Showing papers on "Serotonin published in 2002"
TL;DR: The hypothesis that a stimulant‐induced increase in serotonin is necessary for the appearance of stereotyped behaviors is not supported, as methylphenidate promotes a dose‐dependent behavioral profile that is very comparable to that of amphetamine.
Abstract: Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.
600 citations
TL;DR: For instance, this paper showed that the turnover of serotonin by the brain was lowest in winter (p=0.013), and the rate of production of serotonin was directly related to the prevailing duration of bright sunlight (r = 0.294, p= 0.010), and rose rapidly with increased luminosity.
488 citations
TL;DR: The ability of estrogens and progestins to alter the function of the serotonin neural system at various levels provides a cellular mechanism whereby ovarian hormones can impact cognition, mood or arousal, hormone secretion, pain, and other neural circuits.
454 citations
TL;DR: Assessment of the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depression symptoms in cancer patients undergoing cytokine therapy indicates that the development of depressive symptoms in patients undergoing chemotherapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophile.
Abstract: Cytokine therapy for cancer or viral diseases is accompanied by the development of depressive symptoms in a significant proportion of patients. Despite the increasing number of studies on the neurotoxic effects of cytokines, the mechanisms by which cytokines induce depressive symptoms remain largely unknown. In view of the relationship between neurotransmitter precursors and mood, the present study aimed at assessing the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depressive symptoms in cancer patients undergoing cytokine therapy. Sixteen cancer patients eligible to receive immunotherapy with interleukin-2 and/or interferon-alpha participated in the study. At baseline and after one week and one month of therapy, depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), and blood samples were collected for the determination of the large neutral amino acids (LNAA) (tryptophan, tyrosine, valine, leucine, isoleucine, phenylalanine) which compete for transport across the blood-brain barrier. Serum concentrations of tryptophan as well as the tryptophan/LNAA ratio significantly decreased between baseline, one week and one month of therapy. The development and severity of depressive symptoms, especially anorexia, pessimistic thoughts, suicidal ideation and loss of concentration were positively correlated with the magnitude of the decreases in tryptophan concentrations during treatment. These findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophan.
451 citations
TL;DR: It is concluded that activation of both peripheral and central 5-HT3 receptors is pronociceptive and that the contribution of peripheral 5- HT3 receptors involves a novel complement of primary afferent nociceptors.
Abstract: Serotonin is a major component of the inflammatory chemical milieu and contributes to the pain of tissue injury via an action on multiple receptor subtypes. Here we studied mice after genetic or pharmacological disruption of the 5-HT 3 receptor, an excitatory serotonin-gated ion channel. We demonstrate that tissue injury-induced persistent, but not acute, nociception is significantly reduced after functional elimination of this receptor subtype. Specifically, in the setting of tissue injury, the 5-HT 3 receptor mediates activation of nociceptors but does not contribute to injury-associated edema. This result is explained by the localization of 5-HT 3 receptor transcripts to a previously uncharacterized subset of myelinated and unmyelinated afferents, few of which express the proinflammatory neuropeptide substance P. Finally, we provide evidence that central serotonergic circuits modulate nociceptive transmission via a facilitatory action at spinal 5-HT 3 receptors. We conclude that activation of both peripheral and central 5-HT 3 receptors is pronociceptive and that the contribution of peripheral 5-HT 3 receptors involves a novel complement of primary afferent nociceptors.
382 citations
TL;DR: In the acute tryptophan depletion (ATD) technique as mentioned in this paper, subjects ingest a mixture of amino acids devoid of Tryptophan, and this results in a transient decline in tissue TPs and in brain serotonin, which can result in lower mood and increase in irritability or aggressive responding.
Abstract: Alterations in brain tryptophan levels cause changes in brain serotonin synthesis, and this has been used to study the implication of altered serotonin levels in humans. In the acute tryptophan depletion (ATD) technique, subjects ingest a mixture of amino acids devoid of tryptophan. This results in a transient decline in tissue tryptophan and in brain serotonin. ATD can result in lower mood and increase in irritability or aggressive responding. The magnitude of the effect varies greatly depending on the susceptibility of the subject to lowered mood or aggressivity. Unlike ATD, tryptophan can be given chronically. Tryptophan is an antidepressant in mild to moderate depression and a small body of data suggests that it can also decrease aggression. Preliminary data indicate that tryptophan also increases dominant behavior during social interactions. Overall, studies manipulating tryptophan levels support the idea that low serotonin can predispose subjects to mood and impulse control disorders. Higher levels of serotonin may help to promote more constructive social interactions by decreasing aggression and increasing dominance.
