Zorbax SB-C18 column using a gradient elution with acetonitrile and 0.2% formic acid and detected on an electrospray ionization mass spectrometer in positive-ion multiple-reaction-monitoring mode. The susceptibility and variability of these analytes as potential biomarkers in response to MAO inhibition in vivo were evaluated after application to three MAO inhibitors, tranylcypromine, clorgyline, and pargyline. A dramatic increase (about 40-fold) in PEA brain level and a decrease in 5-HIAA by more than 90% were observed after administration of 15 mg/kg of the nonselective MAO inhibitor tranylcypromine. As expected, the brain level of PEA escalated to about 6-fold, while the 5-HIAA level remained unchanged following a dose of the MAO B inhibitor pargyline at 2 mg/kg. In contrast, the brain level of 5-HIAA reduced by approximately 53%, but the PEA level was unaffected following the same dose of the MAO A inhibitor clorgyline. The results indicated that 5-HIAA and PEA were susceptible and effective biomarkers in the rat brain in response to MAO A and B inhibition, respectively. The LC/MS/MS method is useful not only for the determination of inhibitory potency but also for the differentiation of the selectivity of a MAO inhibitor against rat brain MAO A and B in vivo.

Nucleus accumbens serotonin 1A receptors control cocaine-induced hyperactivity but not local serotonin increase: an in vivo microdialysis study

The nucleus accumbens (Nac) is an important structure for cocaine-induced hyperactivity and receives a dense serotonergic (5-HT) innervation. Previous studies showed that a systemic activation of 5-HT 1A receptors potentiates cocaine-induced hyperlocomotion, but attenuates the cocaine-induced 5-HT increase in the Nac. In order to address the role of Nac 5-HT 1A receptors in the control of cocaine-induced and spontaneous behavioural activity and local 5-HT release, we used in vivo microdialysis in freely moving rats. The 5-HT 1A-receptor agonist, 8-OH-DPAT (0, 1 and 10 μM), was applied locally into the Nac by reverse dialysis followed by a cocaine (10 mg/kg) or saline i.p. injection. The Nac 5-HT 1A-receptor activation potentiated cocaine-induced hyperlocomotion, but attenuated rearing behaviour dose-dependently. Parallel to that, the cocaine-induced increase in Nac 5-HT dialysate level was unaffected, as were the decreases in 5-HIAA and DOPAC dialysate levels after cocaine. In saline treated rats, the local application of 8-OH-DPAT into the Nac affected neither spontaneous behavioural activity nor 5-HT, 5-HIAA or DOPAC dialysate levels in the Nac. These data suggest that Nac 5-HT 1A receptors exert a bi-directional control of cocaine-induced hyperactivity, while not affecting spontaneous behaviour. Furthermore, accumbal 5-HT 1A receptors do not appear to be directly involved in the acute effects of cocaine on 5-HT, 5-HIAA or DOPAC levels in the Nac.

Acute effect of milnacipran on the relationship between the locus coeruleus noradrenergic and dorsal raphe serotonergic neuronal transmitters

The present studies sought to investigate the effect of milnacipran called the serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor (SNRI) on the interaction of central locus coeruleus noradrenergic and dorsal raphe nucleus serotonergic functional activity by utilizing in vivo microdialysis. A single administration of milnacipran (60 mg/kg, s.c.) markedly decreased the levels of NA and its metabolite, 4-hydroxy-3-methoxymandelic acid (HMMA), in the locus coeruleus and the levels of, a metabolite of 5-hydroxytryptamine (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA) in the dorsal raphe nucleus. Combined administration of yohimbine (2 mg/kg, s.c.),?α 2-adrenoceptor?antagonist, at 2 h after milnacipran (60 mg/kg, s.c.) led to a significant increase in NA levels in the locus coeruleus, although yohimbine alone had no effect on these levels. Under similar experimental condition, 5-HIAA levels in the dorsal raphe nucleus remained unchanged. NAN-190 (1 mg/kg, s.c.), 5-HT 1A receptor partial agonist, alone markedly decreased the levels of 5-HIAA in the dorsal raphe nucleus, although this level was not affected by WAY100635, the selective 5-HT 1A receptor antagonist. WAY100635 recovered the milnacipran-induced decrease of 5-HIAA levels in the dorsal raphe nucleus to control levels. On the other hand, NAN-190 did not affect the milnacipran-induced decrease of 5-HIAA levels. Behavioral signs (locomotion and rearing) were markedly observed following milnacipran alone or combined administration of milnacipran and yohimbine. However, the behavioral signs after coadministration of milnacipran and WAY100635 or NAN-190 were relatively poor. These results may suggest that an increase of NA in the locus coeruleus with the treatment of yohimbine after milnacipran results from negative feedback following the blockade of α 2-adrenoceptors achieved with yohimbine, and that WAY100635 but not NAN-190 recovered milnacipran-induced decrease of 5-HIAA in the dorsal raphe nucleus to control levels by preventing the activation for the presynaptic 5-HT 1A autoreceptor.

