Serotonin depletion and barrel cortex development: impact of growth impairment vs. serotonin effects on thalamocortical endings.
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Converging evidence supports a role of serotonin (5-hydroxytryptamine; 5-HT) in barrel cortex development. Systemic administration of 5-HT-depleting drugs reduces cross-sectional whisker barrel areas in the somatosensory cortex (SSC) of neonatal rats. Here we assess the relative impact on barrel pattern formation of (i) 5-HT depletion and (ii) decreased brain growth, which is often associated with pharmacological 5-HT depletion, by comparing the effects of 5-HT-depleting drugs with those of reduced protein intake. Left hemisphere 5-HT levels in the SSC and right hemisphere whisker barrel areas were assessed at postnatal day 6 (P6) in the same animal following injection of p-chloroamphetamine (PCA) or p-chlorophenylalanine (PCPA) at P0. Both drugs significantly reduced cortical 5-HT content and mean barrel areas at P6, but also body and brain growth. Differences in brain weight accounted for 84.4% of the variance in barrel size, with negligible contributions by cortical 5-HT content. PCPA-treated animals sacrificed at P14 yielded similar trends, albeit less pronounced. Finally, reduced protein intake resulted in lower body weight and cortical 5-HT levels at P6, but yielded no change in brain weight or mean barrel area. Barrel formation therefore appears markedly less sensitive to 5-HT depletion per se than to drug-induced growth impairment. (+info)
Effects of fenfluramine combined with electroacupuncture on monoamine release in periaqueductal gray of rat brain.
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AIM: To study the changes of monoamines in ventrolatoral periaqueductal gray of rat brain before and after electroacupuncture (EA) analgesia (EAA) was enhanced by fenfluramine (Fen), a 5-hydroxytryptamine (5-HT) releaser. METHODS: Monoamines were collected by in vivo microdialysis and measured by HPLC connected with electrochemical detector. RESULTS: The level of norepinephrine (Nor) after EA was decreased (P < 0.05 vs NS group). The contents of 5-HT, 5-hydroxyindol acetic acid (5-HIAA), dopamine (DA), and homovanillic acid (HVA) in periaqueductal gray dialysate were increased (P < 0.05 vs NS group). When Fen was combined with EA, the level of 5-HT and 5-HIAA were further increased (P < 0.05 vs NS + EA group). There was no obvious change of Nor, DA, and HVA. CONCLUSION: Fen potentiating EAA may be related to further activation of serotoninergic system. (+info)
Seasonal variation in CSF 5-HIAA concentrations in male rhesus macaques.
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Seasonal changes in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations were assessed on multiple occasions in 103 free-ranging male rhesus macaques (Macaca mulatta). At the time of sampling subjects ranged between the ages of 2 and 6 years. CSF samples were collected between the hours of 0900 and 1600 throughout the Fall, Winter, and Spring from 1990 through 1994. Data were analyzed in a general linear mixed model with random intercepts. Results indicated that CSF 5-HIAA concentrations decreased with age. CSF 5-HIAA concentrations were significantly increased in the Fall (October and November), which is the height of the breeding season, with no evidence of differences between Winter and Spring. There was also some evidence that the seasonal variation in CSF 5-HIAA concentrations was blunted in younger, more immature subjects. (+info)
Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.
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Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years. (+info)
The suitability of [11C]-alpha-methyl-L-tryptophan as a tracer for serotonin synthesis: studies with dual administration of [11C] and [14C] labeled tracer.
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The tracer [11C]-alpha-methyl-L-tryptophan (alphaMTP) has been used to measure brain serotonin synthesis rates with positron emission tomography (PET). To address questions about the accuracy of the kinetic model, [14C]alphaMTP was used to directly measure conversion to [14C]-alpha-methyl-serotonin (alphaM5HT) in monkeys that had been previously studied with PET and [11C]alphaMTP. Four male, fasted, isoflurane-anesthetized rhesus monkeys were studied with [11C]alphaMTP and PET. Immediately after the initial 3-hour scan, a second dose of [11C]alphaMTP was coinjected with 1 mCi of [14C]alphaMTP, and additional PET data were collected. Approximately 90 minutes after the second alphaMTP administration, the animals were killed with an overdose of phenobarbital, and brain samples from 21 regions were taken and analyzed by HPLC. Minimal conversion of alphaMTP to alphaM5HT occurred; HPLC analysis of 14C radioactivity showed that greater than 96% of the total counts were in fractions corresponding to the alphaMTP peak. Brain concentrations of serotonin, tryptophan, 5-hydroxyindole-3-acetic acid, and alphaMTP also were determined fluorometrically using external quantification. Patlak plots generated from PET images acquired over 3 hours showed no time period of linear increase, and final slopes were not significantly different from zero, consistent with the finding of minimal conversion to [14C]alphaM5HT. These data indicate that in the 3-hour period after injection, [11C]alphaMTP is acting predominantly as a tracer of tryptophan uptake, not serotonin synthesis. (+info)
Skin darkening, a potential social signal in subordinate arctic charr (Salvelinus alpinus): the regulatory role of brain monoamines and pro-opiomelanocortin-derived peptides.