368 citations
TL;DR: Agonists of three arousal-related systems impinging on the dorsal raphe caused an inward current and increase in current noise in whole-cell patch-clamp recordings from these neurons in brain slices, suggesting that all three systems act via common effector mechanisms.
Abstract: Dorsal raphe serotonin neurons fire tonically at a low rate during waking. In vitro, however, they are not spontaneously active, indicating that afferent inputs are necessary for tonic firing. Agonists of three arousal-related systems impinging on the dorsal raphe (orexin/hypocretin, histamine and the noradrenaline systems) caused an inward current and increase in current noise in whole-cell patch-clamp recordings from these neurons in brain slices. The inward current induced by all three agonists was significantly reduced in extracellular solution containing reduced sodium (25.6 mm). In extracellular recordings, all three agonists increased the firing rate of serotonin neurons; the excitatory effects of histamine and orexin A were occluded by previous application of phenylephrine, suggesting that all three systems act via common effector mechanisms. The dose-response curve for orexin B suggested an effect mediated by type II (OX2) receptors. Single-cell PCR demonstrated the presence of both OX1 and OX2 receptors in tryptophan hydroxylase-positive neurons. The effects of histamine and the adrenoceptor agonist, phenylephrine, were blocked by antagonists of histamine H1 and alpha1 receptors, respectively. The inward current induced by orexin A and phenylephrine was not blocked by protein kinase inhibitors or by thapsigargin. Three types of current-voltage responses were induced by all three agonists but in no case did the current reverse at the potassium equilibrium potential. Instead, in many cases the orexin A-induced current reversed in calcium-free medium at a value (-23 mV) consistent with the activation of a mixed cation channel (with relative permeabilities for sodium and potassium of 0.43 and 1, respectively).
336 citations
TL;DR: The results suggest that a chronically α‐linolenic‐deficient diet specifically affects the monoaminergic systems in the frontal cortex, and that age-related variations in these systems showed specific age‐related variations but regardless of the diet.
Abstract: The effects of alpha-linolenic acid diet deficiency on rat dopaminergic and serotoninergic neurotransmission systems were investigated in the frontal cortex, striatum, and cerebellum of male rats 2,6,12, and 24 months of age. The diet deficiency induced severe decrease in the 22:6n-3 fatty acid levels in all regions and a compensatory increase in n-6 fatty acid levels. A recovery in the levels of 22:6n-3 was observed in deficient rats between 2 and 12 months of age; however, this recovery was lower in frontal cortex than in striatum and cerebellum. In the striatum and cerebellum, dopaminergic and serotoninergic receptor densities and endogenous dopamine and serotonin levels were affected by aging regardless of the diet. In contrast, a 40-75% lower level of endogenous dopamine in the frontal cortex occurred in deficient rats according to age. The deficiency also induced an 18-46% increase in serotonin 5-HT2 receptor density in the frontal cortex during aging, without variation in endogenous serotonin level, and a 10% reduction in density of dopaminergic D2 receptors. Monoamine oxidase-A and -B activities showed specific age-related variations but regardless of the diet. Our results suggest that a chronically alpha-linolenic-deficient diet specifically affects the monoaminergic systems in the frontal cortex.
324 citations
TL;DR: Comparing the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex suggests that fluoxetine is an atypical SSRI.
Abstract: Rationale: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. Objective: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. Methods: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. Results: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT2C receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. Conclusion: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.
320 citations
TL;DR: A cation-pi interaction between serotonin and Trp183 of the serotonin channel 5-HT(3A)R is identified for the first time, precisely locating the ligand-binding site of this receptor.
