Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?

Science.gov (United States)

Bijlsma, Elisabeth Y; Chan, Johnny S W; Olivier, Berend; Veening, Jan G; Millan, Mark J; Waldinger, Marcel D; Oosting, Ronald S

2014-06-01

Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization. This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling. © 2013 Elsevier Inc. All rights reserved.

DHA involvement in neurotransmission process

Directory of Open Access Journals (Sweden)

Vancassel Sylvie

2007-05-01

Full Text Available The very high enrichment of the nervous system in the polyunsaturated fatty acids, arachidonic (AA, 20: 4n-6 and docosahexaenoic acids (DHA, 22: 6n-3, is dependant of the dietary availability of their respective precursors, linoleic (18: 2n-6 and_-linolenic acids (18: 3n-3. Inadequate amounts of DHA in brain membranes have been linked to a wide variety of abnormalities ranging from visual acuity and learning irregularities, to psychopathologies. However, the molecular mechanisms involved remain unknown. Several years ago, we hypothesized that a modification of DHA contents of neuronal membranes by dietary modulation could change the neurotransmission function and then underlie inappropriate behavioural response. We showed that, in parallel to a severe loss of brain DHA concomitant to a compensatory substitution by 22:5n-6, the dietary lack of α-linolenic acid during development induced important changes in the release of neurotransmitters (dopamine, serotonin, acetylcholine in cerebral areas specifically involved in learning, memory and reward processes. Data suggested alteration of presynaptic storage process and dysregulations of reciprocal functional interactions between monoaminergic and cholinergic pathways. Moreover, we showed that recovery of these neurochemical changes was possible when the deficient diet was switched to a diet balanced in n-3 and n-6 PUFA before weaning. The next step is to understand the mechanism involved. Particularly, we focus on the study of the metabolic cooperation between the endothelial cell, the astrocyte and the neuron which regulate synaptic transmission.These works could contribute to the understanding of the link between some neuropsychiatric disorders and the metabolism of n-3 PUFA, through their action on neurotransmission.

Cognitive Function and Monoamine Neurotransmission in Schizophrenia: Evidence From Positron Emission Tomography Studies

Directory of Open Access Journals (Sweden)

Harumasa Takano

2018-05-01

Full Text Available Positron emission tomography (PET is a non-invasive imaging technique used to assess various brain functions, including cerebral blood flow, glucose metabolism, and neurotransmission, in the living human brain. In particular, neurotransmission mediated by the monoamine neurotransmitters dopamine, serotonin, and norepinephrine, has been extensively examined using PET probes, which specifically bind to the monoamine receptors and transporters. This useful tool has revealed the pathophysiology of various psychiatric disorders, including schizophrenia, and the mechanisms of action of psychotropic drugs. Because monoamines are implicated in various cognitive processes such as memory and executive functions, some PET studies have directly investigated the associations between monoamine neurotransmission and cognitive functions in healthy individuals and patients with psychiatric disorders. In this mini review, I discuss the findings of PET studies that investigated monoamine neurotransmission under resting conditions, specifically focusing on cognitive functions in patients with schizophrenia. With regard to the dopaminergic system, some studies have examined the association of dopamine D1 and D2/D3 receptors, dopamine transporters, and dopamine synthesis capacity with various cognitive functions in schizophrenia. With regard to the serotonergic system, 5-HT1A and 5-HT2A receptors have been studied in the context of cognitive functions in schizophrenia. Although relatively few PET studies have examined cognitive functions in patients with psychiatric disorders, these approaches can provide useful information on enhancing cognitive functions by administering drugs that modulate monoamine transmission. Moreover, another paradigm of techniques such as those exploring the release of neurotransmitters and further development of radiotracers for novel targets are warranted.

A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: an in vivo molecular imaging study in humans

DEFF Research Database (Denmark)

Erritzoe, David; Holst, Klaus; Frokjaer, Vibe G.

2010-01-01

Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT2A) receptor and the presynaptic serotonin transporter (SERT) are sensitive...... tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT2A receptor binding. An inverted U-shaped relationship between the 5-HT2A receptor and the SERT binding was identified. The observed regional intercorrelation...

A dualistic conformational response to substrate binding in the human serotonin transporter reveals a high affinity state for serotonin

DEFF Research Database (Denmark)

Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida

2015-01-01

Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across...... the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes...

Effects of sleep deprivation on extracellular serotonin in hippocampus and frontal cortex of the rat

OpenAIRE

Bjorvatn, B; Grønli, J; Hamre, F; Sørensen, E; Fiske, E; Bjorkum, Alvhild Alette; Portas, CM; Ursin, R

2002-01-01

Sleep deprivation improves the mood of depressed patients, but the exact mechanism behind this effect is unclear. An enhancement of serotonergic neurotransmission has been suggested. In this study, we used in vivo microdialysis to monitor extracellular serotonin in the hippocampus and the frontal cortex of rats during an 8 h sleep deprivation period. These brain regions were selected since both have been implicated in depression. The behavioral state of the animal was continuously monitored b...

High brain serotonin levels in migraine between attacks

DEFF Research Database (Denmark)

Deen, Marie; Hansen, Hanne D; Hougaard, Anders

2018-01-01

Migraine has been hypothesized to be a syndrome of chronic low serotonin (5-HT) levels, but investigations of brain 5-HT levels have given equivocal results. Here, we used positron emission tomography (PET) imaging of the 5-HT4receptor as a proxy for brain 5-HT levels. Given that the 5-HT4receptor...

Aging and depression vulnerability interaction results in decreased serotonin innervation associated with reduced BDNF levels in hippocampus of rats bred for learned helplessness

DEFF Research Database (Denmark)

Aznar, Susana; Klein, Anders B; Santini, Martin A

2010-01-01

Epidemiological studies have revealed a strong genetic contribution to the risk for depression. Both reduced hippocampal serotonin neurotransmission and brain-derived neurotrophic factor (BDNF) levels have been associated with increased depression vulnerability and are also regulated during aging...... density. Hippocampal BDNF protein levels were measured by ELISA. An exacerbated age-related loss of serotonin fiber density specific for the CA1 area was observed in the cLH animals, whereas reduced hippocampal BDNF levels were seen in young and old cLH when compared with age-matched cNLH controls...

Tryptophan: the key to boosting brain serotonin synthesis in depressive illness.

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Badawy, Abdulla A-B

2013-10-01

It has been proposed that focusing on brain serotonin synthesis can advance antidepressant drug development. Biochemical aspects of the serotonin deficiency in major depressive disorder (MDD) are discussed here in detail. The deficiency is caused by a decreased availability of the serotonin precursor tryptophan (Trp) to the brain. This decrease is caused by accelerated Trp degradation, most likely induced by enhancement of the hepatic enzyme tryptophan 2,3-dioxygenase (TDO) by glucocorticoids and/or catecholamines. Induction of the extrahepatic Trp-degrading enzyme indolylamine 2,3-dioxygenase (IDO) by the modest immune activation in MDD has not been demonstrated and, if it occurs, is unlikely to make a significant contribution. Liver TDO appears to be a target of many antidepressants, the mood stabilisers Li(+) and carbamazepine and possibly other adjuncts to antidepressant therapy. The poor, variable and modest antidepressant efficacy of Trp is due to accelerated hepatic Trp degradation, and efficacy can be restored or enhanced by combination with antidepressants or other existing or new TDO inhibitors. Enhancing Trp availability to the brain is thus the key to normalisation of serotonin synthesis and could form the basis for future antidepressant drug development.

Acute running stimulates hippocampal dopaminergic neurotransmission in rats, but has no influence on brain-derived neurotrophic factor

OpenAIRE

Goekint, Maaike; Bos, Inge; Heyman, Elsa; Meeusen, Romain; Michotte, Yvette; Sarre, Sophie

2011-01-01

Hippocampal brain-derived neurotrophic factor (BDNF) protein is increased with exercise in rats. Monoamines seem to play a role in the regulation of BDNF, and monoamine neurotransmission is known to increase with exercise. The purpose of this study was to examine the influence of acute exercise on monoaminergic neurotransmission and BDNF protein concentrations. Hippocampal microdialysis was performed in rats that were subjected to 60 min of treadmill running at 20 m/min or rest. Two hours pos...

Functional significance of brain glycogen in sustaining glutamatergic neurotransmission.

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Sickmann, Helle M; Walls, Anne B; Schousboe, Arne; Bouman, Stephan D; Waagepetersen, Helle S

2009-05-01

The involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present unclear. The significance of glycogen in fueling glutamate uptake into astrocytes was specifically addressed in cultured astrocytes. Moreover, the objective was to elucidate whether glycogen derived energy is important for maintaining glutamatergic neurotransmission, induced by repetitive exposure to NMDA in co-cultures of cerebellar neurons and astrocytes. In the astrocytes it was shown that uptake of the glutamate analogue D-[3H]aspartate was impaired when glycogen degradation was inhibited irrespective of the presence of glucose, signifying that energy derived from glycogen degradation is important for the astrocytic compartment. By inhibiting glycogen degradation in co-cultures it was evident that glycogen provides energy to sustain glutamatergic neurotransmission, i.e. release and uptake of glutamate. The relocation of glycogen derived lactate to the neuronal compartment was investigated by employing d-lactate, a competitive substrate for the monocarboxylate transporters. Neurotransmitter release was affected by the presence of d-lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment.

Regional distribution of serotonin transporter protein in postmortem human brain

International Nuclear Information System (INIS)

Kish, Stephen J.; Furukawa, Yoshiaki; Chang Lijan; Tong Junchao; Ginovart, Nathalie; Wilson, Alan; Houle, Sylvain; Meyer, Jeffrey H.

2005-01-01

Introduction: The primary approach in assessing the status of brain serotonin neurons in human conditions such as major depression and exposure to the illicit drug ecstasy has been the use of neuroimaging procedures involving radiotracers that bind to the serotonin transporter (SERT). However, there has been no consistency in the selection of a 'SERT-free' reference region for the estimation of free and nonspecific binding, as occipital cortex, cerebellum and white matter have all been employed. Objective and Methods: To identify areas of human brain that might have very low SERT levels, we measured, by a semiquantitative Western blotting procedure, SERT protein immunoreactivity throughout the postmortem brain of seven normal adult subjects. Results: Serotonin transporter could be quantitated in all examined brain areas. However, the SERT concentration in cerebellar cortex and white matter were only at trace values, being approximately 20% of average cerebral cortex and 5% of average striatum values. Conclusion: Although none of the examined brain areas are completely free of SERT, human cerebellar cortex has low SERT binding as compared to other examined brain regions, with the exception of white matter. Since the cerebellar cortical SERT binding is not zero, this region will not be a suitable reference region for SERT radioligands with very low free and nonspecific binding. For SERT radioligands with reasonably high free and nonspecific binding, the cerebellar cortex should be a useful reference region, provided other necessary radioligand assumptions are met

Regional distribution of serotonin transporter protein in postmortem human brain

Energy Technology Data Exchange (ETDEWEB)

Kish, Stephen J. [Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada)]. E-mail: Stephen_Kish@CAMH.net; Furukawa, Yoshiaki [Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Chang Lijan [Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Tong Junchao [Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Ginovart, Nathalie [PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Wilson, Alan [PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Houle, Sylvain [PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Meyer, Jeffrey H. [PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada)

2005-02-01

Introduction: The primary approach in assessing the status of brain serotonin neurons in human conditions such as major depression and exposure to the illicit drug ecstasy has been the use of neuroimaging procedures involving radiotracers that bind to the serotonin transporter (SERT). However, there has been no consistency in the selection of a 'SERT-free' reference region for the estimation of free and nonspecific binding, as occipital cortex, cerebellum and white matter have all been employed. Objective and Methods: To identify areas of human brain that might have very low SERT levels, we measured, by a semiquantitative Western blotting procedure, SERT protein immunoreactivity throughout the postmortem brain of seven normal adult subjects. Results: Serotonin transporter could be quantitated in all examined brain areas. However, the SERT concentration in cerebellar cortex and white matter were only at trace values, being approximately 20% of average cerebral cortex and 5% of average striatum values. Conclusion: Although none of the examined brain areas are completely free of SERT, human cerebellar cortex has low SERT binding as compared to other examined brain regions, with the exception of white matter. Since the cerebellar cortical SERT binding is not zero, this region will not be a suitable reference region for SERT radioligands with very low free and nonspecific binding. For SERT radioligands with reasonably high free and nonspecific binding, the cerebellar cortex should be a useful reference region, provided other necessary radioligand assumptions are met.

Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain.

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Bonnin, A; Levitt, P

2011-12-01

In addition to its role in neurotransmission, embryonic serotonin (5-HT) has been implicated in the regulation of neurodevelopmental processes. For example, we recently showed that a subset of 5-HT1-receptors expressed in the fetal forebrain mediate a serotonergic modulation of thalamocortical axons response to axon guidance cues, both in vitro and in vivo. This influence of 5-HT signaling on fetal brain wiring raised important questions regarding the source of the ligand during pregnancy. Until recently, it was thought that 5-HT sources impacting brain development arose from maternal transport to the fetus, or from raphe neurons in the brainstem of the fetus. Using genetic mouse models, we uncovered previously unknown differences in 5-HT accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. Using additional genetic strategies, a new technology for studying placental biology ex vivo, and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor, in both mice and humans. These results implicate a new, direct role for placental metabolic pathways in modulating fetal brain development and suggest an important role for maternal-placental-fetal interactions and 5-HT in the fetal programming of adult mental disorders. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors

International Nuclear Information System (INIS)

Pazos, A.; Palacios, M.

1985-01-01

The distribution of serotonin-1 (5-HT 1 ) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with [ 3 H]serotonin (5-[ 3 H]HT), 8-hydroxy-2-[N-dipropylamino- 3 H]tetralin (8-OH-[ 3 H]DPAT), [ 3 H]LSD and [ 3 H]mesulergine, and the densities quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Competition experiments for 5-[ 3 H]HT binding by several serotonin-1 agonists led to the identification of brain areas enriched in each one of the three subtypes of 5-HT 1 recognition sites already described. The existence of these 'selective' areas allowed a detailed pharmacological characterization of these sites to be made in a more precise manner than has been attained in membrane-binding studies. Very high concentrations of 5-HT 1 receptors were localized in the choroid plexus, lateroseptal nucleus, globus pallidus and ventral pallidum, dentate gyrus, dorsal subiculum, olivary pretectal nucleus, substantia nigra, reticular and external layer of the entorhinal cortex. The distribution of 5-HT 1 receptors reported here is discussed in correlation with the distribution of serotoninergic neurons and fibers, the related anatomical pathways and the effects which appear to be mediated by these sites. (Auth.)

The short (S) allele of the serotonin transporter polymorphism and acute tryptophan depletion both increase impulsivity in men

OpenAIRE

Walderhaug, Espen; Herman, Aryeh Isaac; Magnusson, Andres; Morgan, Michael John; Landrø, Nils Inge

2010-01-01

Reduced serotonergic neurotransmission is implicated in impulsive behavior. We studied the triallelic system of the serotonin transporter gene linked polymorphic region (5-HTTLPR) and acute manipulation of serotonin together to further delineate the mechanisms by which serotonergic neurotransmission affects impulsivity. Fifty-two healthy participants (38 men and 14 women) underwent acute tryptophan depletion (ATD) or placebo in a randomized, double-blind, parallel group experiment. Impulsive ...

