Modification of 5-hydroxytryptophan-evoked 5-hydroxytryptamine formation of guinea pig colonic mucosa by reactive oxygen species.
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We studied whether reactive oxygen species (ROS) generated by normal colonic mucosa affect 5-hydroxytryptophan (5-HTP)-evoked 5-HT formation (measured as the sum of 5-HT plus 5-hydroxyindole acetic acid (5-HIAA) accumulation) of guinea pig's isolated colonic mucosa. Catalase (3000-6000 U/ml), a hydrogen peroxide (H2O2) scavenger or diphenylene iodonium (DPI, 10-100 microM), an NADPH oxidase inhibitor, concentration-dependently caused an increase of the sum of 5-HT plus 5-HIAA accumulation in the presence of 5-HTP (10 microM), but these drugs did not significantly affect the 5-HT-metabolite in the colonic mucosa measured as the ratio of 5-HIAA/5-HT. Exogenously applied H2O2 (10-100 microM) concentration-dependently inhibited the sum of 5-HT plus 5-HIAA accumulation. In contrast, neither superoxide dismutase (SOD, 100-300 U/ml), superoxide anion scavenger, nor dimetyl sulfoxide (1-5%, DMSO), a hydroxyl radical scavenger affected the sum of 5-HT plus 5-HIAA accumulation. Moreover, mucosa ROS generation was estimated using the chemiluminescence technique. SOD (100-300 U/ml), catalase (3000-6000 U/ml) or DPI (10-100 microM), concentration-dependently reduced luminol-enhanced chemiluminescence signal from the colonic mucosa, while allopurinol (10-100 microM), a xanthine oxidase inhibitor, did not affect the chemiluminescence signal. These results suggest that ROS is formed through an NADPH oxidase system in the guinea pig colonic mucosa, where it exerts a modulatory effect on mucosal 5-HT formation upon addition of 5-HTP. Thus, ROS formation from normal colonic mucosa could be considered to contribute to the control of 5-HT production in mucosa enterochromaffin cells. (+info)
Serotonin metabolism in children with kwashiorkor.
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Intestinal fat absorption, serum 5-hydroxytryptamine (5-HT) and 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) were studied in 13 children with kwashiorkor and 10 matched healthy controls. Eight out of 13 children with kwashiorkor who had steatorrhea also showed raised plasma serotonin levels in parallel with the high urinary excretion of 5-HIAA. In five children with kwashiorkor who showed normal intestinal fat absorption, the serum 5-HT and urinary 5-HIAA levels were comparable to controls. After therapy, concurrent with clinical and biochemical recovery, the intestinal absorption of fat improved, serum 5-HT concentration and the urinary excretion of 5-HIAA returned to normal range. This suggested that the deranged serotonin metabolism in our cases was secondary to the protein-calorie deficiency. The presence of defective metabolism of serotonin (5-HT) in children with kwashiorkor has been reported and its possible role in the etiopathogenesis of steatorrhea-diarrhea, skin lesions and psychomotor changes has been suggested for further work. (+info)
Analysis of monoamines, adenosine and GABA in tissues of the land snail Helix lucorum and lizard Agama stellio stellio during hibernation.