Abstract: A series of tryptophan analogues has been introduced into the binding site regions of two ion channels, the ligand-gated nicotinic acetylcholine and serotonin 5-HT3A receptors, using unnatural amino acid mutagenesis and heterologous expression in Xenopus oocytes. A cation−π interaction between serotonin and Trp183 of the serotonin channel 5-HT3AR is identified for the first time, precisely locating the ligand-binding site of this receptor. The energetic contribution of the observed cation−π interaction between a tryptophan and the primary ammonium ion of serotonin is estimated to be approximately 4 kcal/mol, while the comparable interaction with the quaternary ammonium of acetylcholine is approximately 2 kcal/mol. The binding mode of nicotine to the nicotinic receptor of mouse muscle is examined by the same technique and found to differ significantly from that of the natural agonist, acetylcholine.
300 citations
TL;DR: There is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact on the brain serotonin system, and one mechanism is postulated through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission.
Abstract: The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly. Interaction of the thyroid and monoamine neurotransmitter systems has been suggested as a potential underlying mechanism of action. While catecholamine and thyroid interrelationships have been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal of this article is to review the literature on the relationships between thyroid hormones and the brain serotonin (5-HT) system, limited to studies in adult humans and adult animals. In humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-HT responsiveness that is reversible with thyroid replacement therapy. In adult animals with experimentally-induced hypothyroid states, increased 5-HT turnover in the brainstem is consistently reported while decreased cortical 5-HT concentrations and 5-HT2A receptor density are less frequently observed. In the majority of studies, the effects of thyroid hormone administration in animals with experimentally-induced hypothyroid states include an increase in cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT1A receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermore, there is some indication that thyroid hormones may increase cortical 5-HT2 receptor sensitivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact on the brain serotonin system. Thus it is postulated that one mechanism, among others, through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission, specifically by reducing the sensitivity of 5-HT1A autoreceptors in the raphe area, and by increasing 5-HT2 receptor sensitivity.
TL;DR: Overall, it appears that the extracellular concentration of 5-HT in the DR and the MnR is tightly controlled by intrinsic serotonergic mechanisms as well as afferent connections.
TL;DR: The evidence indicates higher levels of 5-HT(2A) receptor, protein, and mRNA expression in the prefrontal cortex and hippocampus, which have been implicated in emotion, stress, and cognition, are shown to be associated with teenage suicide.
Abstract: OBJECTIVE: Abnormalities of serotonin (5-HT) receptor subtypes have been observed in the postmortem brains of adult suicide victims; however, their role in teenage suicide is unexplored. The authors examined whether 5-HT2A receptor subtypes are altered in the postmortem brains of teenage suicide victims. METHOD: Levels of 5-HT2A receptors were determined through examination of [125I] LSD binding, protein expression (by use of Western blotting with a specific 5-HT2A receptor antibody), and mRNA (by means of quantitative reverse transcription polymerase chain reaction) in the prefrontal cortex, hippocampus, and nucleus accumbens of 15 teenage suicide victims and 15 normal matched teenage subjects. The cellular localization of the 5-HT2A receptors was determined by means of gold immunolabeling. RESULTS: The authors observed significantly higher [125I]LSD binding in the prefrontal cortex and greater protein expression and mRNA levels in the prefrontal cortex and hippocampus but not in the nucleus accumbens of...
TL;DR: This review will summarize the current understanding of the structure and function of the G-protein coupled 5-HT receptors and present examples to demonstrate that a detailed knowledge of the predicted structure of one receptor can be useful for structure-based drug design.
Abstract: 5-hydroxytryptamine (5-HT; serotonin) is a neurotransmitter essential for a large number of physiological processes including the regulation of vascular and non-vascular smooth muscle contraction, modulation of platelet aggregation, and the regulation of appetite, mood, anxiety, wakefulness and perception. To mediate this astonishing array of functions, no fewer than 15 separate receptors have evolved, of which all but two (5-HT(3A) and 5-HT(3B)) are G-protein coupled receptors. This review will summarize our current understanding of the structure and function of the G-protein coupled 5-HT receptors. In particular, a systematic review of the available mutagenesis studies of 5-HT receptors will be presented. This information will be synthesized to provide a working model of agonist and antagonist actions at a prototypic 5-HT receptor the 5-HT(2A) receptor. Finally, examples will be given to demonstrate that a detailed knowledge of the predicted structure of one receptor can be useful for structure-based drug design.