Pharmacology of a novel selective 5-hydroxytryptamine1B receptor antagonist, AR-A000002.

The terminal 5-HT(1B) autoreceptors have attracted great pharmacological interest since they are potential targets for compounds modifying serotonergic neurotransmission. In the present work the in vivo biochemical properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel selective 5-HT(1B) receptor antagonist, are reported. The effects of AR-A000002 on: 5-HT metabolism was measured as the ratio between 5-HIAA and 5-HT concentrations in different brain regions; 5-HT synthesis was measured as the accumulation of 5-HTP after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD1015); 5-HT release was measured using the microdialysis technique. 5-HT, 5-HIAA and 5-HTP concentrations were analyzed using high power liquid chromatography (HPLC) with electrochemical detection. AR-A000002 significantly enhanced 5-HT metabolism (5-HIAA/5-HT ratio) and 5-HT synthesis in guinea pig brain in the dose range 0.9-18 mg/kg s.c. (ED(50)=1 mg/kg s.c. in the four brain regions examined) with maximal effect seen after 2-4 h. AR-A000002 (9 mg/kg s.c.) significantly increased the extracellular concentrations of 5-HT and 5-HIAA by 20% in the guinea pig frontal cortex, measured with the in vivo microdialysis technique in freely moving guinea pigs. AR-A000002 (9 mg/kg s.c.) in combination with the 5-HT uptake inhibitor citalopram (5 mg/kg s.c.) increased the extracellular 5-HT concentration in guinea pig frontal cortex from 250 to 400% of the basal level. Citalopram alone decreased the extracellular 5-HIAA levels to 70% of the basal value. AR-A000002 counteracted the citalopram-induced decrease in 5-HIAA. Since the basal level of extracellular 5-HIAA was 160 times higher than that of 5-HT the 20% increase in 5-HIAA concentrations indicates that only a few percent of the exocytotically released 5-HT from the nerve terminals reached the extracellular space when the re-uptake mechanism was intact. The results also show that the terminal 5-HT(1B) autoreceptors are tonically activated under drug-free as well as citalopram conditions. The increase in plasma level of cortisol after AR-A000002 administration may indicate stimulation of post-synaptic 5-HT receptors. AR-A000002 also blocked 5-HT(1B) agonist-induced (CP-135,807) decrease in 5-HT metabolism and hypothermia (ED(50)=1 mg/kg s.c.), thus indicating competition between these two drugs. It is concluded that AR-A000002 is a 5-HT(1B) receptor antagonist that enhances the serotonergic neurotransmission in guinea pig brain.

N-methyl-D-aspartate receptor-mediated modulation of monoaminergic metabolites and amino acids in the chick forebrain: an in vivo microdialysis and electrophysiology study.