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The aim of the present study was to determine the levels of monoamines, GABA and adenosine in the brain, heart and haemolymph of the land snail Helix lucorum and in the brain, heart and blood of lizard Agama stellio stellio during long-term hibernation. We measured levels of the monoamines serotonin (5-HT) and its main metabolite 5-hydroxyindole-3-acetic acid (5-HIAA), dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), norepinephrine (NE) and epinephrine (E). The most abundant amines detected in the brain and heart of active H. lucorum were 5-HT and DA. Of the metabolites examined only 5-HIAA was found in the brain. NE was found at very low levels but only in the brain, while E was not detected in the brain and heart. The levels of 5-HT and 5-HIAA increased in the brain and heart of H. lucorum within the first months of hibernation, showing a significant decrease thereafter. The levels of DA did not change during hibernation. The results indicated that 5-HT might be involved in preparing snails for entry into hibernation. GABA was only found in the brain of H. lucorum, and the levels were low; these levels remained during hibernation. Adenosine was present in brain and heart of H. lucorum, and during hibernation, the level of adenosine decreased significantly in the brain but remained steady in the heart. The monoamines 5-HT, DA and NE were present in the brain of active lizards A. stellio stellio, whereas E was found only at very low levels. Moreover, the metabolites 5-HIAA, DOPAC and HVA were detected in the brain of active lizards. The monoamines 5-HT, DA, NE and E were also detected in the heart and blood of active lizards. During hibernation the levels of these four monoamines were decreased significantly in the brain and heart of A. stellio stellio. In contrast, the levels of E increased in the heart and blood of hibernating lizards. Adenosine was detected in both heart and brain of active lizards, but hibernation caused a marked decrease in its levels at both tissues. GABA was found at higher levels than monoamines and adenosine in the brain of active lizards, and hibernation caused a significant increase in its levels, indicating an important role of GABA in inhibition of neuronal activity in hibernating lizards. (+info)
Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis).
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Social dominance is a fundamental component of both human and nonhuman primate sociality. However, its neurobiological correlates remain incompletely understood. We evaluated the association between dominance status and monoamine metabolite concentrations in cisternal cerebrospinal fluid (CSF) in adult male (n = 25) and female (n = 21) cynomolgus macaques (Macaca fascicularis) housed in unisexual social groups. Concentrations of the metabolites of dopamine (homovanillic acid [HVA]), norepinephrine (3-methoxy-4-hydroxyphenylglycol [MHPG]) and serotonin (5-hydroxyindoleacetic acid [5-HIAA]) were assayed. Dominant monkeys, both males and females, had significantly higher CSF HVA concentrations than did subordinates (p values <.05). Among males, but not females, dominants also had lower CSF 5-HIAA than subordinates (p <.05). The Dominance-HVA association observed here is consistent with recent speculation that social extraversion, a dominance-related personality trait in humans, may also reflect heightened central nervous system dopaminergic activity. (+info)
Modulation of 5-HT4 receptor function in the rat isolated ileum by fluoxetine: the involvement of endogenous 5-hydroxytryptamine.
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The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 microM. Fluoxetine (10 microM) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5-HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone. Fluoxetine (10 microM) also failed to prevent the relaxation due to exogenous 5-HT and the 5-HT4 receptor agonist 5-methoxytryptamine in tissues taken from the rats treated with para-chlorophenylalanine (300 mg kg-1) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. The contraction of the tissues with GR113808 indicates the presence of an endogenous 5-HT tone at the 5-HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5-HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5-HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis. (+info)
GAP-43 is critical for normal development of the serotonergic innervation in forebrain.
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Serotonergic (5-HT) axons from the raphe nuclei are among the earliest afferents to innervate the developing forebrain. The present study examined whether GAP-43, a growth-associated protein expressed on growing 5-HT axons, is necessary for normal 5-HT axonal outgrowth and terminal arborization during the perinatal period. We found a nearly complete failure of 5-HT immunoreactive axons to innervate the cortex and hippocampus in GAP-43-null (GAP43-/-) mice. Abnormal ingrowth of 5-HT axons was apparent on postnatal day 0 (P0); quantitative analysis of P7 brains revealed significant reductions in the density of 5-HT axons in the cortex and hippocampus of GAP43-/- mice relative to wild-type (WT) controls. In contrast, 5-HT axon density was normal in the striatum, septum, and amygdala and dramatically higher than normal in the thalamus of GAP43-/- mice. Concentrations of serotonin and its metabolite, 5-hydroxyindolacetic acid, and norepinephrine were decreased markedly in the anterior and posterior cerebrum but increased in the brainstem of GAP43-/- mice. Cell loss could not account for these abnormalities, because unbiased stereological analysis showed no significant difference in the number of 5-HT dorsal raphe neurons in P7 GAP43-/- versus WT mice. The aberrant 5-HT innervation pattern persisted at P21, indicating a long-term alteration of 5-HT projections to forebrain in the absence of GAP-43. In heterozygotes, the density and morphology of 5-HT axons was intermediate between WT and homozygous GAP43-/- mice. These results suggest that GAP-43 is a key regulator in normal pathfinding and arborization of 5-HT axons during early brain development. (+info)
Effect of NOS inhibitor on forced swim test and neurotransmitters turnover in the mouse brain.
