Interactions between TrkB signaling and serotonin excess in the developing murine somatosensory cortex: a role in tangential and radial organization of thalamocortical axons.
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Mice lacking monoamine oxidase A (MAOA) display high levels of brain serotonin during the first postnatal week, causing an exuberant outgrowth of thalamocortical axons (TCAs) in layer IV of the somatosensory cortex (S1). We asked whether this exuberance is attributable to abnormal TrkB signaling, because modulation of TrkB signaling during a critical period dramatically influences the segregation and the morphology of TCAs in layer IV of the visual cortex. Using in situ hybridization and ELISA immunoassays, we showed that the levels of trkB mRNA and BDNF and neurotrophin-4 (NT-4) proteins are normal in the thalamus and the cortex of mice lacking MAOA during barrel field formation. Because the release of BDNF and NT-4 could be abnormal in MAOA knock-out (KO) mice, we tested whether abnormal TrkB signaling is required for TCA exuberance in MAOA-KO mice by generating mice lacking both trkB and MAOA. Surprisingly, these mice exhibited more severe phenotypes than those found in MAOA-KO mice: a widespread tangential expansion of TCAs in layer IV of the cortex, resulting in a fusion of all sensory representations and a radial expansion of TCAs in layers II-III of the cortex. Careful examination of mice lacking trkB alone revealed subtle alterations of TCAs, with abnormal invasion of layer III. This study reveals the following: (1) expression of trkB, BDNF, and NT-4 are not modulated by an excess of serotonin during barrel formation, (2) TrkB signaling limits branching of TCAs in inappropriate supragranular cortical layers, and (3) serotonin and TrkB signaling act together to cluster thalamocortical axons in layer IV. (+info)
Prospective study of the ability of histamine, serotonin or serum chromogranin A levels to identify gastric carcinoids in patients with gastrinomas.
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BACKGROUND: Chronic hypergastrinaemia causes gastric enterochromaffin cell proliferation and carcinoid tumours. The only reliable means to diagnose enterochromaffin cell changes/carcinoids is by biopsy. AIM: To assess whether serum histamine, chromogranin A or serotonin and urinary N-methylimidazoleacetic acid or 5-hydroxyindoleacetic acid correlate with advanced enterochromaffin cell changes or gastric carcinoids in patients with gastrinomas. METHODS: Consecutive patients (n=145) had the above assays and endoscopy with gastric biopsies. RESULTS: Lower N-methylimidazoleacetic acid and chromogranin A levels (P < 0.0001) occurred in disease-free patients. In patients with active disease, the fasting serum gastrin levels correlated (P < 0.0001) with both chromogranin A and N-methylimidazoleacetic acid levels. Chromogranin A (P=0.005), but not N-methylimidazoleacetic acid, serotonin, 5-hydroxyindoleacetic acid or histamine levels, correlated with the enterochromaffin cell index. Carcinoids, but not advanced enterochromaffin cell changes only, were associated with higher chromogranin A and N-methylimidazoleacetic acid levels. CONCLUSIONS: Serum chromogranin A levels and urinary N-methylimidazoleacetic acid levels, but not serum histamine or serotonin or urinary 5-hydroxyindoleacetic acid, correlate with the presence of gastric carcinoids. However, no assay identified patients with advanced enterochromaffin cell changes only with high sensitivity/specificity. Thus, N-methylimidazoleacetic acid and chromogranin A levels are unable to identify patients with advanced changes in enterochromaffin cells and therefore neither can replace routine gastric biopsies. (+info)
Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA ("ecstasy").
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The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy") is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency. (+info)
Urinary 5-hydroxyindoleacetic acid in 8-hour collections as an aid in diagnosis of coeliac disease.
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8-hour urine excretions of 5-hydroxyindoleacetic acid (5-HIAA) were measured in 18 children with coeliac disease before treatment and the results expressed as microgram 5-HIAA/mg creatinine. Similar measurements were made on urine collections from an age-matched control group of 24 children. Significantly higher values of 5-HIAA excretion were found in children with untreated coeliac disease. Measurement of the 5-HIAA: creatinine ratio in 8-hour urine collections is therefore proposed as an aid in the diagnosis of coeliac disease. (+info)
Metastatic carcinoid tumor to the heart: echocardiographic-pathologic study of 11 patients.