Aging and depression vulnerability interaction results in decreased serotonin innervation associated with reduced BDNF levels in hippocampus of rats bred for learned helplessness.

Science.gov (United States)

Aznar, Susana; Klein, Anders B; Santini, Martin A; Knudsen, Gitte M; Henn, Fritz; Gass, Peter; Vollmayr, Barbara

2010-07-01

Epidemiological studies have revealed a strong genetic contribution to the risk for depression. Both reduced hippocampal serotonin neurotransmission and brain-derived neurotrophic factor (BDNF) levels have been associated with increased depression vulnerability and are also regulated during aging. Brains from young (5 months old) and old (13 months old) congenital Learned Helplessness rats (cLH), and congenital Non Learned Helplessness rats (cNLH) were immunohistochemically stained for the serotonin transporter and subsequently stereologically quantified for estimating hippocampal serotonin fiber density. Hippocampal BDNF protein levels were measured by ELISA. An exacerbated age-related loss of serotonin fiber density specific for the CA1 area was observed in the cLH animals, whereas reduced hippocampal BDNF levels were seen in young and old cLH when compared with age-matched cNLH controls. These observations indicate that aging should be taken into account when studying the neurobiological factors behind the vulnerability for depression and that understanding the effect of aging on genetically predisposed individuals may contribute to a better understanding of the pathophysiology behind depression, particularly in the elderly.

Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

Science.gov (United States)

Cases, Olivier; Grimsby, Joseph; Gaspar, Patricia; Chen, Kevin; Pournin, Sandrine; Müller, Ulrike; Aguet, Michel; Babinet, Charles; Shih, Jean Chen; De Maeyer, Edward

2010-01-01

Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males. PMID:7792602

Serotonin syndrome

Science.gov (United States)

Hyperserotonemia; Serotonergic syndrome; Serotonin toxicity; SSRI - serotonin syndrome; MAO - serotonin syndrome ... brain area. For example, you can develop this syndrome if you take migraine medicines called triptans together ...

Food choice in hyperthyroidism: potential influence of the autonomic nervous system and brain serotonin precursor availability.

Science.gov (United States)

Pijl, H; de Meijer, P H; Langius, J; Coenegracht, C I; van den Berk, A H; Chandie Shaw, P K; Boom, H; Schoemaker, R C; Cohen, A F; Burggraaf, J; Meinders, A E

2001-12-01

We explored energy and macronutrient intake in patients with Graves' hyperthyroidism. We specifically hypothesized that hyperthyroidism is associated with increased appetite for carbohydrates, because of enhanced sympathetic tone and diminished serotonin mediated neurotransmission in the brain. To test this hypothesis, we measured food intake by dietary history and food selected for lunch in the laboratory in 14 patients with Graves' hyperthyroidism. Twenty-four-hour catecholamine excretion was used as a measure of activity of the sympathetic nervous system (SNS) and the plasma [Trp]/[NAA] ratio was measured to estimate (rate limiting) precursor availability for brain 5-hydroxytryptamine synthesis. All measurements were repeated after the subjects had been treated to establish euthyroidism. In addition, the effects of nonselective beta-adrenoceptor blockade upon these parameters were studied to evaluate the influence of beta-adrenergic hyperactivity on food intake. Hyperthyroidism was marked by increased SNS activity and reduced plasma [Trp]/[NAA] ratio. Accordingly, energy intake was considerably and significantly increased in hyper vs. euthyroidism, which was fully attributable to enhanced carbohydrate consumption, as protein and fat intake were not affected. These results suggest that hyperthyroidism alters the neurophysiology of food intake regulation. Increased SNS activity and reduced Trp precursor availability for 5-hydroxytryptamine synthesis in the brain may drive the marked hyperphagia and craving for carbohydrates that appears to characterize hyperthyroid patients. Because propranolol did not affect food intake in hyperthyroidism, the potential effect of catecholamines on food intake might be mediated by alpha-adrenoceptors.

Boosting serotonin in the brain: is it time to revamp the treatment of depression?

Science.gov (United States)

Torrente, Mariana P; Gelenberg, Alan J; Vrana, Kent E

2012-05-01

Abnormalities in serotonin systems are presumably linked to various psychiatric disorders including schizophrenia and depression. Medications intended for these disorders aim to either block the reuptake or the degradation of this neurotransmitter. In an alternative approach, efforts have been made to enhance serotonin levels through dietary manipulation of precursor levels with modest clinical success. In the last 30 years, there has been little improvement in the pharmaceutical management of depression, and now is the time to revisit therapeutic strategies for the treatment of this disease. Tryptophan hydroxylase (TPH) catalyzes the first and rate-limiting step in the biosynthesis of serotonin. A recently discovered isoform, TPH2, is responsible for serotonin biosynthesis in the brain. Learning how to activate this enzyme (and its polymorphic versions) may lead to a new, more selective generation of antidepressants, able to regulate the levels of serotonin in the brain with fewer side effects.

The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites

International Nuclear Information System (INIS)

Zeng Zhizhen; Chen, T.-B.; Miller, Patricia J.; Dean, Dennis; Tang, Y.S.; Sur, Cyrille; Williams, David L.

2006-01-01

We have characterized the interaction of the serotonin transporter ligand [ 3 H]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine (DASB) with rhesus monkey brain in vitro using tissue homogenate binding and autoradiographic mapping. [ 3 H]-DASB, a tritiated version of the widely used [ 11 C] positron emission tomography tracer, was found to selectively bind to a single population of sites with high affinity (K d =0.20±0.04 nM). The serotonin transporter density (B max ) obtained for rhesus frontal cortex was found to be 66±8 fmol/mg protein using [ 3 H]-DASB, similar to the B max value obtained using the reference radioligand [ 3 H]-citalopram, a well-characterized and highly selective serotonin reuptake inhibitor (83±22 fmol/mg protein). Specific binding sites of both [ 3 H]-DASB and [ 3 H]-citalopram were similarly and nonuniformly distributed throughout the rhesus central nervous system, in a pattern consistent with serotonin transporter localization reported for human brain. Regional serotonin transporter densities, estimated from optical densities of the autoradiographic images, were well correlated between the two radioligands. Finally, DASB and fluoxetine showed dose-dependent full inhibition of [ 3 H]-citalopram binding in a competition autoradiographic study, with K i values in close agreement with those obtained from rhesus brain homogenates. This side-by-side comparison of [ 3 H]-DASB and [ 3 H]-citalopram binding sites in rhesus tissue homogenates and in adjacent rhesus brain slices provides additional support for the use of [ 11 C]-DASB to assess the availability and distribution of serotonin transporters in nonhuman primates

Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system.

Science.gov (United States)

Gupta, Deepali; Kurhe, Yeshwant; Radhakrishnan, Mahesh

2014-04-22

Diabetes is a persistent metabolic disorder, which often leads to depression as a result of the impaired neurotransmitter function. Insulin is believed to have antidepressant effects in depression associated with diabetes; however, the mechanism underlying the postulated effect is poorly understood. In the present study, it is hypothesized that insulin mediates an antidepressant effect in streptozotocin (STZ) induced diabetes in mice through modulation of the serotonin system in the brain. Therefore, the current study investigated the antidepressant effect of insulin in STZ induced diabetes in mice and insulin mediated modulation in the brain serotonin system. In addition, the possible pathways that lead to altered serotonin levels as a result of insulin administration were examined. Experimentally, Swiss albino mice of either sex were rendered diabetic by a single intraperitoneal (i.p.) injection of STZ. After one week, diabetic mice received a single dose of either insulin or saline or escitalopram for 14days. Thereafter, behavioral studies were conducted to test the behavioral despair effects using forced swim test (FST) and tail suspension test (TST), followed by biochemical estimations of serotonin concentrations and monoamine oxidase (MAO) activity in the whole brain content. The results demonstrated that, STZ treated diabetic mice exhibited an increased duration of immobility in FST and TST as compared to non-diabetic mice, while insulin treatment significantly reversed the effect. Biochemical assays revealed that administration of insulin attenuated STZ treated diabetes induced neurochemical alterations as indicated by elevated serotonin levels and decreased MAO-A and MAO-B activities in the brain. Collectively, the data indicate that insulin exhibits antidepressant effects in depression associated with STZ induced diabetes in mice through the elevation of the brain serotonin levels. Copyright © 2014 Elsevier Inc. All rights reserved.

Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

Science.gov (United States)

Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

1983-10-01

Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System.

Science.gov (United States)

Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Højgaard, Liselotte; Fisher, Patrick M; Svarer, Claus; Greve, Douglas N; Knudsen, Gitte M

2017-01-04

The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 4 ) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain. We present a high-resolution positron emission tomography (PET)- and magnetic resonance imaging-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system not only provides insight in the human brain's regional protein

The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites

Energy Technology Data Exchange (ETDEWEB)

Zeng Zhizhen [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States)]. E-mail: zhizhen_zeng@merck.com; Chen, T.-B. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Miller, Patricia J. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Dean, Dennis [Labeled Compound Synthesis Group, Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900 (United States); Tang, Y.S. [Labeled Compound Synthesis Group, Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900 (United States); Sur, Cyrille [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Williams, David L. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States)

2006-05-15

We have characterized the interaction of the serotonin transporter ligand [{sup 3}H]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine (DASB) with rhesus monkey brain in vitro using tissue homogenate binding and autoradiographic mapping. [{sup 3}H]-DASB, a tritiated version of the widely used [{sup 11}C] positron emission tomography tracer, was found to selectively bind to a single population of sites with high affinity (K {sub d}=0.20{+-}0.04 nM). The serotonin transporter density (B {sub max}) obtained for rhesus frontal cortex was found to be 66{+-}8 fmol/mg protein using [{sup 3}H]-DASB, similar to the B {sub max} value obtained using the reference radioligand [{sup 3}H]-citalopram, a well-characterized and highly selective serotonin reuptake inhibitor (83{+-}22 fmol/mg protein). Specific binding sites of both [{sup 3}H]-DASB and [{sup 3}H]-citalopram were similarly and nonuniformly distributed throughout the rhesus central nervous system, in a pattern consistent with serotonin transporter localization reported for human brain. Regional serotonin transporter densities, estimated from optical densities of the autoradiographic images, were well correlated between the two radioligands. Finally, DASB and fluoxetine showed dose-dependent full inhibition of [{sup 3}H]-citalopram binding in a competition autoradiographic study, with K {sub i} values in close agreement with those obtained from rhesus brain homogenates. This side-by-side comparison of [{sup 3}H]-DASB and [{sup 3}H]-citalopram binding sites in rhesus tissue homogenates and in adjacent rhesus brain slices provides additional support for the use of [{sup 11}C]-DASB to assess the availability and distribution of serotonin transporters in nonhuman primates.

A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

DEFF Research Database (Denmark)

Beliveau, Vincent; Ganz-Benjaminsen, Melanie; Feng, Ling

2017-01-01

The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4...... with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human...... brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system...

Brain serotonin content regulates the manifestation of tramadol-induced seizures in rats: disparity between tramadol-induced seizure and serotonin syndrome.

Science.gov (United States)

Fujimoto, Yohei; Funao, Tomoharu; Suehiro, Koichi; Takahashi, Ryota; Mori, Takashi; Nishikawa, Kiyonobu

2015-01-01

Tramadol-induced seizures might be pathologically associated with serotonin syndrome. Here, the authors investigated the relationship between serotonin and the seizure-inducing potential of tramadol. Two groups of rats received pretreatment to modulate brain levels of serotonin and one group was treated as a sham control (n = 6 per group). Serotonin modulation groups received either para-chlorophenylalanine or benserazide + 5-hydroxytryptophan. Serotonin, dopamine, and histamine levels in the posterior hypothalamus were then measured by microdialysis, while simultaneously infusing tramadol until seizure onset. In another experiment, seizure threshold with tramadol was investigated in rats intracerebroventricularly administered with either a serotonin receptor antagonist (methysergide) or saline (n = 6). Pretreatment significantly affected seizure threshold and serotonin fluctuations. The threshold was lowered in para-chlorophenylalanine group and raised in benserazide + 5-hydroxytryptophan group (The mean ± SEM amount of tramadol needed to induce seizures; sham: 43.1 ± 4.2 mg/kg, para-chlorophenylalanine: 23.2 ± 2.8 mg/kg, benserazide + 5-hydroxytryptophan: 59.4 ± 16.5 mg/kg). Levels of serotonin at baseline, and their augmentation with tramadol infusion, were less in the para-chlorophenylalanine group and greater in the benserazide + 5-hydroxytryptophan group. Furthermore, seizure thresholds were negatively correlated with serotonin levels (correlation coefficient; 0.71, P seizure threshold (P seizures, and that serotonin concentrations were negatively associated with seizure thresholds. Moreover, serotonin receptor antagonism precipitated seizure manifestation, indicating that tramadol-induced seizures are distinct from serotonin syndrome.

In vivo regulation of the serotonin-2 receptor in rat brain

International Nuclear Information System (INIS)

Stockmeier, C.A.; Kellar, K.J.

1986-01-01

Serotonin-2 (5-HT-2) receptors in brain were measured using ( 3 H)ketanserin. The authors examined the effects of amitriptyline, an anti-depressant drug, of electroconvulsive shock (ECS) and of drug-induced alterations in presynaptic 5-HT function on ( 3 H)ketanserin binding to 5-HT-2 receptors in rat brain. The importance of intact 5-HT axons to the up-regulation of 5-HT-2 receptors by ECS was also investigated, and an attempt was made to relate the ECS-induced increase in this receptor to changes in 5-HT presynaptic mechanisms. Twelve days of ECS increased the number of 5-HT-2 receptors in frontal cortex. Neither the IC 50 nor the Hill coefficient of 5-HT in competing for ( 3 H)ketanserin binding sites was altered by ECS. Repeated injections of amitriptyline reduced the number of 5-HT-2 receptors in frontal cortex. Reserpine, administered daily for 12 days, caused a significant increase in 5-HT-2 receptors, but neither daily injections of p-chlorophenylalanine (PCPA) nor lesions of 5-HT axons with 5,7-dihydroxytryptamine (5,7-DHT) affected 5-HT-2 receptors. However, regulation of 5-HT-2 receptors by ECS was dependent on intact 5-HT axons since ECS could not increase the number of 5-HT-2 receptors in rats previously lesioned with 5,7-DHT. Repeated ECS, however, does not appear to affect either the high-affinity uptake of ( 3 H)5-HT or ( 3 H)imipramine binding, two presynaptic markers of 5-HT neuronal function. 5-HT-2 receptors appear to be under complex control. ECS or drug treatments such as reserpine or amitriptyline, which affect several monoamine neurotransmission systems including 5-HT, can alter 5-HT-2 receptors. 28 references, 1 figure, 7 tables

Brain serotonin and dopamine transporter bindings in adults with high-functioning autism.