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The previous experiments have demonstrated that NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors have antidepressant- and anxiolytic-like activities in rodents. Moreover, chronic treatments with these agents result in down-regulation of beta-adrenoceptors in the brain cortex with a magnitude comparable to clinically effective antidepressants. However, still little is known about the effect of NOS inhibitors on the regulation of neurotransmitter utilization in vivo. The aim of present study was to elucidate the effect of NOS inhibitor at doses active in forced swim test (FST) on dopamine and serotonin turnover in the mouse brain structures. Mice were treated with imipramine (15 mg/kg ip), electroconvulsive shock (ECS) and NOS inhibitor, N(G)-nitro-L-arginine (L-NA) acutely (at doses of 1, 3, 10 mg/kg ip) and chronically (0.3, 1, 3 mg/kg ip). Experiments were carried out 1 h after single and 3 h after chronic (21 days) administration. Metabolism of dopamine and serotonin was investigated using high pressure liquid chromatography (HPLC) with electrochemical detection. The metabolism rate was calculated as a ratio of a metabolite to the parent amine. FST was performed using protocol described previously by Porsolt et al. Now we report that L-NA decreases the level of immobility with potency similar to imipramine. The effect of L-NA was reversed by NOS substrate, L-arginine. L-NA given acutely at doses active in FST did not change the dopamine metabolism rate but it did decrease the serotonin turnover rate in the frontal cortex in a manner similar to imipramine. Thus, it appears that under basal conditions endogenous NO may influence the serotonin turnover, and the acute inhibition of NOS can mimic the effect of imipramine what may result in the antidepressant-like effect in FST. Imipramine given acutely produced massive increase in the level of serotonin in the frontal cortex as well as in the hypothalamus (by 40%, p < 0.01) what was reflected in significant decreases in the metabolism rate. Contrary to acute effect, chronic treatment of L-NA (the most effective dose was 1 mg/kg) produced increase in the dopamine metabolism rate within all investigated structures. In the present study, we demonstrated for the first time that L-NA may alter the neurotransmitter utilization in vivo and the observed effect may be due to adaptational changes in neuronal function. (+info)
Alterations of amino acids and monoamine metabolism in male Fmr1 knockout mice: a putative animal model of the human fragile X mental retardation syndrome.
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The Fragile X syndrome, a common form of mental retardation in humans, is caused by silencing the fragile X mental retardation (FMR1) gene leading to the absence of the encoded fragile X mental retardation protein 1 (FMRP). We describe morphological and behavioral abnormalities for both affected humans and Fmr1 knockout mice, a putative animal model for the human Fragile X syndrome. The aim of the present study was to identify possible neurochemical abnormalities in Fmr1 knockout mice, with particular focus on neurotransmission. Significant region-specific differences of basal neurotransmitter and metabolite levels were found between wildtype and Fmr1 knockout animals, predominantly in juveniles (post-natal days 28 to 31). Adults (postnatal days 209 to 221) showed only few abnormalities as compared with the wildtype. In juvenile knockout mice, aspartate and taurine were especially increased in cortical regions, striatum, hippocampus, cerebellum, and brainstem. In addition, juveniles showed an altered balance between excitatory and inhibitory amino acids in the caudal cortex, hippocampus, and brainstem. We detected very few differences in monoamine turnover in both age stages. The results presented here provide the first evidence that lack of FMRP expression in FMRP knockout mice is accompanied by age-dependent, region-specific alterations in neurotransmission. (+info)