TL;DR: In vivo microdialysis data are supportive of a state‐dependent, stimulatory role of 5‐HT in the regulation of dopamine release, and are consistent with the view that MDMA increases the extracellular concentration of 4,4‐methylenedioxymethamphetamine by facilitating carrier‐mediated 5‐ HT release, which can be enhanced greatly under conditions in which5‐HT synthesis is stimulated.
Abstract: In vivo microdialysis was used to determine whether the 3,4-methylenedioxymethamphetamine (MDMA)-induced release of serotonin (5-HT) in vivo involves a carrier-mediated process and to investigate further the state-dependent interaction between 5-HT and dopamine. MDMA produced a dose-dependent increase in the extracellular concentration of 5-HT in the striatum and prefrontal cortex that was attenuated by treatment with fluoxetine but not by tetrodotoxin. Suppression by fluoxetine of the MDMA-induced release of 5-HT was accompanied by a suppression of the MDMA-induced release of dopamine. Administration of MDMA to rats treated with carbidopa and L-5-hydroxytryptophan resulted in a synergistic elevation of the extracellular concentration of 5-HT that was much greater than that produced by either treatment alone. The MDMA-induced release of dopamine by MDMA also was potentiated in 5-hydroxytryptophan-treated rats. These data are consistent with the view that MDMA increases the extracellular concentration of 5-HT by facilitating carrier-mediated 5-HT release, which can be enhanced greatly under conditions in which 5-HT synthesis is stimulated. Moreover, these data are supportive of a state-dependent, stimulatory role of 5-HT in the regulation of dopamine release.
TL;DR: The results suggest that dietary protein rich in alpha-lactalbumin improves cognitive performance in stress-vulnerable subjects via increased brain tryptophan and serotonin activities.
TL;DR: It is concluded that endogenously activated 5-HT2A receptors are required for maintaining fictive respiratory activity in the brainstem slice by modulating sodium conductances via a PKC pathway.
Abstract: Endogenous amines and peptides continuously modulate the activity of neuronal networks and are required even for their normal operation. The respiratory rhythm generator, localized in the pre-Botzinger complex, is not an exception. This network is modulated by various neurotransmitters, including serotonin (5-HT). In this study, we isolated the respiratory network in brainstem slices and demonstrate that the endogenous activation of 5-HT2A is required for the generation of the respiratory rhythm in vitro . At the network level, activation of 5-HT2A receptors with 4-iodo-2,5-dimethoxyamphetamine or the 5-HT uptake blocker alaproclate increased the frequency of respiratory activity. Blockade of endogenously activated 5-HT2A receptors with three different antagonists decreased the frequency, amplitude, and regularity of respiratory population activity, an effect that was blocked by protein kinase C (PKC) activators. At the cellular level, blockade of 5-HT2A receptors reduced the action potential discharge in all examined respiratory neurons, which was associated with a reduction in the fast and the persistent sodium current. Continuous application of 5-HT2A-receptor antagonists differentially affected pacemaker neurons. Pacemaker activity was eliminated in cadmium-insensitive pacemaker neurons. In cadmium-sensitive pacemaker neurons, the frequency of pacemaker activity was unaffected and the amplitude of pacemaker bursts was enhanced. It is assumed that cadmium-insensitive pacemakers rely on the persistent sodium current, whereas cadmium-sensitive pacemakers depend on the activation of calcium currents. We conclude that endogenously activated 5-HT2A receptors are required for maintaining fictive respiratory activity in the brainstem slice by modulating sodium conductances via a PKC pathway.
TL;DR: A clear correlation is established between the presence of the 5-HT3A receptor subunit in neocortical VIP/CCK GABAergic interneurons, its functional expression, and its synaptic activation by serotonergic afferent fibers from the brainstem raphe nuclei.