Science.gov (United States)

Nakamura, Kazuhiko; Sekine, Yoshimoto; Ouchi, Yasuomi; Tsujii, Masatsugu; Yoshikawa, Etsuji; Futatsubashi, Masami; Tsuchiya, Kenji J; Sugihara, Genichi; Iwata, Yasuhide; Suzuki, Katsuaki; Matsuzaki, Hideo; Suda, Shiro; Sugiyama, Toshiro; Takei, Nori; Mori, Norio

2010-01-01

Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown. To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems. Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 ((11)C)-labeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652) and 2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane ([(11)C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. Participants recruited from the community. Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects. Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = -0.61; P = .004). The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.

Lower brain levels of serotonin in rainbow trout larvae with a propensity for social dominance

DEFF Research Database (Denmark)

Höglund, Erik; Åberg Andersson, Madelene

performed on socially naive animals, predisposed to different levels of aggression, are needed to investigate to which extent inherited differences in 5-HTergic transmission underlie this behavioral variability. In this work we show that rainbow trout larvae, having a large yolk during emergence from......There is general consensus that low levels of brain serotonin are associated with aggression and social dominance. However, most of the studies investigating the relationship between serotonin (5-HT) and aggressive behavior have been performed in animals with previous social experience. Studies...... the spawning nests, also have higher probability to become social dominant. Furthermore, newly emerged socially naïve individuals with larger yolk also had lower brain 5-HT levels. This demonstrates a propensity to social dominance, which is associated with lower brain serotonin levels, in larvae that emerge...

Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis

Science.gov (United States)

Jenkins, Trisha A.; Nguyen, Jason C. D.; Polglaze, Kate E.; Bertrand, Paul P.

2016-01-01

The serotonergic system forms a diffuse network within the central nervous system and plays a significant role in the regulation of mood and cognition. Manipulation of tryptophan levels, acutely or chronically, by depletion or supplementation, is an experimental procedure for modifying peripheral and central serotonin levels. These studies have allowed us to establish the role of serotonin in higher order brain function in both preclinical and clinical situations and have precipitated the finding that low brain serotonin levels are associated with poor memory and depressed mood. The gut-brain axis is a bi-directional system between the brain and gastrointestinal tract, linking emotional and cognitive centres of the brain with peripheral functioning of the digestive tract. An influence of gut microbiota on behaviour is becoming increasingly evident, as is the extension to tryptophan and serotonin, producing a possibility that alterations in the gut may be important in the pathophysiology of human central nervous system disorders. In this review we will discuss the effect of manipulating tryptophan on mood and cognition, and discuss a possible influence of the gut-brain axis. PMID:26805875

Serotonergic mechanisms in the migraine brain

DEFF Research Database (Denmark)

Christensen, Marie Deen; Christensen, Casper Emil; Hougaard, Anders

2017-01-01

role of brain serotonergic mechanisms remains a matter of controversy. Methods We systematically searched PubMed for studies investigating the serotonergic system in the migraine brain by either molecular neuroimaging or electrophysiological methods. Results The literature search resulted in 59 papers......, of which 13 were eligible for review. The reviewed papers collectively support the notion that migraine patients have alterations in serotonergic neurotransmission. Most likely, migraine patients have a low cerebral serotonin level between attacks, which elevates during a migraine attack. Conclusion...... This review suggests that novel methods of investigating the serotonergic system in the migraine brain are warranted. Uncovering the serotonergic mechanisms in migraine pathophysiology could prove useful for the development of future migraine drugs....

Effects of sugar rich diet on brain serotonin, hyperphagia and anxiety in animal model of both genders.

Science.gov (United States)

Inam, Qurrat-ul-Aen; Ikram, Huma; Shireen, Erum; Haleem, Darakhshan Jabeen

2016-05-01

Lower levels of 5-hydroxytryptamine (5-HT; serotonin) in the brain elicit sugar craving, while ingestion of sugar rich diet improves mood and alleviates anxiety. Gender differences occur not only in brain serotonin metabolism but also in a serotonin mediated functional responses. The present study was therefore designed to investigate gender related differences on the effects of long term consumption of sugar rich diet on the metabolism of serotonin in the hypothalamus and whole brain which may be relevant with the hyperphagic and anxiety reducing effects of sugar rich diet. Male and female rats were fed freely on a sugar rich diet for five weeks. Hyperphagic effects were monitored by measuring total food intake and body weights changes during the intervention. Anxiolytic effects of sugar rich diet was monitored in light-dark transition test. The results show that ingestion of sugar rich diet decreased serotonin metabolism more in female than male rats. Anxiolytic effects were elicited only in male rats. Hyperphagia was comparable in both male and female rats. Finings would help in understanding the role of sugar rich diet-induced greater decreases of serotonin in sweet craving in women during stress.

Linoleic acid participates in the response to ischemic brain injury through oxidized metabolites that regulate neurotransmission.

Science.gov (United States)

Hennebelle, Marie; Zhang, Zhichao; Metherel, Adam H; Kitson, Alex P; Otoki, Yurika; Richardson, Christine E; Yang, Jun; Lee, Kin Sing Stephen; Hammock, Bruce D; Zhang, Liang; Bazinet, Richard P; Taha, Ameer Y

2017-06-28

Linoleic acid (LA; 18:2 n-6), the most abundant polyunsaturated fatty acid in the US diet, is a precursor to oxidized metabolites that have unknown roles in the brain. Here, we show that oxidized LA-derived metabolites accumulate in several rat brain regions during CO 2 -induced ischemia and that LA-derived 13-hydroxyoctadecadienoic acid, but not LA, increase somatic paired-pulse facilitation in rat hippocampus by 80%, suggesting bioactivity. This study provides new evidence that LA participates in the response to ischemia-induced brain injury through oxidized metabolites that regulate neurotransmission. Targeting this pathway may be therapeutically relevant for ischemia-related conditions such as stroke.

Effects of diets containing unripe plantain diet on brain serotonin in ...

African Journals Online (AJOL)

In this study, the effect of plantain-containing mouse diet on brain serotonin mice was investigated in mice. Thirty adult Swiss mice were divided into three groups of ten each and fed normal rodent chow containing 0%, 50% and 100% unripe plantain. After thirty days, the brain levels of 5-HT and 5-HTP were measured using ...

Neuromolecular Imaging Shows Temporal Synchrony Patterns between Serotonin and Movement within Neuronal Motor Circuits in the Brain

Directory of Open Access Journals (Sweden)

Patricia A. Broderick

2013-06-01

Full Text Available The present discourse links the electrical and chemical properties of the brain with neurotransmitters and movement behaviors to further elucidate strategies to diagnose and treat brain disease. Neuromolecular imaging (NMI, based on electrochemical principles, is used to detect serotonin in nerve terminals (dorsal and ventral striata and somatodendrites (ventral tegmentum of reward/motor mesocorticolimbic and nigrostriatal brain circuits. Neuronal release of serotonin is detected at the same time and in the same animal, freely moving and unrestrained, while open-field behaviors are monitored via infrared photobeams. The purpose is to emphasize the unique ability of NMI and the BRODERICK PROBE® biosensors to empirically image a pattern of temporal synchrony, previously reported, for example, in Aplysia using central pattern generators (CPGs, serotonin and cerebral peptide-2. Temporal synchrony is reviewed within the context of the literature on central pattern generators, neurotransmitters and movement disorders. Specifically, temporal synchrony data are derived from studies on psychostimulant behavior with and without cocaine while at the same time and continuously, serotonin release in motor neurons within basal ganglia, is detected. The results show that temporal synchrony between the neurotransmitter, serotonin and natural movement occurs when the brain is NOT injured via, e.g., trauma, addictive drugs or psychiatric illness. In striking contrast, in the case of serotonin and cocaine-induced psychostimulant behavior, a different form of synchrony and also asynchrony can occur. Thus, the known dysfunctional movement behavior produced by cocaine may well be related to the loss of temporal synchrony, the loss of the ability to match serotonin in brain with motor activity. The empirical study of temporal synchrony patterns in humans and animals may be more relevant to the dynamics of motor circuits and movement behaviors than are studies of

Neuromolecular Imaging Shows Temporal Synchrony Patterns between Serotonin and Movement within Neuronal Motor Circuits in the Brain.

Science.gov (United States)

Broderick, Patricia A

2013-06-21

The present discourse links the electrical and chemical properties of the brain with neurotransmitters and movement behaviors to further elucidate strategies to diagnose and treat brain disease. Neuromolecular imaging (NMI), based on electrochemical principles, is used to detect serotonin in nerve terminals (dorsal and ventral striata) and somatodendrites (ventral tegmentum) of reward/motor mesocorticolimbic and nigrostriatal brain circuits. Neuronal release of serotonin is detected at the same time and in the same animal, freely moving and unrestrained, while open-field behaviors are monitored via infrared photobeams. The purpose is to emphasize the unique ability of NMI and the BRODERICK PROBE® biosensors to empirically image a pattern of temporal synchrony, previously reported, for example, in Aplysia using central pattern generators (CPGs), serotonin and cerebral peptide-2. Temporal synchrony is reviewed within the context of the literature on central pattern generators, neurotransmitters and movement disorders. Specifically, temporal synchrony data are derived from studies on psychostimulant behavior with and without cocaine while at the same time and continuously, serotonin release in motor neurons within basal ganglia, is detected. The results show that temporal synchrony between the neurotransmitter, serotonin and natural movement occurs when the brain is NOT injured via, e.g., trauma, addictive drugs or psychiatric illness. In striking contrast, in the case of serotonin and cocaine-induced psychostimulant behavior, a different form of synchrony and also asynchrony can occur. Thus, the known dysfunctional movement behavior produced by cocaine may well be related to the loss of temporal synchrony, the loss of the ability to match serotonin in brain with motor activity. The empirical study of temporal synchrony patterns in humans and animals may be more relevant to the dynamics of motor circuits and movement behaviors than are studies of static parameters

Adaptations in pre- and postsynaptic 5-HT(1A) receptor function and cocaine supersensitivity in serotonin transporter knockout rats

NARCIS (Netherlands)

Homberg, Judith R; De Boer, Sietse F; Raasø, Halfdan S; Olivier, Jocelien D A; Verheul, Mark; Ronken, Eric; Cools, Alexander R; Ellenbroek, Bart A; Schoffelmeer, Anton N M; Vanderschuren, Louk J M J; De Vries, Taco J; Cuppen, Edwin

2008-01-01

RATIONALE: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. OBJECTIVES: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout

Autoradiographic localization of 3H-paroxetine-labeled serotonin uptake sites in rat brain

International Nuclear Information System (INIS)

De Souza, E.B.; Kuyatt, B.L.

1987-01-01

Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin

Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding

DEFF Research Database (Denmark)

Frokjaer, Vibe G.; Erritzoe, David; Juul, Anders

2010-01-01

the effect of plasma sex hormone levels on neocortical 5-HT2A receptor binding as imaged with [18F]altanserin PET. The effect of endogenous sex-hormone levels was evaluated by multiple linear regression analysis. Results: Mean neocortical 5-HT2A receptor binding was positively correlated with estradiol (p......Background: Sex-hormones influence brain function and are likely to play a role in the gender predisposition to mood and anxiety disorders. Acute fluctuations of sex-hormone levels including hormonal replacement therapy appear to affect serotonergic neurotransmission, but it is unknown if baseline...... levels affect serotonergic neurotransmission. This study was undertaken to examine if baseline levels of endogenous sex hormones are associated with cerebral serotonin 2A (5-HT2A) receptor binding in men. Methods: In a group of 72 healthy men (mean age 37.5 years ±17.4 SD, range 19.6–81.7) we studied...

Cerebral serotonin transporter binding is inversely related to body mass index

DEFF Research Database (Denmark)

Erritzoe, D; Frokjaer, V G; Haahr, M T

2010-01-01

Overweight and obesity is a health threat of increasing concern and understanding the neurobiology behind obesity is instrumental to the development of effective treatment regimes. Serotonergic neurotransmission is critically involved in eating behaviour; cerebral level of serotonin (5-HT...

The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined

DEFF Research Database (Denmark)

Pinborg, Lars H; Arfan, Haroon; Haugbol, Steven

2007-01-01

With the appropriate radiolabeled tracers, positron emission tomography (PET) enables in vivo human brain imaging of markers for neurotransmission, including neurotransmitter synthesis, receptors, and transporters. Whereas structural imaging studies have provided compelling evidence that the human...... brain anatomy is largely genetically determined, it is currently unknown to what degree neuromodulatory markers are subjected to genetic and environmental influence. Changes in serotonin 2A (5-HT(2A)) receptors have been reported to occur in various neuropsychiatric disorders and an association between...

Effects of Docosahexaenoic Acid on Neurotransmission

OpenAIRE

Tanaka, Kazuhiro; Farooqui, Akhlaq A.; Siddiqi, Nikhat J.; Alhomida, Abdullah S.; Ong, Wei-Yi

2012-01-01

Docosahexaenoic acid (DHA) is the major polyunsaturated fatty acid (PUFA) in the brain and a structural component of neuronal membranes. Changes in DHA content of neuronal membranes lead to functional changes in the activity of receptors and other proteins which might be associated with synaptic function. Accumulating evidence suggests the beneficial effects of dietary DHA supplementation on neurotransmission. This article reviews the beneficial effects of DHA on the brain; uptake, incorporat...

Immunodetection of the serotonin transporter protein is a more valid marker for serotonergic fibers than serotonin

DEFF Research Database (Denmark)

Nielsen, Kirsten; Brask, Dorthe; Knudsen, Gitte M.

2006-01-01

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...... 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...

Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin

Science.gov (United States)

Migliarini, Sara; Pacini, Giulia; Pasqualetti, Massimo

2015-01-01

Serotonin has been gaining increasing attention during the last two decades due to the dual function of this monoamine as key regulator during critical developmental events and as neurotransmitter. Importantly, unbalanced serotonergic levels during critical temporal phases might contribute to the onset of neuropsychiatric disorders, such as schizophrenia and autism. Despite increasing evidences from both animal models and human genetic studies have underpinned the importance of serotonin homeostasis maintenance during central nervous system development and adulthood, the precise role of this molecule in time-specific activities is only beginning to be elucidated. Serotonin synthesis is a 2-step process, the first step of which is mediated by the rate-limiting activity of Tph enzymes, belonging to the family of aromatic amino acid hydroxylases and existing in two isoforms, Tph1 and Tph2, responsible for the production of peripheral and brain serotonin, respectively. In the present study, we generated and validated a conditional knockout mouse line, Tph2 flox/flox, in which brain serotonin can be effectively ablated with time specificity. We demonstrated that the Cre-mediated excision of the third exon of Tph2 gene results in the production of a Tph2 null allele in which we observed the near-complete loss of brain serotonin, as well as the growth defects and perinatal lethality observed in serotonin conventional knockouts. We also revealed that in mice harbouring the Tph2 null allele, but not in wild-types, two distinct Tph2 mRNA isoforms are present, namely Tph2Δ3 and Tph2Δ3Δ4, with the latter showing an in-frame deletion of amino acids 84–178 and coding a protein that could potentially retain non-negligible enzymatic activity. As we could not detect Tph1 expression in the raphe, we made the hypothesis that the Tph2Δ3Δ4 isoform can be at the origin of the residual, sub-threshold amount of serotonin detected in the brain of Tph2 null/null mice. Finally, we set

A Dualistic Conformational Response to Substrate Binding in the Human Serotonin Transporter Reveals a High Affinity State for Serotonin*

Science.gov (United States)

Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida; Wiborg, Ove; Sinning, Steffen

2015-01-01

Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes that occur in the human SERT upon binding of ions, the translocation of substrate, and the role of cholesterol in this interplay are not fully elucidated. Here we show that serotonin induces a dualistic conformational response in SERT. We exploited the substituted cysteine scanning method under conditions that were sensitized to detect a more outward-facing conformation of SERT. We found a novel high affinity outward-facing conformational state of the human SERT induced by serotonin. The ionic requirements for this new conformational response to serotonin mirror the ionic requirements for translocation. Furthermore, we found that membrane cholesterol plays a role in the dualistic conformational response in SERT induced by serotonin. Our results indicate the existence of a subpopulation of SERT responding differently to serotonin binding than hitherto believed and that membrane cholesterol plays a role in this subpopulation of SERT. PMID:25614630

Positron emission tomography studies of brain receptors

International Nuclear Information System (INIS)

Maziere, B.; Maziere, M.