The associative avian forebrain region medio-rostral neostriatum/hyperstriatum ventrale (MNH) is involved in auditory filial imprinting and may be considered the avian analogue of the mammalian prefrontal cortex. In search of the neurochemical and physiological mechanisms which play a role in this learning process, we introduced microdialysis and a combined microdialysis/electrophysiological approach in domestic chicks a few days old. With this technique, we were able to follow changes of the extracellular levels of glutamate, taurine, 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, and homovanillic acid (HVA), a metabolite of dopamine, and neuronal activity simultaneously in freely moving animals. We obtained first evidence of a modulatory interaction between glutamatergic and monoaminergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors. During local intracerebral infusion of 300 microM NMDA via reverse microdialysis, an increase of taurine and a decrease of 5-HIAA and HVA were detected, accompanied by enhanced extracellular spike rates. Glutamate was increased only during consecutive infusion of increasing NMDA concentrations, when higher (1 mM) NMDA concentrations were infused. The effects of NMDA were antagonized by D, L-2-amino-5-phosphonovaleric acid (1 mM). Infusion of high potassium induced similar changes in taurine, 5-HIAA, and HVA, as found during infusion of NMDA, but decreased extracellular spike rates, which indicates that different cellular mechanisms may underlie the observed neurochemical changes. Neither urethane anesthesia nor different delays between probe implantation and experiment influenced the neurochemical and electrophysiological results; however, changes of taurine were observed only in chronically implanted, awake animals. In summary, microdialysis in combination with electrophysiology provides a powerful tool to detect changes of neuronal activity and transmitter release in the avian brain, with which the role of transmitter interactions can be followed during and after different learning events.

Self-Injurious Behavior Is Decreased by Cyproterone Acetate in Adult Male Rhesus (Macaca mulatta)

Self-injurious behavior (SIB) presents a serious problem in laboratory macaques that cannot be socially housed for scientific reasons and among institutionalized children and adults where it is often associated with different forms of brain dysfunction. We have experienced limited success in reducing SIB in macaques by enhancing their environment with enrichment devices. Psychotropic drugs also help, but problems are associated with their use. Because sexual and aggressive behavioral problems in men have been treated with progestational drugs, we tested the efficacy of cyproterone acetate (CA, 5–10 mg/kg/week) on reducing SIB in 8 singly housed, adult male rhesus macaques. The main findings were: (1) SIB and other atypical behaviors were significantly reduced during CA treatment; (2) serum testosterone was significantly reduced during CA treatment; (3) cerebral spinal fluid (CSF) levels of 5HIAA and HVA, metabolites of serotonin and dopamine, respectively, declined significantly during CA treatment; (4) the duration of SIB positively correlated with levels of 5HIAA in CSF; but (5) sperm counts were not reduced during treatment. Thus, CA was a partially effective treatment (3 months) for adult male macaques whose behavioral problems include SIB. In summary, CA reduced SIB, overall aggression, serum testosterone, CSF 5HIAA, and CSF HVA. We hypothesized that the progestin activity of CA represses the hypothalamic gonadal axis and decreases testosterone, which in turn decreases SIB. In addition, we speculate that the decrease in 5HIAA and HVA in CSF may have been caused by progestins decreasing the activity of MAO. Therefore, the reduction of SIB may also be related to an increase in the availability of active monoamines in the CNS.

Monoaminergic effects of high-dose corticotropin in corticotropin-responsive pediatric opsoclonus-myoclonus.

Children with the opsoclonus-myoclonus syndrome (OMS) usually respond to corticotropin (adrenocorticotrophic hormone, ACTH) treatment but the mechanism of benefit is unknown. We previously showed that both cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) concentrations are low in pediatric OMS. In this study, we measured levels of CSF Dopa, catecholamines, deaminated metabolites of catecholamines, as well as HVA and 5-HIAA in eight patients before and during treatment with ACTH. All the children were ACTH-responsive with 50-70% improvement in multiple clinical features of OMS. ACTH treatment reduced the HVA concentration in every child by a mean of 21% (p < 0.001). Treatment with ACTH was associated with significant correlations between dopaminergic markers such as HVA, dihydroxyphenylacetic acid (DOPAC), and Dopa. There were no significant changes in the CSF concentrations of the noradrenergic markers norepinephrine (NE) and dihydroxyphenylglycol (DHPG), or the serotonergic marker 5-HIAA. The only child with a marked inflammatory pattern in CSF, which was reversed by ACTH, was atypical for a large increase in NE and decrease in 5-HIAA during ACTH treatment. Beneficial effects of ACTH in OMS are not associated with normalization of HVA or 5-HIAA levels. The pattern of decreased HVA and unchanged DOPAC levels could reflect decreased extraneuronal uptake of catecholamines (which steroids inhibit) or decreased 0-methylation of catecholamines in nonneuronal cells.