Abstract: Neocortical neurons expressing the serotonin 5-HT3 receptor (5-HT3R) were characterized in rat acute slices by using patch-clamp recordings combined with single-cell RT-PCR and histochemical labeling. The 5-HT3A receptor subunit was expressed selectively in a subset of GABAergic interneurons coexpressing cholecystokinin (CCK) and vasoactive intestinal peptide (VIP). The 5-HT3B subunit was never detected, indicating that 5-HT3Rs expressed by neocortical interneurons did not contain this subunit. In 5-HT3A-expressing VIP/CCK interneurons, serotonin induced fast membrane potential depolarizations by activating an inward current that was blocked by the selective 5-HT3R antagonist tropisetron. Furthermore, we observed close appositions between serotonergic fibers and the dendrites and somata of 5-HT3R-expressing neurons, suggestive of possible synaptic contacts. Indeed, in interneurons exhibiting rapid excitation by serotonin, local electrical stimulations evoked fast EPSCs of large amplitude that were blocked by tropisetron. Finally, 5-HT3R-expressing neurons were also excited by a nicotinic agonist, indicating that serotonergic and cholinergic fast synaptic transmission could converge onto VIP/CCK interneurons. Our results establish a clear correlation between the presence of the 5-HT3A receptor subunit in neocortical VIP/CCK GABAergic interneurons, its functional expression, and its synaptic activation by serotonergic afferent fibers from the brainstem raphe nuclei.
TL;DR: The use of central monoamine depletion studies has demonstrated that it is elevated synaptic monoamine levels themselves, rather than some downstream postsynaptic changes in, for example, receptor sensitivity, that are responsible for the therapeutic effect of antidepressant drugs.
Abstract: Several classes of antidepressant drug exist, divided into three broad families, the monoamine reuptake inhibitors, the monoamine oxidase inhibitors and the monoamine receptor antagonists. All these drugs have a common pharmacological effect, to raise the synaptic concentrations of noradrenaline and serotonin. Although different drugs have different relative selectivity for noradrenaline and serotonin systems, these two neurotransmitter pathways work in parallel and in a coherent manner to produce the same final antidepressant response. The lag-time in the onset of action of antidepressants can be explained by the activation of inhibitory autoreceptors on serotonergic and noradrenergic neurones which initially attenuate the effects of antidepressants on synaptic transmitter levels. Over time, these autoreceptors desensitize, allowing the emergence of an overt antidepressant response. This theory has led to the proposition that antagonists at these autoreceptors such as pindolol may be useful adjuncts to antidepressant treatment, in order to hasten the appearance of a clinical response. Evidence for the clinical validity of this idea remains equivocal, however. The use of central monoamine depletion studies has demonstrated that it is elevated synaptic monoamine levels themselves, rather than some downstream postsynaptic changes in, for example, receptor sensitivity, that are responsible for the therapeutic effect of antidepressant drugs. Taken together, the data collected over the last 40 years have allowed the emergence of a unified monoamine hypothesis of antidepressant drug action.
TL;DR: Enhanced neopterin concentrations together with increased degradation of tryptophan and low serum levels of tryPTophan correlate with neuropsychiatric abnormalities like cognitive decline and depressive symptoms especially in long-lasting and chronic diseases.
Abstract: The cytokine interferon-gamma stimulates human monocytes/macrophages to release large amounts of neopterin. Increased neopterin concentrations in body fluids of patients are observed during diseases with activated cellular (=TH1-type) immune response such as allograft rejection, virus infections, autoimmune disorders, or malignant tumors but also in neurodegenerative diseases or during pregnancy. In various cells interferon-gamma induces indoleamine 2,3-dioxygenase (IDO) which degrades tryptophan via the kynurenine pathway. Therefore like increased neopterin formation, enhanced tryptophan degradation is observed in diseases concomitant with cellular immune activation. Disturbed metabolism of tryptophan affects biosynthesis of neurotransmitter 5-hydroxytryptamine (serotonin), and it appears to be associated with an increased susceptibility for depression. In fact, enhanced neopterin concentrations together with increased degradation of tryptophan and low serum levels of tryptophan correlate with neuropsychiatric abnormalities like cognitive decline and depressive symptoms especially in long-lasting and chronic diseases. Activation of IDO could represent an important link between the immunological network and the pathogenesis of depression.
TL;DR: Serotonin uptake, mediated by the serotonin transporter (SERT), is blocked acutely by antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but such blockade does not correlate temporally with the onset of therapeutic improvement.