1991-01-01

Probing the regional distribution and affinity of receptors in the brain, in vivo, in human and non human primates has become possible with the use of selective ligands labelled with positron emitting radionuclides and positron emission tomography (PET). After describing the techniques used in positron emission tomography to characterize a ligand receptor binding and discussing the choice of the label and the limitations and complexities of the in vivo approach, the results obtained in the PET studies of various neurotransmission systems: dopaminergic, opiate, benzodiazepine, serotonin and cholinergic systems are reviewed

Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy.

Science.gov (United States)

Llansola, Marta; Montoliu, Carmina; Agusti, Ana; Hernandez-Rabaza, Vicente; Cabrera-Pastor, Andrea; Gomez-Gimenez, Belen; Malaguarnera, Michele; Dadsetan, Sherry; Belghiti, Majedeline; Garcia-Garcia, Raquel; Balzano, Tiziano; Taoro, Lucas; Felipo, Vicente

2015-09-01

The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia-thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Preservation of Essential Odor-Guided Behaviors and Odor-Based Reversal Learning after Targeting Adult Brain Serotonin Synthesis.

Science.gov (United States)

Carlson, Kaitlin S; Whitney, Meredith S; Gadziola, Marie A; Deneris, Evan S; Wesson, Daniel W

2016-01-01

The neurotransmitter serotonin (5-HT) is considered a powerful modulator of sensory system organization and function in a wide range of animals. The olfactory system is innervated by midbrain 5-HT neurons into both its primary and secondary odor-processing stages. Facilitated by this circuitry, 5-HT and its receptors modulate olfactory system function, including odor information input to the olfactory bulb. It is unknown, however, whether the olfactory system requires 5-HT for even its most basic behavioral functions. To address this question, we established a conditional genetic approach to specifically target adult brain tryptophan hydroxylase 2 ( Tph2 ), encoding the rate-limiting enzyme in brain 5-HT synthesis, and nearly eliminate 5-HT from the mouse forebrain. Using this novel model, we investigated the behavior of 5-HT-depleted mice during performance in an olfactory go/no-go task. Surprisingly, the near elimination of 5-HT from the forebrain, including the olfactory bulbs, had no detectable effect on the ability of mice to perform the odor-based task. Tph2 -targeted mice not only were able to learn the task, but also had levels of odor acuity similar to those of control mice when performing coarse odor discrimination. Both groups of mice spent similar amounts of time sampling odors during decision-making. Furthermore, odor reversal learning was identical between 5-HT-depleted and control mice. These results suggest that 5-HT neurotransmission is not necessary for the most essential aspects of olfaction, including odor learning, discrimination, and certain forms of cognitive flexibility.

High brain serotonin levels in migraine between attacks

DEFF Research Database (Denmark)

Deen, Marie; Hansen, Hanne D.; Hougaard, Anders

2017-01-01

Objectives To investigate brain 5-HT4-receptor binding with positron emission tomography (PET) as a proxy of serotonin (5-hydroxytryptamine, 5-HT) levels in migraine patients between attacks. Methods Brain 5-HT4-receptor binding, assessed with PET imaging of the specific 5-HT4-receptor radioligand......, [11C]SB207145, is inversely related to long-term changes in brain 5-HT-levels. Eighteen migraine patients without aura (≥48 hours migraine free) and 16 age- and sex-matched controls underwent PET-scanning after injection of [11C]SB207145. Patients who reported a migraine attack ≤48 hours after...... the scan were excluded. The mean neocortical [11C]SB207145 binding potential (BPND) was calculated in a blinded manner. Results Fifteen patients (age 29.6 ± 10.2 years, 2 men) and 16 controls (28.9 ± 10.2 years, 3 men) completed the study. Migraine patients had significantly lower neocortical 5-HT4...

New Insights on Different Response of MDMA-Elicited Serotonin Syndrome to Systemic and Intracranial Administrations in the Rat Brain.

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Shokry, Ibrahim M; Callanan, John J; Sousa, John; Tao, Rui

2016-01-01

In spite of the fact that systemic administration of MDMA elicits serotonin syndrome, direct intracranial administration fails to reproduce the effect. To reconcile these findings, it has been suggested that the cause of serotonin syndrome is attributed mainly to MDMA hepatic metabolites, and less likely to MDMA itself. Recently, however, this explanation has been challenged, and alternative hypotheses need to be explored. Here, we tested the hypothesis that serotonin syndrome is the result of excessive 5HT simultaneously in many brain areas, while MDMA administered intracranially fails to cause serotonin syndrome because it produces only a localized effect at the delivery site and not to other parts of the brain. This hypothesis was examined using adult male Sprague Dawley rats by comparing 5HT responses in the right and left hemispheric frontal cortices, right and left hemispheric diencephalons, and medullar raphe nucleus. Occurrence of serotonin syndrome was confirmed by measuring change in body temperature. Administration routes included intraperitoneal (IP), intracerebroventricular (ICV) and reverse microdialysis. First, we found that IP administration caused excessive 5HT in all five sites investigated and induced hypothermia, suggesting the development of the serotonin syndrome. In contrast, ICV and reverse microdialysis caused excessive 5HT only in regions of delivery sites without changes in body-core temperature, suggesting the absence of the syndrome. Next, chemical dyes were used to trace differences in distribution and diffusion patterns between administration routes. After systemic administration, the dyes were found to be evenly distributed in the brain. However, the dyes administered through ICV or reverse microdialysis injection still remained in the delivery sites, poorly diffusing to the brain. In conclusion, intracranial MDMA administration in one area has no or little effect on other areas, which must be considered a plausible reason for the

New Insights on Different Response of MDMA-Elicited Serotonin Syndrome to Systemic and Intracranial Administrations in the Rat Brain.

Directory of Open Access Journals (Sweden)

Ibrahim M Shokry

Full Text Available In spite of the fact that systemic administration of MDMA elicits serotonin syndrome, direct intracranial administration fails to reproduce the effect. To reconcile these findings, it has been suggested that the cause of serotonin syndrome is attributed mainly to MDMA hepatic metabolites, and less likely to MDMA itself. Recently, however, this explanation has been challenged, and alternative hypotheses need to be explored. Here, we tested the hypothesis that serotonin syndrome is the result of excessive 5HT simultaneously in many brain areas, while MDMA administered intracranially fails to cause serotonin syndrome because it produces only a localized effect at the delivery site and not to other parts of the brain. This hypothesis was examined using adult male Sprague Dawley rats by comparing 5HT responses in the right and left hemispheric frontal cortices, right and left hemispheric diencephalons, and medullar raphe nucleus. Occurrence of serotonin syndrome was confirmed by measuring change in body temperature. Administration routes included intraperitoneal (IP, intracerebroventricular (ICV and reverse microdialysis. First, we found that IP administration caused excessive 5HT in all five sites investigated and induced hypothermia, suggesting the development of the serotonin syndrome. In contrast, ICV and reverse microdialysis caused excessive 5HT only in regions of delivery sites without changes in body-core temperature, suggesting the absence of the syndrome. Next, chemical dyes were used to trace differences in distribution and diffusion patterns between administration routes. After systemic administration, the dyes were found to be evenly distributed in the brain. However, the dyes administered through ICV or reverse microdialysis injection still remained in the delivery sites, poorly diffusing to the brain. In conclusion, intracranial MDMA administration in one area has no or little effect on other areas, which must be considered a plausible

Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism.

Directory of Open Access Journals (Sweden)

Michael J Kane

Full Text Available Autism is a complex neurodevelopmental disorder characterized by impaired reciprocal social interaction, communication deficits and repetitive behaviors. A very large number of genes have been linked to autism, many of which encode proteins involved in the development and function of synaptic circuitry. However, the manner in which these mutated genes might participate, either individually or together, to cause autism is not understood. One factor known to exert extremely broad influence on brain development and network formation, and which has been linked to autism, is the neurotransmitter serotonin. Unfortunately, very little is known about how alterations in serotonin neuronal function might contribute to autism. To test the hypothesis that serotonin dysfunction can contribute to the core symptoms of autism, we analyzed mice lacking brain serotonin (via a null mutation in the gene for tryptophan hydroxylase 2 (TPH2 for behaviors that are relevant to this disorder. Mice lacking brain serotonin (TPH2-/- showed substantial deficits in numerous validated tests of social interaction and communication. These mice also display highly repetitive and compulsive behaviors. Newborn TPH2-/- mutant mice show delays in the expression of key developmental milestones and their diminished preference for maternal scents over the scent of an unrelated female is a forerunner of more severe socialization deficits that emerge in weanlings and persist into adulthood. Taken together, these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism. Our findings should stimulate new studies that focus on determining how brain hyposerotonemia during critical neurodevelopmental periods can alter the maturation of synaptic circuits known to be mis-wired in autism and how prevention of such deficits might prevent this disorder.

[Effect of nociceptin on histamine and serotonin release in the central nervous system].

Science.gov (United States)

Gyenge, Melinda; Hantos, Mónika; Laufer, Rudolf; Tekes, Korniléa

2006-01-01

Role in pain sensation of both nociceptin (NC), the bioactive heptadecapeptide sequence of preproorphaninFQ and of histamine has been widely evidenced in the central nervous system (CNS). In the current series of experiments effect of intracerebroventricularly (i.c.v.) administered NC (5.5 nmol/rat) on histamine and serotonin levels in blood plasma, CSF and brain areas (hypothalamus and hippocampus) was studies and compared to the effect of the mast cell degranulator Compound 48/80(100microg/kg, i.c.v.) and the neuroactive peptide Substance P (50nmol/rat, i.c.v.). It was found that all the three compounds increased the histamine level in the CNS, however their activity concerning the mast cell-, and neuronal histamine release is different. NC could release histamine from both the mast cells and the neurons and it decreased CNS serotonin levels. Substance P was found the most potent in increasing CNS histamine levels. Compound 48/80 treatment resulted in elevated histamine levels both in the CNS and blood plasma. It is concluded that the histamine releasing effects of i.c.v. administered NC and SP are limited to the CNS, but in the effect of Compound 48/80 its blood-brain barrier impairing activity is also involved. Data also demonstrate that NC has significant effect on both the histaminergic and serotonergic neurotransmission in the CNS.

SPECT imaging with the serotonin transporter radiotracer [123I]p ZIENT in nonhuman primate brain

International Nuclear Information System (INIS)

Cosgrove, Kelly P.; Staley, Julie K.; Baldwin, Ronald M.; Bois, Frederic; Plisson, Christophe; Al-Tikriti, Mohammed S.; Seibyl, John P.; Goodman, Mark M.; Tamagnan, Gilles D.

2010-01-01

Introduction: Serotonin dysfunction has been linked to a variety of psychiatric diseases; however, an adequate SPECT radioligand to probe the serotonin transporter system has not been successfully developed. The purpose of this study was to characterize and determine the in vivo selectivity of iodine-123-labeled 2β-carbomethoxy-3β-(4'-((Z)-2-iodoethenyl)phenyl)nortropane, [ 123 I]p ZIENT, in nonhuman primate brain. Methods: Two ovariohysterectomized female baboons participated in nine studies (one bolus and eight bolus to constant infusion at a ratio of 9.0 h) to evaluate [ 123 I]p ZIENT. To evaluate the selectivity of [ 123 I]p ZIENT, the serotonin transporter blockers fenfluramine (1.5, 2.5 mg/kg) and citalopram (5 mg/kg), the dopamine transporter blocker methylphenidate (0.5 mg/kg) and the norepinephrine transporter blocker nisoxetine (1 mg/kg) were given at 8 h post-radiotracer injection. Results: In the bolus to constant infusion studies, equilibrium was established by 4-8 h. [ 123 I]p ZIENT was 93% and 90% protein bound in the two baboons and there was no detection of lipophilic radiolabeled metabolites entering the brain. In the high-density serotonin transporter regions (diencephalon and brainstem), fenfluramine and citalopram resulted in 35-71% and 129-151% displacement, respectively, whereas methylphenidate and nisoxetine did not produce significant changes ( 123 I]p ZIENT is a favorable compound for in vivo SPECT imaging of serotonin transporters with negligible binding to norepinephrine and dopamine transporters.

The impact of peripheral serotonin on leptin-brain serotonin axis, bone metabolism and strength in growing rats with experimental chronic kidney disease.

Science.gov (United States)

Pawlak, Dariusz; Domaniewski, Tomasz; Znorko, Beata; Oksztulska-Kolanek, Ewa; Lipowicz, Paweł; Doroszko, Michał; Karbowska, Malgorzata; Pawlak, Krystyna

2017-12-01

Chronic kidney disease (CKD) results in decreased bone strength. Serotonin (5-HT) is one of the critical regulators of bone health, fulfilling distinct functions depending on its synthesis site: brain-derived serotonin (BDS) favors osteoblast proliferation, whereas gut-derived serotonin (GDS) inhibits it. We assessed the role of BDS and peripheral leptin in the regulation of bone metabolism and strength in young rats with 5/6 nephrectomy. BDS synthesis was accelerated during CKD progression. Decreased peripheral leptin in CKD rats was inversely related to BDS content in the hypothalamus, brainstem and frontal cortex. Serotonin in these brain regions affected bone strength and metabolism in the studied animals. The direct effect of circulating leptin on bone was not shown in uremia. At the molecular level, there was an inverse association between elevated GDS and the expression of cAMP responsive element-binding protein (Creb) gene in bone of CKD animals. In contrast, increased expression of activating transcription factor 4 (Atf4) was shown, which was associated with GDS-dependent transcription factor 1 (Foxo1), clock gene - Cry-1, cell cycle genes: c-Myc, cyclins, and osteoblast differentiation genes. These results identified a previously unknown molecular pathway, by which elevated GDS can shift in Foxo1 target genes from Creb to Atf4-dependent response, disrupting the leptin-BDS - dependent gene pathway in the bone of uremic rats. Thus, in the condition of CKD the effect of BDS and GDS on bone metabolism and strength can't be distinguished. Copyright © 2017 Elsevier Inc. All rights reserved.

