6R-L-erythro-Tetrahydrobiopterin Triggers Serotonin Release with 5HT-loaded RBL2H3 Cells, a Rat Mast Cell Line
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Abstract A new function of tetrahydrobiopterin (BH 4 ) was demonstrated in vitro in which BH 4 stimulated serotonergic cells to release serotonin (5HT). RBL2H3 cells were pre-loaded with serotonin at 100 μM for 6 hours. The cells were able to release serotonin in response to either 30 mM KCl or 30 nM A23187 up to 2.26±2.06% (n=15) or 9.75± 1.38% (n=15 ), respectively. On exposure to 6R-L-erythrotetrahydrobiopterin (6RBH 4 ) at 100 μM, the 5HT-Ioaded cells secreted serotonin up to 8.13± 1.43% of the cellular 5HT within 60 min. The effect was a concentration dependent response and the half maximum output was observed at 1 nM or lower. Sepiapterin (> 10 μM) caused minimal release and 6S-L-erythro-tetrahydrobiopterin (6SBH 4 ,≤0 .4 mM) did not cause significant release. The results suggest that the effect of 6RBH 4 was highly stereospecific and that it worked extracellularly.Keywords:
Serotonin Agonist
Tracking serotonergic pathways in the brain through immunodetection of serotonin has widely been used for the anatomical characterization of the serotonergic system. Immunostaining for serotonin is also frequently applied for the visualization of individual serotonin containing fibers and quantification of serotonin positive fibers has been widely used to detect changes in the serotonergic innervation. However, particularly in conditions with enhanced serotonin metabolism the detection level of serotonin may lead to an underestimation of the true number of serotonergic fibers. The serotonin transporter (SERT) protein, on the other hand, is less liable to metabolism and for that reason we hypothetized that SERT immunostaining is a more stable marker of serotonergic fibers. Rats were pretreated with monoamine oxidase (MAO) inhibitor and compared with placebo treated rats. Brains were double immunostained for serotonin and SERT protein and colocalization was quantified in several brain areas by confocal microscopy. In comparison with untreated rats, MAO inhibitor treated rats had a significantly higher number (almost 200% increase) of serotonin immunopositive fibers whereas no difference was observed in the number of the SERT positive fibers. Colocalization between serotonin and SERT positive fibers was close to 100% in MAO inhibitor treated animals but only 30% in untreated rats. We conclude that the rapid metabolism of serotonin leads to an underestimation of immunodetected serotonergic fibers and that in many instances, SERT immunostaining may be a better indicator of serotonergic fibers. Synapse 59:270–276, 2006. © 2006 Wiley-Liss, Inc.
Colocalization
Immunostaining
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5-Hydroxytryptophan
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According to the monoamine hypothesis, the development of depression is associated with dysfunctions of the serotonergic system. Alterations in the serotonin transporter gene (5-HTTLPR), the serotonergic activity in the brain, and the content of serotonin (5-HT) have been related to depression and were examined separately by previous studies. This study investigates these parameters in 89 depressed patients and 89 healthy participants. We investigated the serotonergic activity measured by the loudness dependence of auditory evoked potentials (LDAEP). In addition to the examination of the serotonin content (serum and platelet), enzyme-linked immunosorbent assays (ELISA) were used and 5-HTTLPR genotypes were analyzed. We observed a lower serotonin content in patients compared to healthy participants. Further, we noticed a correlation between anxiety and depression-associated symptoms with serotonergic activity. Patients treated with SSRI/SNRI showed decreased contents of serum serotonin compared to patients without any psychotropic medication or other psychotropic medications. Since the serotonergic activity, peripheral serotonin content, and 5-HTTLPR were unrelated, the results suggest independent alterations of central and peripheral serotonergic systems in depression. In line with this finding, serotonergic activity was related to anxiety and depression symptoms. Furthermore, the applied medication seems to influence serum serotonin content in patients with depression.
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Serotonin (5-hydroxytryptophan, 5-HT) is an important gastrointestinal neurotransmitter. It is also a major component of enteric nervous system (ENS). Serotonin exhibits multiple physiological functions via its many different receptors. Over 90% of the body's serotonin is contained in the gut where it plays an important role in the control of gastrointestinal (GI) sensitivity, motility and muscle tone by activating different receptor subtypes. This minireview focuses the effects of serotonin, its agonists, antagonists and serotonergic neurons on the GI functions and points the mechanisms of serotonergic agents in GI motility and functional bowel disorders.
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Mice were made alcoholic on an alcohol liquid diet. The rate of serotonin synthesis in the brains of chronically alcoholic mice was found to be almost half that of the control group. However, the effect of acute alcoholism demonstrated a tendency to increase the rate of serotonin synthesis. Brain levels of 5HIAA were decreased during chronic alcohol ingestion, however, the brain levels of serotonin in alcoholic mice were similar to those in the untreated mice. These data suggest that serotonergic units in the central nervous system are inhibited during chronic alcoholism.
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"Scottie Cramp" is a genetic neurologic disease which occurs in the Scottish terrier breed of dogs. Decreasing central nervous system (CNS) concentrations of serotonin (5-HT) via para-chlorophenylalanine (pCPA) will profoundly increase the severity of the disease although the basic defect does not involve serotonergic neurons. The purpose of this study was to attempt to correlate the effect of p-CPA on the clinical signs of the disease with the alteration in serotonin synthesis and concentration in the CNS. Synthesis was estimated by following the rise in cisternal cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations with time following probenecid injection. Concentration of serotonin in the CNS was estimated by measuring cisternal CSF 5-HIAA concentrations. The results suggest that serotonin may be synthesized in excess of neuronal transmitter needs and that the estimation of whole brain turnover rates and concentrations of 5-HT may not yield a true measure of serotonergic neuronal activity.
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5-Hydroxyindoleacetic acid
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