Abstract: Serotonin uptake, mediated by the serotonin transporter (SERT), is blocked acutely by antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but such blockade does not correlate temporally with the onset of therapeutic improvement. Treatment with SSRIs for 21 d induced downregulation of the SERT (Benmansour et al., 1999). The time course of SERT downregulation as well as the time course for its recovery after cessation of treatment with the SSRI sertraline were investigated using tritiated cyanoimipramine to measure SERT binding sites. To determine if there was a temporal correlation between the time when sertraline induced downregulation of the SERT and when marked alteration in SERT function occurred, clearance of locally applied 5-HT into the CA3 region of hippocampus was achieved using in vivo electrochemistry. After 4 or 10 d treatment with sertraline, SERT binding sites decreased very little (15-30%), and the chronoamperometric signals for serotonin in sertraline-treated rats were comparable with ones obtained in control animals. By contrast, after 15 d of treatment, when SERT binding sites were markedly reduced by 80%, there was robust decrease in the clearance of 5-HT. Moreover, the functional consequences of SERT downregulation as measured by chronoamperometry were significantly greater than those seen after acute blockade of the SERT by SSRIs. SERT binding sites decreases are not a consequence of reduced SERT gene expression, as revealed by in situ hybridization measurements. SSRI-induced downregulation of the SERT may be a key component for the clinical response to SSRIs.
TL;DR: Two potentially autism-inducing teratogens, thalidomide and valproic acid, have the same effect on early monoamine system development in the brain and the blood, which may explain the pathogenesis of autism.
Abstract: Autism is defined as a congenital neurodevelopmental disorder in which serotonergic dysfunction may be involved in its pathogenesis. One of the characteristic laboratory findings in autistic patients is hyperserotonemia, although its mechanism has not been elucidated to date because of difficulties in studying human patients. Recent reports have demonstrated that thalidomide or valproic acid exposure during early embryonic days (first trimester) in humans causes higher incidence of autism. Morphologic abnormalities found in autism (e.g. cerebellar anomalies, reduced motor neuron numbers) have been reported in animals administered with these teratogens prenatally, suggesting the possibility of the use of these animals as an experimental autistic model. In this study, we evaluated monoamine levels in the brain and blood of rats exposed to teratogens prenatally. Of the groups exposed to thalidomide on embryonic day (E)2, E4, E7, E9, and E11, a significant increase of hippocampal serotonin was only observed in the group exposed on E9. Furthermore, E9 thalidomide and valproic acid exposure both resulted in an increase of hippocampal serotonin, frontal cortex dopamine, and hyperserotonemia. These results thus indicate that two potentially autism-inducing teratogens, thalidomide and valproic acid, have the same effect on early monoamine system development in the brain and the blood, which may explain the pathogenesis of autism.
TL;DR: 5-HT-associated valve disease may be, in part, because of TGF-beta1 mechanisms, and results strongly support the view that G-protein-related signal transduction is involved in 5-HT up-regulation of T GF- beta1.
Abstract: Clinical disorders associated with increased serotonin [5-hydroxytryptamine (5-HT)] levels, such as carcinoid syndrome, and the use of serotonin agonists, such as fenfluoramine have been associated with a valvulopathy characterized by hyperplastic valvular and endocardial lesions with increased extracellular matrix. Furthermore, 5-HT has been demonstrated to up-regulate transforming growth factor (TGF)-β in mesangial cells via G-protein signal transduction. We investigated the hypothesis that increased exposure of heart valve interstitial cells to 5-HT may result in increased TGF-β1 expression and activity because of serotonin receptor-mediated signal transduction with activation of Gαq, and subsequently up-regulation of phospholipase C. Thus, in the present study we performed a clinical-pathological investigation of retrieved carcinoid and normal valve cusps using immunohistochemical techniques to detect the presence of TGF-β1 and other proteins associated with TGF-β expression, including TGF-β receptors I and II, latent TGF-β-associated peptide (LAP), and α-smooth muscle actin. Carcinoid valve cusps demonstrated the unusual finding of widespread smooth muscle actin involving the interstitial cells in the periphery of carcinoid nodules; these same cells were also positive for LAP. Normal valve cusps were only focally positive for smooth muscle actin and LAP. In sheep aortic valve interstitial cell cultures 5-HT induced TGF-β1 mRNA production and increased TGF-β1 activity. 5-HT also increased collagen biosynthesis at the dosages studied. Furthermore, TGF-β1 added to SAVIC cultures increased the production of sulfated glycan and hyaluronic acid. In addition, overexpression of Gαq using an adenoviral expression vector for a constitutively active Gαq mutant (Q209L-Gαq) resulted in increased phospholipase C activity as well as up-regulation of TGF-β expression and activity. These results strongly support the view that G-protein-related signal transduction is involved in 5-HT up-regulation of TGF-β1. In conclusion, 5-HT-associated valve disease may be, in part, because of TGF-β1 mechanisms.