Amphetamine Action at the Cocaine- and Antidepressant-Sensitive Serotonin Transporter Is Modulated by αCaMKII

DEFF Research Database (Denmark)

Steinkellner, Thomas; Montgomery, Therese R; Hofmaier, Tina

2015-01-01

Serotonergic neurotransmission is terminated by reuptake of extracellular serotonin (5-HT) by the high-affinity serotonin transporter (SERT). Selective 5-HT reuptake inhibitors (SSRIs) such as fluoxetine or escitalopram inhibit SERT and are currently the principal treatment for depression and anx...... and efflux at monoamine transporters are asymmetric processes that can be targeted separately. Ultimately, this may provide a molecular mechanism for putative drug developments to treat amphetamine addiction....

Acute pharmacologically induced shifts in serotonin availability abolish emotion-selective responses to negative face emotions in distinct brain networks

DEFF Research Database (Denmark)

Grady, Cheryl Lynn; Siebner, Hartwig R; Hornboll, Bettina

2013-01-01

Pharmacological manipulation of serotonin availability can alter the processing of facial expressions of emotion. Using a within-subject design, we measured the effect of serotonin on the brain's response to aversive face emotions with functional MRI while 20 participants judged the gender...... of neutral, fearful and angry faces. In three separate and counterbalanced sessions, participants received citalopram (CIT) to raise serotonin levels, underwent acute tryptophan depletion (ATD) to lower serotonin, or were studied without pharmacological challenge (Control). An analysis designed to identify...

Synthesis and evaluation of 125I 2-aminophenylthio-5-iodo-N,N-dimethyl benzylamine for Exploration of Serotonin Transporter Exploration

International Nuclear Information System (INIS)

Palakas, S.; Vercouillie, J; Emond, P.; Guilloteau, D

2009-07-01

Full text: Serotonin transporter (T-5-HT) plays an important roles in the control of serotoninergic neurotransmission in both amplitude and interaction period. The imbalance in serotoninergic neurotransmission leads to neuropsychiatric symptom such as depression and in neuro degenerative diseases, Parkinson and Alzheimer diseases. In the present study, the [125 I ] 2-aminophenylthio-5-iodo-N,N-dimethyl benzylamine, a derivative of the 2-[[2-((dimethylamino)methyl)phenyl]thio]-5-iodo phenylamine (ADAM) was synthesized with iodine atom transferred from aniline ring of ADAM to the N,N-dimethyl benzylamine ring by chemical synthesis. The I-125 labeling efficiency was 60%. It is expected that this will be useful for serotonin transporter exploration

Serotonin 5HT1A receptor availability and pathological crying after stroke

DEFF Research Database (Denmark)

Møller, Mette; Andersen, G; Gjedde, A

2007-01-01

OBJECTIVES: Post-stroke depression and pathological crying (PC) implicate an imbalance of serotonergic neurotransmission. We claim that PC follows serotonin depletion that raises the binding potential (p(B)) of the 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635, which is reversible...... by selective serotonin re-uptake inhibitor (SSRI) treatment. MATERIALS AND METHODS: We PET scanned patients with acute stroke and PC and age-matched control subjects. Maps of receptor availability were generated from the images of eight cortical regions and raphe nuclei. RESULTS: The maps showed highest...

IMAGING BRAIN SIGNAL TRANSDUCTION AND METABOLISM VIA ARACHIDONIC AND DOCOSAHEXAENOIC ACID IN ANIMALS AND HUMANS

Science.gov (United States)

Basselin, Mireille; Ramadan, Epolia; Rapoport, Stanley I.

2012-01-01

The polyunsaturated fatty acids (PUFAs), arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), important second messengers in brain, are released from membrane phospholipid following receptor-mediated activation of specific phospholipase A2 (PLA2) enzymes. We developed an in vivo method in rodents using quantitative autoradiography to image PUFA incorporation into brain from plasma, and showed that their incorporation rates equal their rates of metabolic consumption by brain. Thus, quantitative imaging of unesterified plasma AA or DHA incorporation into brain can be used as a biomarker of brain PUFA metabolism and neurotransmission. We have employed our method to image and quantify effects of mood stabilizers on brain AA/DHA incorporation during neurotransmission by muscarinic M1,3,5, serotonergic 5-HT2A/2C, dopaminergic D2-like (D2, D3, D4) or glutamatergic N-methyl-D-aspartic acid (NMDA) receptors, and effects of inhibition of acetylcholinesterase, of selective serotonin and dopamine reuptake transporter inhibitors, of neuroinflammation (HIV-1 and lipopolysaccharide) and excitotoxicity, and in genetically modified rodents. The method has been extended for the use with positron emission tomography (PET), and can be employed to determine how human brain AA/DHA signaling and consumption are influenced by diet, aging, disease and genetics. PMID:22178644

Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia.

Science.gov (United States)

Devor, A; Andreassen, O A; Wang, Y; Mäki-Marttunen, T; Smeland, O B; Fan, C-C; Schork, A J; Holland, D; Thompson, W K; Witoelar, A; Chen, C-H; Desikan, R S; McEvoy, L K; Djurovic, S; Greengard, P; Svenningsson, P; Einevoll, G T; Dale, A M

2017-06-01

The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters-glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids-and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate 'slow' (G-protein-coupled receptors) and 'fast' (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an 'associative' disorder-a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways-and may unify a number of currently competing hypotheses of SCZ pathophysiology.

Serotonin and conditioning: focus on Pavlovian psychostimulant drug conditioning.

Science.gov (United States)

Carey, Robert J; Damianopoulos, Ernest N

2015-04-01

Serotonin containing neurons are located in nuclei deep in the brainstem and send axons throughout the central nervous system from the spinal cord to the cerebral cortex. The vast scope of these connections and interactions enable serotonin and serotonin analogs to have profound effects upon sensory/motor processes. In that conditioning represents a neuroplastic process that leads to new sensory/motor connections, it is apparent that the serotonin system has the potential for a critical role in conditioning. In this article we review the basics of conditioning as well as the serotonergic system and point up the number of non-associative ways in which manipulations of serotonin neurotransmission have an impact upon conditioning. We focus upon psychostimulant drug conditioning and review the contribution of drug stimuli in the use of serotonin drugs to investigate drug conditioning and the important impact drug stimuli can have on conditioning by introducing new sensory stimuli that can create or mask a CS. We also review the ways in which experimental manipulations of serotonin can disrupt conditioned behavioral effects but not the associative processes in conditioning. In addition, we propose the use of the recently developed memory re-consolidation model of conditioning as an approach to assess the possible role of serotonin in associative processes without the complexities of performance effects related to serotonin treatment induced alterations in sensory/motor systems. Copyright © 2014 Elsevier B.V. All rights reserved.

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [(11)C]MADAM PET study.

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Finnema, Sjoerd J; Halldin, Christer; Bang-Andersen, Benny; Bundgaard, Christoffer; Farde, Lars

2015-11-01

A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment. The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [(11)C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved. Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans. Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

Brain serotonin, psychoactive drugs, and effects on reproduction.

Science.gov (United States)

Ayala, María Elena

2009-12-01

Serotonin, a biogenic amine, is present in significant amounts in many structures of the CNS. It is involved in regulation of a wide variety of physiological functions, such as sensory and motor functions, memory, mood, and secretion of hormones including reproductive hormones. It has also been implicated in the etiology of a range of psychiatric disorders such as anxiety, depression, and eating disorders, along with other conditions such as obesity and migraine. While some drugs that affect serotonin, such as fenfluramine and fluoxetine, have been successfully used in treatment of a range of psychiatric diseases, others, such as the amphetamine analogues MDMA and METH, are potent psychostimulant drugs of abuse. Alterations in serotonergic neurons caused by many of these drugs are well characterized; however, little is known about the reproductive consequences of such alterations. This review evaluates the effects of drugs such as MDMA, pCA, fenfluramine, and fluoxetine on serotonergic transmission in the brain, examines the relationships of these drug effects with the neuroendocrine mechanisms modulating reproductive events such as gonadotropin secretion, ovulation, spermatogenesis, and sexual behavior in animal models, and discusses possible reproductive implications of these drugs in humans.

An approach for serotonin depletion in pigs: effects on serotonin receptor binding

DEFF Research Database (Denmark)

Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

2011-01-01

Depletion of central serotonin (5-HT) levels and dysfunction in serotonergic transmission are implicated in a variety of human CNS disorders. The mechanisms behind these serotonergic deficits have been widely studied using rodent models, but only to a limited extent in larger animal models. The pig...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT₄ receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

An approach for serotonin depletion in pigs: effects on serotonin receptor binding

DEFF Research Database (Denmark)

Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

2011-01-01

Depletion of central serotonin (5-HT) levels and dysfunction in serotonergic transmission are implicated in a variety of human CNS disorders. The mechanisms behind these serotonergic deficits have been widely studied using rodent models, but only to a limited extent in larger animal models. The pig...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT4 receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

Serotonin shapes risky decision making in monkeys.

Science.gov (United States)

Long, Arwen B; Kuhn, Cynthia M; Platt, Michael L

2009-12-01

Some people love taking risks, while others avoid gambles at all costs. The neural mechanisms underlying individual variation in preference for risky or certain outcomes, however, remain poorly understood. Although behavioral pathologies associated with compulsive gambling, addiction and other psychiatric disorders implicate deficient serotonin signaling in pathological decision making, there is little experimental evidence demonstrating a link between serotonin and risky decision making, in part due to the lack of a good animal model. We used dietary rapid tryptophan depletion (RTD) to acutely lower brain serotonin in three macaques performing a simple gambling task for fluid rewards. To confirm the efficacy of RTD experiments, we measured total plasma tryptophan using high-performance liquid chromatography (HPLC) with electrochemical detection. Reducing brain serotonin synthesis decreased preference for the safe option in a gambling task. Moreover, lowering brain serotonin function significantly decreased the premium required for monkeys to switch their preference to the risky option, suggesting that diminished serotonin signaling enhances the relative subjective value of the risky option. These results implicate serotonin in risk-sensitive decision making and, further, suggest pharmacological therapies for treating pathological risk preferences in disorders such as problem gambling and addiction.

Epilepsy, Regulation of Brain Energy Metabolism and Neurotransmission

OpenAIRE

Cloix, Jean-Fran?ois; H?vor, Tobias

2009-01-01

Seizures are the result of a sudden and temporary synchronization of neuronal activity, the reason for which is not clearly understood. Astrocytes participate in the control of neurotransmitter storage and neurotransmission efficacy. They provide fuel to neurons, which need a high level of energy to sustain normal and pathological neuronal activities, such as during epilepsy. Various genetic or induced animal models have been developed and used to study epileptogenic mechanisms. Methionine su...

SPECT imaging with the serotonin transporter radiotracer [{sup 123}I]p ZIENT in nonhuman primate brain

Energy Technology Data Exchange (ETDEWEB)

Cosgrove, Kelly P., E-mail: kelly.cosgrove@yale.ed [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Staley, Julie K.; Baldwin, Ronald M.; Bois, Frederic [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Plisson, Christophe [Emory University School of Medicine, Atlanta, GA 30322 (United States); Al-Tikriti, Mohammed S. [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Seibyl, John P. [Institute for Neurodegenerative Disorders, New Haven, CT 06510 (United States); Goodman, Mark M. [Emory University School of Medicine, Atlanta, GA 30322 (United States); Tamagnan, Gilles D. [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Institute for Neurodegenerative Disorders, New Haven, CT 06510 (United States)

2010-07-15

Introduction: Serotonin dysfunction has been linked to a variety of psychiatric diseases; however, an adequate SPECT radioligand to probe the serotonin transporter system has not been successfully developed. The purpose of this study was to characterize and determine the in vivo selectivity of iodine-123-labeled 2{beta}-carbomethoxy-3{beta}-(4'-((Z)-2-iodoethenyl)phenyl)nortropane, [{sup 123}I]p ZIENT, in nonhuman primate brain. Methods: Two ovariohysterectomized female baboons participated in nine studies (one bolus and eight bolus to constant infusion at a ratio of 9.0 h) to evaluate [{sup 123}I]p ZIENT. To evaluate the selectivity of [{sup 123}I]p ZIENT, the serotonin transporter blockers fenfluramine (1.5, 2.5 mg/kg) and citalopram (5 mg/kg), the dopamine transporter blocker methylphenidate (0.5 mg/kg) and the norepinephrine transporter blocker nisoxetine (1 mg/kg) were given at 8 h post-radiotracer injection. Results: In the bolus to constant infusion studies, equilibrium was established by 4-8 h. [{sup 123}I]p ZIENT was 93% and 90% protein bound in the two baboons and there was no detection of lipophilic radiolabeled metabolites entering the brain. In the high-density serotonin transporter regions (diencephalon and brainstem), fenfluramine and citalopram resulted in 35-71% and 129-151% displacement, respectively, whereas methylphenidate and nisoxetine did not produce significant changes (<10%). Conclusion: These findings suggest that [{sup 123}I]p ZIENT is a favorable compound for in vivo SPECT imaging of serotonin transporters with negligible binding to norepinephrine and dopamine transporters.

Tryptophan as an evolutionarily conserved signal to brain serotonin : Molecular evidence and psychiatric implications

NARCIS (Netherlands)

Russo, Sascha; Kema, Ido P.; Bosker, Fokko; Haavik, Jan; Korf, Jakob

2009-01-01

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is

Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons

NARCIS (Netherlands)

Reneman, L.; Booij, J.; de Bruin, K.; Reitsma, J. B.; de Wolff, F. A.; Gunning, W. B.; den Heeten, G. J.; van den Brink, W.

2001-01-01

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to damage brain serotonin neurons in high doses. However, effects of moderate MDMA use on serotonin neurons have not been studied, and sex differences and the long-term effects of MDMA

Effects of Junk Foods on Brain Neurotransmitters (Dopamine and Serotonin) and some Biochemical Parameters in Albino Rats

International Nuclear Information System (INIS)

Abd Elmonem, H.A.; Ali, E.A.

2011-01-01

Nutritional Habits have changed significantly and junk foods have become widely popular, in recent years. The present study aimed to shed the light on the effect of potato chips and / or ketchup consumption on some biochemical parameters. Sixty four male and female albino rats were used in the study. Animals were maintained on 0.25 g potato chips/ rat and / or 0.125 g ketchup / rat, 5 days a week for 4 weeks. Potato chips showed the lowest body wt gain in the male rats after 4 weeks but, ketchup modulated this negative effect of the potato chips in the group of male animals fed on potato chips plus ketchup. Potato chips significantly decreased brain serotonin, liver glutathione (GSH) and catalase (CAT) in both sexes; brain dopamine, serum total proteins, albumin, total globulins, α 2 - and β 1 -globulins in the females and serum thyroxine (T 4 ) in the male rats. Ketchup apparently affected serum T 4 and A / G ratio in both sexes, brain dopamine and liver GSH in the males in addition to brain serotonin, serum total globulins and ?1-globulin in the female rats. Potato chips plus ketchup significantly changed T 4 , dopamine, GSH, CAT, α 1 and α 2 -globulins in both sexes; serotonin and β 1 -globulin in the male rats, total proteins and albumin in the females. It could be concluded that potato chips consumption might induce numerous adverse effects in various body organs

A role for the serotonin reuptake transporter in the brain and intestinal features of autism spectrum disorders and developmental antidepressant exposure.