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OBJECTIVE: We sought to investigate the clinical and echocardiographic (echo) characteristics of metastatic carcinoid tumor in the heart. BACKGROUND: Right-sided valvular dysfunction is the hallmark of carcinoid heart disease. Cardiac metastases are uncommon in carcinoid syndrome. Features of patients with metastatic carcinoid tumor involving the heart (MCH) have not been well described. METHODS: From 1985 through 1999, 11 patients (8 male, 3 female), mean age +/- standard deviation, 58 +/- 6 years, were seen who had pathologically confirmed MCH. All patients had echoes, which were reviewed retrospectively. RESULTS: All patients with MCH had carcinoid syndrome. The primary carcinoid tumor was in the small bowel in 83% of patients, and all patients had hepatic metastases. On pathologic review, the 11 patients had 15 MCH tumors. All metastases were intramyocardial. The MCH involved the right ventricle in 40%, left ventricle in 53%, and ventricular septum in 7%. The average size of macroscopic tumors was 1.8 +/- 1.2 cm. Nine MCH tumors were detected by echo in 6 of the 11 patients (55%). Mean echo-detected tumor size was 2.4 cm (range, 1.2 to 4). All tumors noted by echo were well circumscribed, non-infiltrating, and homogeneous. In the 5 other patients, review of autopsy records revealed 6 macroscopic tumors, mean size 0.35 cm (range, 0.2 to 0.4), none detected by echo even retrospectively. Carcinoid valve disease was present in 8 of the 11 MCH patients. The tricuspid valve was affected in all 8 patients (73%), pulmonary valve in 7 (64%), and left sided valves in 4 (36%) All patients with MCH identified by echo had cardiac surgery, 3 primarily for carcinoid valve disease and 2 for non-carcinoid cardiac disease; in 1 patient, MCH was the primary indication for cardiac surgery. CONCLUSIONS: MCH is uncommon but can be easily identified by echo if tumor size is >/=1.0 cm. In patients without valvular dysfunction, MCH may be the only manifestation of carcinoid heart disease. A search for MCH should be an integral part of the echo exam in patients with carcinoid syndrome. (+info)
2'-NH(2)-MPTP [1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine] depletes serotonin and norepinephrine in rats: a comparison with 2'-CH(3)-MPTP [1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine].
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The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analog, 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH(2)-MPTP), depletes brain serotonin and norepinephrine in mice without affecting striatal dopamine. The present study was conducted to determine whether 2'-NH(2)-MPTP would be similarly neurotoxic to rats. Four injections of 20 mg/kg 2'-NH(2)-MPTP caused 80 to 90% depletions in serotonin and norepinephrine in frontal cortex and hippocampus in rats 1 week post-treatment. A lower dose of 2'-NH(2)-MPTP (4 x 15 mg/kg) also produced large decrements in serotonin and norepinephrine levels and in serotonin transporter density measured 3 weeks after neurotoxin administration. Furthermore, this lower dose of 2'-NH(2)-MPTP altered functional serotonin neurotransmission as evidenced by a 2-fold potentiation of 1-(3-chlorophenyl)-piperazine.2HCl-induced hyperthermia, an index of serotonergic denervation supersensitivity. At both doses, 2'-NH(2)-MPTP was without effect on striatal dopamine. For comparison, additional rats were treated with a second 2'-substituted analog of MPTP, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH(3)-MPTP), at 2 x 20 mg/kg. This dosing regimen causes substantial striatal dopamine depletion in mice. 2'-CH(3)-MPTP had no effect on brain levels of serotonin, norepinephrine, or dopamine in rats. Together, these results demonstrate that rats are sensitive to the toxic effects of 2'-NH(2)-MPTP but not to 2'-CH(3)-MPTP at doses known to cause neurotoxicity in mice. Moreover, this study clearly shows that 2'-NH(2)-MPTP can be utilized in rats as a tool to study the serotonergic and noradrenergic neurotransmitter systems. (+info)
Effect of glucoprivation on serotonin neurotoxicity induced by substituted amphetamines.
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The present studies were conducted to further explore the potential role of metabolic compromise in substituted amphetamine-induced serotonin (5-HT) neurotoxicity. To this end, we examined the glucoprivic effects of 2-deoxy-D-glucose (2-DG) on the 5-HT neurotoxic effects of fenfluramine (FEN) and methylenedioxymethamphetamine (MDMA). Rats were treated with either FEN or MDMA, alone and in combination, with doses of 2-DG known to produce glucoprivic effects at either 22 +/- 1 or 28 +/- 1 degrees C. At 22 +/- 1 degrees C, FEN produced hypothermia, MDMA induced hyperthermia, and both drugs produced significant long-term reductions in regional brain 5-HT neuronal markers. 2-DG did not enhance 5-HT neurotoxicity induced by either FEN or MDMA; indeed, in some instances, it afforded partial neuroprotection. Although 2-DG afforded partial protection from both FEN and MDMA-induced 5-HT neurotoxic changes, it also caused significant hypothermia, raising the possibility that protection was due to a lowered temperature. Increasing the ambient temperature to 28 +/- 1 degrees C largely eliminated drug-induced hypothermia and eliminated the neuroprotective effects of 2-DG. Thus, even without the confounding effect of temperature, 2-DG still did not potentiate FEN or MDMA-induced 5-HT neurotoxicity. These findings suggest that the role of metabolic compromise in amphetamine-induced 5-HT neurotoxicity merits further study. (+info)
Effects of narcotic analgesics on serotonin metabolism in brain of rats and mice.
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The effects of narcotic analgesics on the brain 5-hydroxytryptamine (5-Ht) and 5-hydroxyindoleacetic acid (5-HIAA) levels of rats and mice were investigated in relation to our preceding data on the effect of humoral modulatorents. The results suggest that morphine accelerates the release of brain 5-HT both in rats and mice, and that neither methadone nor pethidine alters the brain 5-HT and 5-HIAA levels in rats. The morphine-induced increase in brain 5-HT turnover is likely to be involved in the morphine-induced decrease in locomotor activity and hypothermia in rats. The activity-decreasing effects of methadone or pethidine, on the other hand, are mediated by mechanisms different from those which mediate the effects of morphine. In contrast, an increase in brain 5-HT turnover in mice apparently does not play an important role on activity-increasing effects of morphine but rather participates in other pharmacological effects of morphine. (+info)