TL;DR: The in situ hybridization histochemistry and reverse transcriptase-PCR amplification was used to demonstrate that 5-HT3Asubunit transcripts are expressed in central and peripheral neurons, and it was determined that neurons of NG projecting to the nucleus tractus solitarium and those of dorsal root ganglia projecting to superficial layers of the spinal cord express 5- HT3A/3B subunits.
Abstract: The type 3 serotonin (5-HT3) receptor is the only ligand-gated ion channel receptor for serotonin in vertebrates. Two 5-HT3 receptor subunits have been cloned, subunit A (5-HT3A) and subunit B (5-HT3B). We used in situ hybridization histochemistry and reverse transcriptase-PCR amplification to demonstrate that 5-HT3Asubunit transcripts are expressed in central and peripheral neurons. In contrast, 5-HT3B subunit transcripts are restricted to peripheral neurons. Thus, the prevalent form of 5-HT3receptor synthesized within the CNS lacks the 5-HT3Bsubunit. Because coexpression of 5-HT3A and 5-HT3B subunits produces heteromeric 5-HT3A/3Breceptors with properties that differ from those of 5-HT3Ahomomeric receptors, we investigated possible coexpression of both subunits at the cellular level. We found that near to 90% of all 5-HT3B expressing neurons coexpress the 5-HT3Asubunit in superior cervical and nodose ganglia (NG). In addition, there is a cellular population that expresses only the 5-HT3A subunit. Therefore, peripheral neurons have the capacity to synthesize two different 5-HT3 receptors, 5-HT3A+/3B− and 5-HT3A+/3B+ receptors. We also determined that neurons of NG projecting to the nucleus tractus solitarium and those of dorsal root ganglia projecting to superficial layers of the spinal cord express 5-HT3A or 5-HT3A/3B subunits. Thus, presynaptic 5-HT3 receptors containing the 5-HT3B subunit might be present in these target brain areas. The compartmentalized structural composition of the 5-HT3 receptor may be the basis of functional diversity within this receptor. This raises the possibility that 5-HT3 receptors participating in sympathetic, parasympathetic and sensory functions may be functionally different from those involved in cognition and emotional behavior.
TL;DR: In this paper, a reverse-phase HPLC method was used to quantify serum concentrations of kynurenine and tryptophan in parallel with use of 3-nitro-l-tyrosine as an internal standard.
Abstract: The essential amino acid l-tryptophan is important in nitrogen balance and the maintenance of muscle mass and body weight in humans (1). Moreover, tryptophan is the precursor for the biosynthesis of the neurotransmitter serotonin (5-hydroxytryptamine). Insufficient availability of tryptophan may increase susceptibility for mental depression (2). On activation of cellular immunity, the T-cell-derived cytokine interferon-γ stimulates the enzyme indoleamine-(2,3)-dioxygenase (IDO) in various cells (3)(4). IDO catalyzes the initial step of tryptophan catabolism within the biosynthetic pathway of nicotinamide dinucleotides, and N -formyl-kynurenine is formed as a first intermediate.
The kynurenine-to-tryptophan ratio has been a sensitive estimate to monitor the activation status of IDO and of cellular immunity both in vivo and in vitro (3)(5). In patients, a decrease in serum tryptophan and a parallel increase of kynurenine attributable to IDO activation is found in various diseases associated with T-cell activation, such as viral infections, autoimmune disorders, and malignant diseases (3)(5)(6)(7)(8). More recently, activation of IDO in monocytes/macrophages was found to interfere with the proliferative capacity of T cells in response to antigenic stimulation by the withdrawal of tryptophan (9). This finding has attracted immunologic researchers especially to explore the possible involvement of IDO in tolerance induction and in diseases that are associated with acquired immunodeficiency.