Science.gov (United States)

Margolis, Kara Gross

2017-10-01

Many disease conditions considered CNS-predominant harbor significant intestinal comorbidities. Serotonin (5-HT) and the serotonin reuptake transporter (SERT) have increasingly been shown to play important roles in both brain and intestinal development and long-term function. 5-HT and SERT may thus modulate critical functions in the development and perpetuation of brain-gut axis disease. We discuss the potential roles of 5-HT and SERT in the brain and intestinal manifestations of autism spectrum disorders and developmental antidepressant exposure. The potential therapeutic value of 5-HT 4 modulation in the subsequent treatment of these conditions is also addressed. Copyright © 2017 Elsevier B.V. All rights reserved.

Copper: From neurotransmission to neuroproteostasis

Directory of Open Access Journals (Sweden)

Carlos M Opazo

2014-07-01

Full Text Available Copper is critical for the Central Nervous System (CNS development and function. In particular, different studies have shown the effect of copper at brain synapses, where it inhibits Long Term Potentation (LTP and receptor pharmacology. Paradoxically, according to recent studies copper is required for a normal LTP response. Copper is released at the synaptic cleft, where it blocks glutamate receptors, which explain its blocking effects on excitatory neurotransmission. Our results indicate that copper also enhances neurotransmission through the accumulation of PSD95 protein, which increase the levels of AMPA receptors located at the plasma membrane of the post-synaptic density. Thus, our findings represent a novel mechanism for the action of copper, which may have implications for the neurophysiology and neuropathology of the CNS. These data indicate that synaptic configuration is sensitive to transient changes in transition metal homeostasis. Our results suggest that copper increases GluA1 subunit levels of the AMPA receptor through the anchorage of AMPA receptors to the plasma membrane as a result of PSD-95 accumulation. Here, we will review the role of copper on neurotransmission of CNS neurons. In addition, we will discuss the potential mechanisms by which copper could modulate neuronal proteostasis (neuroproteostasis in the CNS with focus in the Ubiquitin Proteasome System, which is particularly relevant to neurological disorders such Alzheimer’s disease (AD where copper and protein dyshomeostasis may contribute to neurodegeneration. An understanding of these mechanisms may ultimately lead to the development of novel therapeutic approaches to control metal and synaptic alterations observed in AD patients.

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain.

Science.gov (United States)

Kesby, James P; Turner, Karly M; Alexander, Suzanne; Eyles, Darryl W; McGrath, John J; Burne, Thomas H J

2017-11-01

Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. Ubiquitous reductions in the levels of glutamine (12-24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat

Increased brain temserotoneric transporter availability in adult migraineurs: ([18F]FP-CIT PET imaging pilot study

International Nuclear Information System (INIS)

Park, Eun Kyung; Hwang, Yu Mi; Chu, Min Kyung; Jung, Ki Young

2016-01-01

Recent studies have proposed central serotonergic dysfunction as a major pathophysiology of migraine. We investigated serotonin transporter (SERT) availability in migraineurs using F-18-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([18F]FP-CIT) positron emission tomography (PET). Brain [18F]FP-CIT PET images were obtained in eight women with migraine during headache free phase and 12 healthy adult women, 120 min after injection of 185 MBq. Non-displaceable binding potential (BP ND) of [18F]FP-CIT, which is an estimate of SERT availability, was calculated at the brainstem and compared with clinical parameters. BP ND at the brainstem was significantly higher in adult migraineurs (n = 6, 1.15 ± 0.17) than healthy subjects (0.95 ± 0.14) (p = 0.04). Healthy subjects demonstrated negative correlation between brainstem BP ND and age (r = −0.64, p = 0.02), whereas this age-related decline pattern was not found in the migraineurs. Severity of migraine attack was significantly correlated with brainstem BP ND (r = 0.66, p = 0.02), when age and duration of illness were corrected. Increased SERT availability in the brainstem of adult migraineurs indicates low serotonin neurotransmission during headache-free phase. Patients who experience more painful headaches have lower serotonin neurotransmission. [18F]FP-CIT PET is a useful in vivo imaging technique for evaluating brainstem SERT availability in migraineurs

Increased brain temserotoneric transporter availability in adult migraineurs: ([18F]FP-CIT PET imaging pilot study

Energy Technology Data Exchange (ETDEWEB)

Park, Eun Kyung [Dept. of Nuclear Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Hwang, Yu Mi [Center for Research Information, Korea University, Seoul (Korea, Republic of); Chu, Min Kyung [Dept. of Neurology, Sacred Heart Hospital, Hallym University College of Medicine, Anyang (Korea, Republic of); Jung, Ki Young [Dept. of Neurology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

2016-03-15

Recent studies have proposed central serotonergic dysfunction as a major pathophysiology of migraine. We investigated serotonin transporter (SERT) availability in migraineurs using F-18-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([18F]FP-CIT) positron emission tomography (PET). Brain [18F]FP-CIT PET images were obtained in eight women with migraine during headache free phase and 12 healthy adult women, 120 min after injection of 185 MBq. Non-displaceable binding potential (BP ND) of [18F]FP-CIT, which is an estimate of SERT availability, was calculated at the brainstem and compared with clinical parameters. BP ND at the brainstem was significantly higher in adult migraineurs (n = 6, 1.15 ± 0.17) than healthy subjects (0.95 ± 0.14) (p = 0.04). Healthy subjects demonstrated negative correlation between brainstem BP ND and age (r = −0.64, p = 0.02), whereas this age-related decline pattern was not found in the migraineurs. Severity of migraine attack was significantly correlated with brainstem BP ND (r = 0.66, p = 0.02), when age and duration of illness were corrected. Increased SERT availability in the brainstem of adult migraineurs indicates low serotonin neurotransmission during headache-free phase. Patients who experience more painful headaches have lower serotonin neurotransmission. [18F]FP-CIT PET is a useful in vivo imaging technique for evaluating brainstem SERT availability in migraineurs.

In vitro and in vivo characterisation of nor-β-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain

International Nuclear Information System (INIS)

Bergstroem, K.A.; Halldin, C.; Hall, H.; Lundkvist, C.; Ginovart, N.; Swahn, C.G.; Farde, L.

1997-01-01

Radiolabelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) has been used in clinical studies for the imaging of dopamine and serotonin transporters with single-photon emission tomography (SPET). 2β-Carbomethoxy-3β-(4-iodophenyl)nortropane (nor-β-CIT) is a des-methyl analogue of β-CIT, which in vitro has tenfold higher affinity (IC 50 =0.36 nM) to the serotonin transporter than β-CIT (IC 50 =4.2 nM). Nor-β-CIT may thus be a useful radioligand for imaging of the serotonin transporter. In the present study iodine-125 and carbon-11 labelled nor-β-CIT were prepared for in vitro autoradiographic studies on post-mortem human brain cryosections and for in vivo positron emission tomography (PET) studies in Cynomolgus monkeys. Whole hemisphere autoradiography with [ 125 I[nor-β-CIT demonstrated high binding in the striatum, the thalamus and cortical regions of the human brain. Addition of a high concentration (1 μM) of citalopram inhibited binding in the thalamus and the neocortex, but not in the striatum. In PET studies with [ 11 C[nor-β-CIT there was rapid uptake of radioactivity in the monkey brain (6% of injected dose at 15 min) and high accumulation of radioactivity in the striatum, thalamus and neocortex. Thalamus to cerebellum and cortex to cerebellum ratios were 2.5 and 1.8 at 60 min, respectively. The ratios obtained with [ 11 C[nor-β-CIT were 20%-40% higher than those previously obtained with [ 11 C[β-CIT. Radioactivity in the thalamus and the neocortex but not in the striatum was displaceable with citalopram (5 mg/kg). In conclusion, nor-β-CIT binds to the serotonin transporter in the primate brain in vitro and in vivo and has potential for PET and SPET imaging of the serotonin transporter in human brain. (orig.). With 4 figs

Decreased frontal serotonin 5-HT2a receptor binding index in deliberate self-harm patients

International Nuclear Information System (INIS)

Audenaert, K.; Laere, K. van; Dierckx, R.A.; Dumont, F.; Slegers, G.; Mertens, J.; Heeringen, C. van

2001-01-01

Studies of serotonin metabolites in body fluids in attempted suicide patients and of post-mortem brain tissue of suicide victims have demonstrated the involvement of the serotonergic neurotransmission system in the pathogenesis of suicidal behaviour. Recently developed neuroimaging techniques offer the unique possibility of investigating in vivo the functional characteristics of this system. In this study the 5-HT 2a receptor population of patients who had recently attempted suicide was studied by means of the highly specific radio-iodinated 5-HT 2a receptor antagonist 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl] -5-iodo-2-methox ybenzamide or 123 I-5-I-R91150. Nine patients who had recently (1-7 days) attempted suicide and 12 age-matched healthy controls received an intravenous injection of 185 MBq 123 I-5-I-R91150 and were scanned with high-resolution brain single-photon emission tomography (SPET). Stereotactic realigned images were analysed semi-quantitatively using predefined volumes of interest. Serotonin binding capacity was expressed as the ratio of specific to non-specific activity. The cerebellum was used as a measure of non-specific activity. An age-dependent 5-HT 2a binding index was found, in agreement with previous literature. Deliberate self-harm patients had a significantly reduced mean frontal binding index after correction for age (P=0.002) when compared with controls. The reduction was more pronounced among deliberate self-injury patients (DSI) (P 2a serotonin receptor system in attempted suicide patients who are free of drugs influencing the serotonergic system shows in vivo evidence of a decreased frontal binding index of the 5-HT 2a receptor, indicating a decrease in the number and/or in the binding affinity of 5-HT 2a receptors. (orig.)

Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area

NARCIS (Netherlands)

Dremencov, Eliyahu; El Mansari, Mostafa; Blier, Pierre

Background: Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are efficacious in depression because of their ability to increase 5-HT neurotransmission. However, owing to a purported inhibitory effect of 5- HT on dopamine (DA) neuronal activity in the ventral tegmental area (VTA), this increase

[Schizophrenia and cortical GABA neurotransmission].

Science.gov (United States)

Hashimoto, Takanori; Matsubara, Takuro; Lewis, David A

2010-01-01

Individuals with schizophrenia show disturbances in a number of brain functions that regulate cognitive, affective, motor, and sensory processing. The cognitive deficits associated with dysfunction of the dorsolateral prefrontal cortex result, at least in part, from abnormalities in GABA neurotransmission, as reflected in a specific pattern of altered expression of GABA-related molecules. First, mRNA levels for the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), an enzyme principally responsible for GABA synthesis, and the GABA membrane transporter GAT1, which regulates the reuptake of synaptically released GABA, are decreased in a subset of GABA neurons. Second, affected GABA neurons include those that express the calcium-binding protein parvalbumin (PV), because PV mRNA levels are decreased in the prefrontal cortex of subjects with schizophrenia and GAD67 mRNA is undetectable in almost half of PV-containing neurons. These changes are accompanied by decreased GAT1 expression in the presynaptic terminals of PV-containing neurons and by increased postsynaptic GABA-A receptor alpha2 subunit expression at the axon initial segments of pyramidal neurons. These findings indicate decreased GABA synthesis/release by PV-containing GABA neurons and compensatory changes at synapses formed by these neurons. Third, another subset of GABA neurons that express the neuropeptide somatostatin (SST) also appear to be affected because their specific markers, SST and neuropeptide Y mRNAs, are decreased in a manner highly correlated with the decreases in GAD67 mRNA. Finally, mRNA levels for GABA-A receptor subunits for synaptic (alpha1 and gamma2) and extra-synaptic (delta) receptors are decreased, indicating alterations in both synaptic and extra-synaptic GABA neurotransmission. Together, this pattern of changes indicates that the altered GABA neurotransmission is specific to PV-containing and SST-containing GABA neuron subsets and involves both synaptic and extra

Serotonin-S2 and dopamine-D2 receptors are the same size in membranes

International Nuclear Information System (INIS)

Brann, M.R.

1985-01-01

Target size analysis was used to compare the sizes of serotonin-S2 and dopamine-D2 receptors in rat brain membranes. The sizes of these receptors were standardized by comparison with the muscarinic receptor, a receptor of known size. The number of serotonin-S2 receptors labeled with (3H)ketanserin or (3H)spiperone in frontal cortex decreased as an exponential function of radiation dose, and receptor affinity was not affected. The number of dopamine-D2 receptors labeled with (3H)spiperone in striatum also decreased as an exponential function of radiation dose, and D2 and S2 receptors were equally sensitive to radiation. In both striatum and frontal cortex, the number of muscarinic receptors labeled with (3H)QNB decreased as an exponential function of radiation dose, and were much less sensitive to radiation than S2 and D2 receptors. These data indicate that in rat brain membranes, S2 and D2 receptors are of similar size, and both molecules are much larger than the muscarinic receptor

Decreased frontal serotonin 5-HT{sub 2a} receptor binding index in deliberate self-harm patients

Energy Technology Data Exchange (ETDEWEB)

Audenaert, K. [Dept. of Psychiatry and Medical Psychology, Ghent University Hospital (Belgium); Dept. of Nuclear Medicine, Ghent University Hospital (Belgium); Laere, K. van; Dierckx, R.A. [Dept. of Nuclear Medicine, Ghent University Hospital (Belgium); Dumont, F.; Slegers, G. [Dept. of Radiopharmacy, Ghent Univ. (Belgium); Mertens, J. [VUB-Cyclotron, Brussels (Belgium); Heeringen, C. van [Dept. of Psychiatry and Medical Psychology, Ghent University Hospital (Belgium)

2001-02-01

Studies of serotonin metabolites in body fluids in attempted suicide patients and of post-mortem brain tissue of suicide victims have demonstrated the involvement of the serotonergic neurotransmission system in the pathogenesis of suicidal behaviour. Recently developed neuroimaging techniques offer the unique possibility of investigating in vivo the functional characteristics of this system. In this study the 5-HT{sub 2a} receptor population of patients who had recently attempted suicide was studied by means of the highly specific radio-iodinated 5-HT{sub 2a} receptor antagonist 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide or {sup 123}I-5-I-R91150. Nine patients who had recently (1-7 days) attempted suicide and 12 age-matched healthy controls received an intravenous injection of 185 MBq {sup 123}I-5-I-R91150 and were scanned with high-resolution brain single-photon emission tomography (SPET). Stereotactic realigned images were analysed semi-quantitatively using predefined volumes of interest. Serotonin binding capacity was expressed as the ratio of specific to non-specific activity. The cerebellum was used as a measure of non-specific activity. An age-dependent 5-HT{sub 2a} binding index was found, in agreement with previous literature. Deliberate self-harm patients had a significantly reduced mean frontal binding index after correction for age (P=0.002) when compared with controls. The reduction was more pronounced among deliberate self-injury patients (DSI) (P<0.001) than among deliberate self-poisoning patients (DSP). Frontal binding index was significantly lower in DSI patients than in DSP suicide attempters (P<0.001). It is concluded that brain SPET of the 5-HT{sub 2a} serotonin receptor system in attempted suicide patients who are free of drugs influencing the serotonergic system shows in vivo evidence of a decreased frontal binding index of the 5-HT{sub 2a} receptor, indicating a decrease in the number and/or in

Changes in sensitivity of brain dopamine and serotonin receptors during long-term treatment with carbidine

International Nuclear Information System (INIS)

Zharkovskii, A.M.; Allikmets, L.K.; Chereshka, K.S.; Zharkovskaya, T.A.