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Arctic charr were allowed to interact in groups of three for 5 days. Skin darkness was quantified by measuring the mean brightness of individual fish before and after social interaction. Brain levels of monoamines and monoamine metabolites and plasma concentrations of cortisol, adrenocorticotropic hormone (ACTH), N-acetyl-(beta)-endorphin and alpha-melanocyte-stimulating hormone (alpha-MSH) were analysed. The results show that social subordination resulted in a significant skin darkening. Furthermore, plasma concentrations of alpha-MSH, ACTH and cortisol were elevated in subordinates, and these fish also displayed elevated levels of 5-hydroxyindoleacetic acid (5-HIAA) in the telencephalon. The ratio of [5-HIAA] to serotonin [5-HT] was increased in several brain areas. In addition, the ratio of 3-methoxy-4-hydroxyphenylglycol (MHPG) to norepinephrine (NE) concentrations was significantly increased in the optic tectum of subordinate fish. Skin darkness following social interaction showed a significant positive correlation with plasma levels of alpha-MSH. Plasma levels of ACTH and alpha-MSH were both positively correlated with that of cortisol. Brain [5-HIAA]/[5-HT] ratios were positively correlated with circulating plasma levels of ACTH, and a similar positive correlation was seen between [MHPG]/[NE] ratios in the optic tectum and plasma levels of ACTH, alpha-MSH and N-acetyl-beta-endorphin. In contrast, hypothalamic [MHPG]/[NE] ratios displayed a negative correlation with plasma alpha-MSH concentrations. The present study demonstrates that social stress induces skin darkening in Arctic charr and that this effect could be mediated by a stress-induced increase in the levels of alpha-MSH in the circulation. Furthermore, the results suggest that 5-HT and NE in the central nervous system could be factors regulating the pituitary release of ACTH and alpha-MSH. (+info)
Cerebrospinal fluid studies in children with cerebral malaria: an excitotoxic mechanism?
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The pathogenesis of cerebral malaria is poorly understood. One hypothesis is that activation of microglia and astrocytes in the brain might cause the cerebral symptoms by excitotoxic mechanisms. Cerebrospinal fluid was sampled in 97 Kenyan children with cerebral malaria, 85% within 48 hr of admission. When compared with an age-matched reference range, there were large increases in concentrations of the excitotoxin quinolinic acid (geometric mean ratio cerebral malaria/reference population [95% confidence limits] = 14.1 [9.8-20.4], P < 0.001) and total neopterin (10.9 [9.1-13.0], P < 0.001) and lesser increases in tetra-hydrobiopterin, di-hydrobiopterin, and 5-hydroxyindoleacetic acid. There was no change in tryptophan concentration. In contrast, nitrate plus nitrite concentrations were decreased (geometric mean ratio = 0.45 [0.35-0.59], P < 0.001). There was a graded increment in quinolinic acid concentration across outcome groups of increasing severity. The increased concentration of quinolinic acid suggests that excitotoxic mechanisms may contribute to the pathogenesis of cerebral malaria. (+info)
Dopamine function in Lesch-Nyhan disease.
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Lesch-Nyhan disease is a disorder of purine metabolism resulting from mutations in the gene for hypoxanthine guanine phosphoribosyl transferase on the X chromosome. It is characterized by hyperuricemia and all of its consequences, as in gout; but in addition, patients have impressive disease of the central nervous system. This includes spasticity, involuntary movements, and retardation of motor development. The behavioral phenotype is best remembered by self-injurious biting behavior with attendant destruction of tissue. The connection between aberrant metabolism of purines and these neurologic and behavioral features of the disease is not clear. Increasing evidence points to imbalance of neurotransmitters. There is increased excretion of the serotonin metabolite 5-hydroxyindoleacetic acid in the urine. There are decreased quantities and activities of a number of dopaminergic functions. Positron emission tomography scanning has indicated deficiency in the dopamine transporter. (+info)