We have described a reverse-phase HPLC method to quantify serum concentrations of kynurenine and tryptophan in parallel with use of 3-nitro-l-tyrosine as an internal standard (10). Here we report an optimized protocol that uses a shorter HPLC column and a different elution buffer, allowing faster throughput of samples …
TL;DR: The X-ray crystal structure of a truncated functional form of human tryptophan hydroxylase with the bound cofactor analogue 7,8-dihydro-L-biopterin is determined, providing the first atomic-resolution information for the catalytic domain of this important enzyme.
Abstract: Tryptophan hydroxylase oxidizes l-tryptophan to 5-hydroxy-l-tryptophan in the rate-determining step of serotonin biosynthesis. We have determined the X-ray crystal structure (1.7 A) of a truncated ...
TL;DR: An anatomical basis is provided for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT(2A) receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism.
TL;DR: The results provide partial support for the hypothesis that impulsive behavior is related to low serotonin function, and further suggests that the role of serotonin depends on genetic factors related to alcoholism.
TL;DR: Data indicate that editing of 5-HT2C pre-mRNA is a mechanism that retains basic response properties of 5 -HT2Creceptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing.
Abstract: Serotonin 2C (5-HT2C) receptor pre-mRNA is a substrate for RNA editing enzymes that convert five adenosines (named A, B, C', C, and D editing sites) to inosines. Editing of two of these sites (C' and C) is crucial for decreasing the efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of mouse forebrain neocortical 5-HT2C mRNA isoforms revealed that editing at these two sites is regulated in a serotonin-dependent manner. In serotonin-depleted mice, C'- and C-site editing is significantly decreased. This results in an increased expression of 5-HT2C mRNA isoforms encoding receptors with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT2A/2C agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the C' site and leads to increased expression of 5-HT2C mRNA isoforms encoding receptors that activate G-protein least efficiently. None of the drug treatments led to alterations in cytoplasmic 5-HT2C mRNA levels. These data indicate that editing of 5-HT2C pre-mRNA is a mechanism that retains basic response properties of 5-HT2C receptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing. Key words: serotonin; 5.
TL;DR: The data suggest that the transcriptional regulation of MAO by ovarian steroids may play a role in serotonin or catecholamine neurotransmission and hence, mood, affect or cognition in humans.
Abstract: Rationale: The serotonin neural system plays a pivotal role in mood, affective regulation and integrative cognition, as well as numerous autonomic functions. We have shown that ovarian steroids alter the expression of several genes in the dorsal raphe of macaques, which may increase serotonin synthesis and decrease serotonin autoinhibition. Another control point in aminergic neurotransmission involves degradation by MAO. This enzyme occurs in two isoforms, A and B, which have different substrate preferences. Objectives: We questioned the effect of ovarian steroid hormones on MAO-A and MAO-B mRNA expression in the dorsal raphe nucleus and hypothalamus using in situ hybridization in non-human primates. Methods: Rhesus monkeys (Macaca mulatta; n=5/group) were spayed and either placebo treated (controls), estrogen (E) treated (28 days), progesterone (P) treated (14 days placebo+14 days P), or E+P treated (14 days E+14 days E+P). Perfusion-fixed sections (25 µm) were hybridized with a 233 bp MAO-A, or a 373 bp MAO-B, radiolabeled-antisense monkey specific probes. Autoradiographic films were analyzed by densitometry, which was performed with NIH Image Software. Results: MAO-A and -B mRNAs were detected in the dorsal raphe nucleus (DRN) and in the hypothalamic suprachiasmatic nucleus (SCN), preoptic area (POA), paraventricular nucleus (PVN), supraoptic nucleus (SON), lateral hypothalamus (LH) and ventromedial nucleus (VMN). MAO-A mRNA optical density was significantly decreased by E, P, and E+P in the DRN and in the hypothalamic PVN, LH and VMN. Ovarian hormones had no effect on MAO-B mRNA expression in the DRN. However, there was a significant decrease in MAO-B optical density in the hypothalamic POA, LH and VMN with E, P or E+P treatment. Pixel area generally reflected optical density. Conclusions: Ovarian steroids decreased MAO-A, but not B, in the raphe nucleus. However, both MAO-A and B were decreased in discrete hypothalamic nuclei by hormone replacement. These data suggest that the transcriptional regulation of MAO by ovarian steroids may play a role in serotonin or catecholamine neurotransmission and hence, mood, affect or cognition in humans.