1986-01-01

The authors study the state of the dopamine and serotonin receptors of the brain during chronic administration of carbidine to animals. Parts of the brain from two rats were pooled and binding of tritium-spiperone and tritium-LSD was determined. Statistical analysis of the data for apomorphine sterotypy was carried out and the Student's test was used for analysis of the remaining data. It is shown that after discontinuation of carbidine binding of tritium-spiperone and tritium-LSD in the cortex was reduced

Mitochondrial monoaminoxidase activity and serotonin content in rat brain after whole-body γ-irradiation

International Nuclear Information System (INIS)

Savitskij, I.V.; Tsybul'skij, V.V.; Grivtsev, B.A.

1985-01-01

It is shown that γ-irradiation of albino rats with a dose of 30 Gy leads to pronounced phase changes in monoaminoxidase activity and serotonin content in rat brain at early times after whole-body exposure. These is a similar direction of changes in the activity of the enzyme and in the content of the substrate adequate to the latter

Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure.

Science.gov (United States)

Cauley, Edmund; Wang, Xin; Dyavanapalli, Jhansi; Sun, Ke; Garrott, Kara; Kuzmiak-Glancy, Sarah; Kay, Matthew W; Mendelowitz, David

2015-10-01

Hypertension, cardiac hypertrophy, and heart failure (HF) are widespread and debilitating cardiovascular diseases that affect nearly 23 million people worldwide. A distinctive hallmark of these cardiovascular diseases is autonomic imbalance, with increased sympathetic activity and decreased parasympathetic vagal tone. Recent device-based approaches, such as implantable vagal stimulators that stimulate a multitude of visceral sensory and motor fibers in the vagus nerve, are being evaluated as new therapeutic approaches for these and other diseases. However, little is known about how parasympathetic activity to the heart is altered with these diseases, and this lack of knowledge is an obstacle in the goal of devising selective interventions that can target and selectively restore parasympathetic activity to the heart. To identify the changes that occur within the brain stem to diminish the parasympathetic cardiac activity, left ventricular hypertrophy was elicited in rats by aortic pressure overload using a transaortic constriction approach. Cardiac vagal neurons (CVNs) in the brain stem that generate parasympathetic activity to the heart were identified with a retrograde tracer and studied using patch-clamp electrophysiological recordings in vitro. Animals with left cardiac hypertrophy had diminished excitation of CVNs, which was mediated both by an augmented frequency of spontaneous inhibitory GABAergic neurotransmission (with no alteration of inhibitory glycinergic activity) as well as a diminished amplitude and frequency of excitatory neurotransmission to CVNs. Opportunities to alter these network pathways and neurotransmitter receptors provide future targets of intervention in the goal to restore parasympathetic activity and autonomic balance to the heart in cardiac hypertrophy and other cardiovascular diseases. Copyright © 2015 the American Physiological Society.

In vitro and in vivo characterisation of nor-{beta}-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain

Energy Technology Data Exchange (ETDEWEB)

Bergstroem, K.A. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden)]|[Kuopio University Hospital, Clinical Physiology, FIN-70210 Kuopio (Finland); Halldin, C. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Hall, H. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Lundkvist, C. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Ginovart, N. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Swahn, C.G. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Farde, L. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden)

1997-06-10

Radiolabelled 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane ({beta}-CIT) has been used in clinical studies for the imaging of dopamine and serotonin transporters with single-photon emission tomography (SPET). 2{beta}-Carbomethoxy-3{beta}-(4-iodophenyl)nortropane (nor-{beta}-CIT) is a des-methyl analogue of {beta}-CIT, which in vitro has tenfold higher affinity (IC{sub 50}=0.36 nM) to the serotonin transporter than {beta}-CIT (IC{sub 50}=4.2 nM). Nor-{beta}-CIT may thus be a useful radioligand for imaging of the serotonin transporter. In the present study iodine-125 and carbon-11 labelled nor-{beta}-CIT were prepared for in vitro autoradiographic studies on post-mortem human brain cryosections and for in vivo positron emission tomography (PET) studies in Cynomolgus monkeys. Whole hemisphere autoradiography with [{sup 125}I]nor-{beta}-CIT demonstrated high binding in the striatum, the thalamus and cortical regions of the human brain. Addition of a high concentration (1 {mu}M) of citalopram inhibited binding in the thalamus and the neocortex, but not in the striatum. In PET studies with [{sup 11}C]nor-{beta}-CIT there was rapid uptake of radioactivity in the monkey brain (6% of injected dose at 15 min) and high accumulation of radioactivity in the striatum, thalamus and neocortex. Thalamus to cerebellum and cortex to cerebellum ratios were 2.5 and 1.8 at 60 min, respectively. The ratios obtained with [{sup 11}C]nor-{beta}-CIT were 20%-40% higher than those previously obtained with [{sup 11}C]{beta}-CIT. Radioactivity in the thalamus and the neocortex but not in the striatum was displaceable with citalopram (5 mg/kg). In conclusion, nor-{beta}-CIT binds to the serotonin transporter in the primate brain in vitro and in vivo and has potential for PET and SPET imaging of the serotonin transporter in human brain. (orig.). With 4 figs.

[3]tetrahydrotrazodone binding. Association with serotonin binding sites

International Nuclear Information System (INIS)

Kendall, D.A.; Taylor, D.P.; Enna, S.J.

1983-01-01

High (17 nM) and low (603 nM) affinity binding sites for [ 3 ]tetrahydrotrazodone ([ 3 ] THT), a biologically active analogue of trazodone, have been identified in rat brain membranes. The substrate specificity, concentration, and subcellular and regional distributions of these sites suggest that they may represent a component of the serotonin transmitter system. Pharmacological analysis of [ 3 ]THT binding, coupled with brain lesion and drug treatment experiments, revealed that, unlike other antidepressants, [ 3 ] THT does not attach to either a biogenic amine transporter or serotonin binding sites. Rather, it would appear that [ 3 ]THT may be an antagonist ligand for the serotonin binding site. This probe may prove of value in defining the mechanism of action of trazodone and in further characterizing serotonin receptors

Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors

International Nuclear Information System (INIS)

Pazos, A.; Cortes, R.; Palacios, J.M.

1985-01-01

The distribution of serotonin-2 (5-HT 2 ) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with four ligands: [ 3 H]ketanserin, [ 3 H]mesulergine, [ 3 H]LSD and [ 3 H]spiperone, which are reported to show high affinity for 5-HT 2 receptors. Very high concentrations were localized in the claustrum, olfactory tubercle and layer IV of the neocortex. The anterior olfactory nucleus, piriform cortex and layer I of neocortex were also rich in 5-HT 2 receptors. The specificity of the different ligands used is discussed in terms of the other populations of sites recognized by them. The distribution of 5-HT 2 receptors here reported is discussed in correlation with (a) the known distribution of serotoninergic terminals, (b) the specific anatomical systems and (c) the central effects reported to be mediated by 5-HT 2 -selective drugs. (Auth.)

Protracted effects of chronic stress on serotonin dependent thermoregulation

Science.gov (United States)

Natarajan, Reka; Northrop, Nicole A.; Yamamoto, Bryan K.

2016-01-01

Chronic stress is known to affect serotonin (5HT) neurotransmission in the brain and to alter body temperature. Body temperature is controlled in part, by the medial preoptic area of the hypothalamus (mPOA). To investigate the effect of chronic stress on 5HT and how it affects body temperature regulation, we examined whether exposure to a chronic unpredictable stress paradigm (CUS) produces long-term alterations in thermoregulatory function of the mPOA through decreased 5HT neurotransmission. Adult male Sprague-Dawley rats underwent 21 days of CUS. Four days after last stress exposure, basal body temperature in the home cage and body temperature in a cold room maintained at 10°C were recorded. CUS rats had significantly higher subcutaneous basal body temperature at 13:00 h compared to unstressed (NoStress) rats. Whereas the NoStress rats were able to significantly elevate body temperature from basal levels at 30 and 60 min of exposure to the cold room, the CUS rats showed a hypothermic response to the cold. Treatment during CUS with metyrapone, a corticosterone synthesis inhibitor, blocked stress-induced decrease in body temperature in response to the cold challenge. CUS also decreased 5HT transporter protein immunoreactivity in the mPOA and 5HT2A/C agonist injection into the mPOA after CUS exposure caused stressed rats to exhibit a sensitized hyperthermic response to cold. These results indicate that CUS induced changes to the 5HTergic system alters mPOA function in thermoregulation. These findings help explain mechanisms underlying chronic stress induced disorders such as chronic fatigue syndrome wherein long lasting thermoregulatory deficits are observed. PMID:26414686

The serotonin system in autism spectrum disorder: from biomarker to animal models

Science.gov (United States)

Muller, Christopher L.; Anacker, Allison M.J.; Veenstra-VanderWeele, Jeremy

2015-01-01

Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker. PMID:26577932

Measuring the serotonin uptake site using [3H]paroxetine--a new serotonin uptake inhibitor

International Nuclear Information System (INIS)

Gleiter, C.H.; Nutt, D.J.

1988-01-01

Serotonin is an important neurotransmitter that may be involved in ethanol preference and dependence. It is possible to label the serotonin uptake site in brain using the tricyclic antidepressant imipramine, but this also binds to other sites. We have used the new high-affinity uptake blocker paroxetine to define binding to this site and report it to have advantages over imipramine as a ligand

The modulatory action of harmane on serotonergic neurotransmission in rat brain.

Science.gov (United States)

Abu Ghazaleh, Haya; Lalies, Maggie D; Nutt, David J; Hudson, Alan L

2015-02-09

The naturally occurring β-carboline, harmane, has been implicated in various physiological and psychological conditions. Some of these effects are attributed to its interaction with monoaminergic systems. Previous literature indicates that certain β-carbolines including harmane modulate central monoamine levels partly through monoamine oxidase (MAO) inhibition. However, this is not always the case and thus additional mechanisms may be involved. This study set to assess the potential modulatory role of harmane on the basal or K(+) stimulated release of preloaded radiolabelled noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in rat brain cortex in vitro in the presence of the MAO inhibitor pargyline. Harmane displayed an overt elevation in K(+) -evoked [(3)H]5-HT release; whilst little and no effect was reported with [(3)H]DA and [(3)H]NA respectively. The effect of harmane on [(3)H]5-HT efflux was partially compensated in K(+)-free medium. Further analyses demonstrated that removal of Ca(2+) ions and addition of 1.2mM EGTA did not alter the action of harmane on [(3)H]5-HT release from rat brain cortex. The precise mechanism of action however remains unclear but is unlikely to reflect an involvement of MAO inhibition. The current finding aids our understanding on the modulatory action of harmane on monoamine levels and could potentially be of therapeutic use in psychiatric conditions such as depression and anxiety. Copyright © 2014 Elsevier B.V. All rights reserved.

Brain dopamine and serotonin transporter binding are associated with visual attention bias for food in lean men

NARCIS (Netherlands)

Koopman, K. E.; Roefs, A.; Elbers, D. C. E.; Fliers, E.; Booij, J.; Serlie, M. J.; La Fleur, S. E.

2016-01-01

In rodents, the striatal dopamine (DA) system and the (hypo)thalamic serotonin (5-HT) system are involved in the regulation of feeding behavior. In lean humans, little is known about the relationship between these brain neurotransmitter systems and feeding. We studied the relationship between

What would 5-HT do? Regional diversity of 5-HT1 receptor modulation of primary afferent neurotransmission

OpenAIRE

Connor, Mark

2012-01-01

5-HT (serotonin) is a significant modulator of sensory input to the CNS, but the only analgesics that selectively target G-protein-coupled 5-HT receptors are highly specific for treatment of headache. Two recent papers in BJP shed light on this puzzling situation by showing that primary afferent neurotransmission to the superficial layers of the spinal and trigeminal dorsal is inhibited by different subtypes of the 5-HT1 receptor – 5-HT1B(and 1D) in the trigeminal dorsal horn and 5-HT1A in th...

Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-β Oligomers in Mice.

Science.gov (United States)

Ledo, Jose Henrique; Azevedo, Estefania P; Beckman, Danielle; Ribeiro, Felipe C; Santos, Luis E; Razolli, Daniela S; Kincheski, Grasielle C; Melo, Helen M; Bellio, Maria; Teixeira, Antonio L; Velloso, Licio A; Foguel, Debora; De Felice, Fernanda G; Ferreira, Sergio T

2016-11-30

Considerable clinical and epidemiological evidence links Alzheimer's disease (AD) and depression. However, the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble Aβ oligomers (AβOs), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves AβO-induced microglial activation, aberrant TNF-α signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-α and abolished depressive-like behavior induced by AβOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AβOs failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that AβOs trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the world. Brain accumulation of amyloid-β oligomers (AβOs) is a major feature in the pathogenesis of AD. Although clinical and epidemiological data suggest a strong connection between AD and depression, the underlying mechanisms linking these two disorders remain largely unknown. Here, we report that aberrant activation of the brain innate immunity and decreased serotonergic tonus in the brain are key players in AβO-induced depressive-like behavior in mice. Our findings may open up new possibilities for the development of effective therapeutics for AD and depression aimed at modulating microglial function. Copyright © 2016 the authors 0270-6474/16/3612106-11$15.00/0.

Central 5-HT Neurotransmission Modulates Weight Loss following Gastric Bypass Surgery in Obese Individuals

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Haahr, M. E.; Hansen, D. L.; Fisher, P. M.

2015-01-01

The cerebral serotonin (5-HT) system shows distinct differences in obesity compared with the lean state. Here, it was investigated whether serotonergic neurotransmission in obesity is a stable trait or changes in association with weight loss induced by Roux-in-Y gastric bypass (RYGB) surgery....... In vivo cerebral 5-HT2A receptor and 5-HT transporter binding was determined by positron emission tomography in 21 obese [four men; body mass index (BMI), 40.1 ± 4.1 kg/m(2)] and 10 lean (three men; BMI, 24.6 ± 1.5 kg/m(2)) individuals. Fourteen obese individuals were re-examined after RYGB surgery. First...

Characterization of the Distance Relationship Between Localized Serotonin Receptors and Glia Cells on Fluorescence Microscopy Images of Brain Tissue.