Effect of single and repeated administration of fluvoxamine on noradrenaline release in rat brain

In vivo microdialysis in conscious rats was used to evaluate the effect of acute and chronic administration of fluvoxamine on extracellular levels of noradrenaline, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex. A single administration of fluvoxamine (12 mg/kg i.p.) during dialysate collection caused a significant delayed decrease in 5-HIAA and a mild increase in noradrenaline with no change in HVA and DOPAC levels. Chronic administration of fluvoxamine (12 mg/kg i.p. daily for 3 weeks, last dose 24 h prior to microdialysis) or a single dose 24 h prior to microdialysis had no effect on noradrenaline, DOPAC and HVA levels in the frontal cortex; 5-HIAA levels were significantly decreased 24 h after a single dose, but increased following long term treatment. Tissue concentrations of 5-HT and 5-HIAA in the frontal cortex showed a mild (though not significant) increase in rats chronically treated with fluvoxamine. Release of noradrenaline in the frontal cortex may be enhanced initially by a 5-HT uptake inhibitor, but this effect is not seen following drug washout.

Central and peripheral neurochemical alterations and immune effects of prenatal ethanol exposure in rats

In contrast to the well known effects of prenatal ethanol exposure on the central nervous system, data about its peripheral effects are scarce. Here, Sprague-Dawley rats were fed a liquid diet (gestational days 0–20) containing 36% ethanol-derived calories (EDCs, group H) or were pair-fed with 18% EDCs (group L) or 0% EDCs (group C. On postnatal day 20, one male and one female from each of 10 litters per group were killed. Norepinephrine (NE) was analyzed in the frontal cortex, spleen and thymus, and dopamine, 5-hydroxytryptamine (serotonin, 5-HT) and their metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were analyzed in the striatum by high-performance liquid chromatography with electrochemical detection. Lymphocyte subpopulations in the spleen and thymus were also assessed in half of these litters. Significant decreases in splenic NE concentration were seen in both sexes of group H (males 27%, females 28%). Decreases in striatal 5-HT and 5-HIAA of group H subjects appeared to be sex specific (only females were significantly affected: 23% decrease in 5-HT, 37% decrease in 5-HIAA). Pronounced, dose-dependent reductions in T cell percentages were observed in both the thymus and spleen. Splenic CD8+ and CD4+ cell percentages were positively correlated with the splenic NE concentrations. It is concluded that the decreases seen in splenic T cell percentages subsequent to prenatal ethanol exposure may be caused, at least partially, by impaired noradrenergic control of this organ.

Changes in serotonin metabolism in pre-eclampsia

Several complications of pregnancy have been reported to be associated with alterations of serotonin (5-HT). This study describes the changes in 5-HT metabolism in patients with preeclampsia. Our examination findings should explain if there are elevated 5-HT and 5-HIAA concentrations in urine and serum of women with preeclampsia. On the other hand it should be proved if the observed chances are due to a decreased kidney function and if there is an important prognostic factor to detect asymptomatic preeclamptic patients. 5-HT and its main metabolite 5-hydroxy-indol-acetic acid (5-HIAA) was evaluated in serum and urine of 24 pregnant women with preeclampsia and of 27 pregnant women without preeclampsia in the last month of pregnancy, within 24 hours after delivery and at the fourth day post partum. Besides 5-HIAA was ascertained in 24-h urine from the 24th week of pregnancy until after delivery. 5-HIAA excretion increased continuously during pregnancy independently of whether the patients developed preeclampsia. A significant less increase and lower concentration of 5-HIAA pre and post partum were observed in preeclamptic patients when compared to non-preeclamptic patients. We noticed a remarkably lower 5-HIAA excretion and a higher concentration of 5-HT in women with preeclampsia. Preeclamptic patients demonstrate a lower decrease of 5-HIAA and a significantly greater increase of 5-HT than women without preeclampsia. These results could be explained by a decreased metabolism of 5-HT due to the placental MAO. The changes observed in our study are not due to a decreased kidney function because creatinine concentrations in women with and without preeclampsia were comparable. Our results indicate that 5-HIAA-/creatinine ratio might be an important prognostic factor.