Science.gov (United States)

Jacak, Jaroslaw; Schaller, Susanne; Borgmann, Daniela; Winkler, Stephan M

2015-08-01

We here present two new methods for the characterization of fluorescent localization microscopy images obtained from immunostained brain tissue sections. Direct stochastic optical reconstruction microscopy images of 5-HT1A serotonin receptors and glial fibrillary acidic proteins in healthy cryopreserved brain tissues are analyzed. In detail, we here present two image processing methods for characterizing differences in receptor distribution on glial cells and their distribution on neural cells: One variant relies on skeleton extraction and adaptive thresholding, the other on k-means based discrete layer segmentation. Experimental results show that both methods can be applied for distinguishing classes of images with respect to serotonin receptor distribution. Quantification of nanoscopic changes in relative protein expression on particular cell types can be used to analyze degeneration in tissues caused by diseases or medical treatment.

A new Drosophila octopamine receptor responds to serotonin.

Science.gov (United States)

Qi, Yi-Xiang; Xu, Gang; Gu, Gui-Xiang; Mao, Fen; Ye, Gong-Yin; Liu, Weiwei; Huang, Jia

2017-11-01

As the counterparts of the vertebrate adrenergic transmitters, octopamine and tyramine are important physiological regulators in invertebrates. They control and modulate many physiological and behavioral functions in insects. In this study, we reported the pharmacological properties of a new α2-adrenergic-like octopamine receptor (CG18208) from Drosophila melanogaster, named DmOctα2R. This new receptor gene encodes two transcripts by alternative splicing. The long isoform DmOctα2R-L differs from the short isoform DmOctα2R-S by the presence of an additional 29 amino acids within the third intracellular loop. When heterologously expressed in mammalian cell lines, both receptors were activated by octopamine, tyramine, epinephrine and norepinephrine, resulting in the inhibition of cAMP production in a dose-dependent manner. The long form is more sensitive to the above ligands than the short form. The adrenergic agonists naphazoline, tolazoline and clonidine can stimulate DmOctα2R as full agonists. Surprisingly, serotonin and serotoninergic agonists can also activate DmOctα2R. Several tested adrenergic antagonists and serotonin antagonists blocked the action of octopamine or serotonin on DmOctα2R. The data presented here reported an adrenergic-like G protein-coupled receptor activated by serotonin, suggesting that the neurotransmission and neuromodulation in the nervous system could be more complex than previously thought. Copyright © 2017 Elsevier Ltd. All rights reserved.

Behavioral and neuropharmacological evidence that serotonin crosses the blood-brain barrier in Coturnix japonica (Galliformes; Aves

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PA. Polo

Full Text Available This study was carried out aiming to reach behavioral and neuropharmacological evidence of the permeability of the blood-brain barrier (BBB to serotonin systemically administered in quails. Serotonin injected by a parenteral route (250-1000 µg.kg-1, sc elicited a sequence of behavioral events concerned with a sleeping-like state. Sleeping-like behaviors began with feather bristling, rapid oral movements, blinking and finally crouching and closure of the eyes. Previous administration of 5-HT2C antagonist, LY53857 (3 mg.kg-1, sc reduced the episodes of feather bristling and rapid oral movements significantly but without altering the frequency of blinking and closure of the eyes. Treatment with the 5-HT2A/2C antagonist, ketanserin (3 mg.kg-1, sc did not affect any of the responses evoked by the serotonin. Quipazine (5 mg.kg-1, sc a 5-HT2A/2C/3 agonist induced intense hypomotility, long periods of yawning-like and sleeping-like states. Previous ketanserin suppressed gaping responses and reduced hypomotility, rapid oral movements and bristling but was ineffective for remaining responses induced by quipazine. Results showed that unlike mammals, serotonin permeates the BBB and activates hypnogenic mechanisms in quails. Studies using serotoninergic agonist and antagonists have disclosed that among the actions of the serotonin, feather bristling, rapid oral movements and yawning-like state originated from activation of 5-HT2 receptors while blinking and closure of the eyes possibly require other subtypes of receptors.

The influence of serotonin depletion on rat behavior in the Vogel test and brain 3H-zolpidem binding.

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Nazar, M; Siemiatkowski, M; Bidziński, A; Członkowska, A; Sienkiewicz-Jarosz, H; Płaźnik, A

1999-01-01

The influence of p-chlorophenylalanine (p-CPA) and 5,7-dihydroxytryptamine (5,7-DHT)-induced serotonin depletion on rat behavior as well as on zolpidem's the behavioral effects and binding to some brain areas of zolpidem, was examined with the help of Vogel's punished drinking test and autoradiography, respectively. Moreover, changes in the serotonin levels and turnover rate were studied in the forebrain and brainstem of rats pretreated with various ligands at the benzodiazepine (BDZ) receptors (midazolam, bretazenil, abecarnil, zolpidem). These drugs were given at doses shown previously to significantly disinhibit animal behavior suppressed by punishment in the Vogel test (Nazar et al., 1997). It was found that serotonin decrease in the frontal cortex and hippocampus after p-CPA significantly and inversely correlated with rat behavior controlled by fear in the VT. p-CPA produced an anticonflict activity in the absence of effect on spontaneous drinking, pain threshold and motility of animals. All applied benzodiazepine receptor ligands decreased the 5-HT turnover rate in the frontal cortex and hippocampus, whereas in the brainstem only abecarnil and zolpidem diminished 5-hydroxyindoleacetic acid levels. This part of the study replicated earlier data with neurotoxins and indicated that the anxiolytic-like effect of 5-HT depletion in some models of anxiety did not depend on changes in animal appetitive behavior or stimulus control. Moreover, the fact that all nonselective and selective (zolpidem) agonists of the type 1 benzodiazepine receptors seemed to produce the same anticonflict effect and decreasing 5-HT turnover indicates that this subtype of benzodiazepine receptor may be important for the interaction between brain 5-HT and GABA/BDZ systems. Accordingly, it was found that serotonin decrease enhanced the anticonflict effect of zolpidem in the Vogel test and increased 3H-zolpidem binding to the occipital cortex and substantia nigra. Altogether, the present study

Protracted effects of chronic stress on serotonin-dependent thermoregulation.

Science.gov (United States)

Natarajan, Reka; Northrop, Nicole A; Yamamoto, Bryan K

2015-01-01

Chronic stress is known to affect serotonin (5HT) neurotransmission in the brain and to alter body temperature. The body temperature is controlled in part, by the medial preoptic area (mPOA) of the hypothalamus. To investigate the effect of chronic stress on 5HT and how it affects body temperature regulation, we examined whether exposure to a chronic unpredictable stress (CUS) paradigm produces long-term alterations in thermoregulatory function of the mPOA through decreased 5HT neurotransmission. Adult male Sprague-Dawley rats underwent 21 d of CUS. Four days after the last stress exposure, basal body temperature in the home cage and body temperature in a cold room maintained at 10 °C were recorded. The CUS rats had significantly higher subcutaneous basal body temperature at 13:00 h compared to unstressed (NoStress) rats. Whereas the NoStress rats were able to significantly elevate body temperature from basal levels at 30 and 60 min of exposure to the cold room, the CUS rats showed a hypothermic response to the cold. Treatment during CUS with metyrapone, a corticosterone synthesis inhibitor, blocked stress-induced decrease in body temperature in response to the cold challenge. CUS also decreased 5HT transporter protein immunoreactivity in the mPOA and 5HT2A/C agonist injection into the mPOA after CUS exposure caused stressed rats to exhibit a sensitized hyperthermic response to cold. These results indicate that the CUS induced changes to the 5HTergic system alter mPOA function in thermoregulation. These findings help us to explain the mechanisms underlying chronic stress-induced disorders such as chronic fatigue syndrome wherein long lasting thermoregulatory deficits are observed.

Effect of beta-endorphin imprinting during late pregnancy on the brain serotonin and plasma nocistatin levels of adult male rats.

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Tekes, K; Gyenge, M; Hantos, M; Csaba, G

2007-07-01

Female rats were treated with 10 microg of beta-endorphin on the 19th day of pregnancy. Offspring were studied when five months old. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in four brain regions were determined by HPLC-EC and the nocistatin levels of blood plasma using RIA methods. In each brain region studied, the 5-HT levels were highly significantly reduced and that of 5-HIAA in three regions was highly significantly increased. When 5HIAA/5HT ratios, as a measure of serotonin turnover, were calculated, imprinted animals showed extremely high values. Plasma nocistatin level was also significantly elevated. The results call attention to the effect of perinatal endorphin imprinting and its long-term consequences (e.g., setting of aggressiveness, pain tolerance).

Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET

DEFF Research Database (Denmark)

Marner, Lisbeth; Gillings, Nic; Madsen, Karine

2010-01-01

Pharmacological stimulation of the serotonin 4 (5-HT(4)) receptor has shown promise for treatment of Alzheimer's disease and major depression. A new selective radioligand, [(11)C]SB207145, for positron emission tomography (PET) was used to quantify brain 5-HT(4) receptors in sixteen healthy......(max) was in accordance with post-mortem brain studies (Spearman's r=0.83, p=0.04), and the regional binding potentials, BP(ND), were on average 2.6 in striatum, 0.42 in prefrontal cortex, and 0.91 in hippocampus. We found no effect of sex but a decreased binding with age (p=0.046). A power analysis showed that, given......-HT(4) receptor binding in human brain can be reliably assessed with [(11)C]SB207145, which is encouraging for future PET studies of drug occupancy or patients with neuropsychiatric disorders....

The serotonin system in autism spectrum disorder: from biomarker to animal models

OpenAIRE

Muller, Christopher L.; Anacker, Allison M.J.; Veenstra-VanderWeele, Jeremy

2015-01-01

Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophy...

Developmental exposure to fluoxetine modulates the serotonin system in hypothalamus.

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Cecilia Berg

Full Text Available The selective serotonin reuptake inhibitor (SSRI fluoxetine (FLU, Prozac® is commonly prescribed for depression in pregnant women. This results in SSRI exposure of the developing fetus. However, there are knowledge gaps regarding the impact of SSRI exposure during development. Given the role of serotonin in brain development and its cross-talk with sex hormone function, we investigated effects of developmental exposure to pharmacologically relevant concentrations of FLU (3 and 30 nM (measured on brain neurotransmitter levels, gonadal differentiation, aromatase activity in brain and gonads, and the thyroid system, using the Xenopus tropicalis model. Tadpoles were chronically exposed (8 weeks until metamorphosis. At metamorphosis brains were cryosectioned and levels of serotonin, dopamine, norepinephrine, and their metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in discrete regions (telencephalon, hypothalamus and the reticular formation of the cryosections using high-performance liquid chromatography. Exposure to 30 nM FLU increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus compared with controls. FLU exposure did not affect survival, time to metamorphosis, thyroid histology, gonadal sex differentiation, or aromatase activity implying that the effect on the serotonergic neurotransmitter system in the hypothalamus region was specific. The FLU concentration that impacted the serotonin system is lower than the concentration measured in umbilical cord serum, suggesting that the serotonin system of the developing brain is highly sensitive to in utero exposure to FLU. To our knowledge this is the first study showing effects of developmental FLU exposure on brain neurochemistry. Given that SSRIs are present in the aquatic environment the current results warrant further investigation into the neurobehavioral effects of SSRIs in aquatic wildlife.

Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder.

Science.gov (United States)

Jacobsen, Jessie C; Wilson, Callum; Cunningham, Vicki; Glamuzina, Emma; Prosser, Debra O; Love, Donald R; Burgess, Trent; Taylor, Juliet; Swan, Brendan; Hill, Rosamund; Robertson, Stephen P; Snell, Russell G; Lehnert, Klaus

2016-03-01

Two male siblings from a consanguineous union presented in early infancy with marked truncal hypotonia, a general paucity of movement, extrapyramidal signs and cognitive delay. By mid-childhood they had made little developmental progress and remained severely hypotonic and bradykinetic. They developed epilepsy and had problems with autonomic dysfunction and oculogyric crises. They had a number of orthopaedic problems secondary to their hypotonia. Cerebrospinal fluid (CSF) neurotransmitters were initially normal, apart from mildly elevated 5-hydroxyindolacetic acid, and the children did not respond favourably to a trial of levodopa-carbidopa. The youngest died from respiratory complications at 10 years of age. Repeat CSF neurotransmitters in the older sibling at eight years of age showed slightly low homovanillic acid and 5-hydroxyindoleacetic acid levels. Whole-exome sequencing revealed a novel mutation homozygous in both children in the monoamine transporter gene SLC18A2 (p.Pro237His), resulting in brain dopamine-serotonin vesicular transport disease. This is the second family to be described with a mutation in this gene. Treatment with the dopamine agonist pramipexole in the surviving child resulted in mild improvements in alertness, communication, and eye movements. This case supports the identification of the causal mutation in the original case, expands the clinical phenotype of brain dopamine-serotonin vesicular transport disease and confirms that pramipexole treatment may lead to symptomatic improvement in affected individuals.

Pharmacological manipulation of serotonin receptors during brain embryogenesis favours stress resiliency in female rats

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Gianluca Lavanco

2018-02-01

Full Text Available Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety- like phenotype. Our results show that perinatal 5- methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats, favouring the occurrence of a stress-resilient phenotype.

Action of selective serotonin reuptake inhibitor on aggressive behavior in adult rat submitted to the neonatal malnutrition

Directory of Open Access Journals (Sweden)

Medeiros Jairza Maria Barreto

2001-01-01

Full Text Available The effect of the malnutrition during suckling on the aggressiveness was investigated in adult rats treated or not with citalopram, a selective serotonin reuptake inhibitor (SSRI. The animals were divided into two groups according to the diet used: nourished group-- the rats received the control diet with 23% protein during the life; and malnourished group-- the rats had its mothers submitted to diet with 7.8% protein during suckling. At 120 days of age, each group was sub-divided according to the treatment: acute -- consisting a single i.p. injection of saline solution or 20-mg/Kg citalopram; chronic -- consisting the single injections (1 per day during 14 days of saline or 20 mg/Kg citalopram. The acute or chronic treatment with SSRI reduces aggressive response in nourished rats, but not in malnourished ones. Thus, the malnutrition during the critical period of brain development seems to induce durable alterations in the function of the serotoninergic neurotransmission

MS-377, a novel selective sigma(1) receptor ligand, reverses phencyclidine-induced release of dopamine and serotonin in rat brain.

Science.gov (United States)

Takahashi, S; Horikomi, K; Kato, T

2001-09-21

A novel selective sigma(1) receptor ligand, (R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377), inhibits phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP)-induced behaviors in animal models. In this study, we measured extracellular dopamine and serotonin levels in the rat brain after treatment with MS-377 alone, using in vivo microdialysis. We also examined the effects of MS-377 on extracellular dopamine and serotonin levels in the rat medial prefrontal cortex after treatment with PCP. MS-377 itself had no significant effects on dopamine release in the striatum (10 mg/kg, p.o.) nor on dopamine or serotonin release in the medial prefrontal cortex (1 and 10 mg/kg, p.o.). PCP (3 mg/kg, i.p.) markedly increased dopamine and serotonin release in the medial prefrontal cortex. MS-377 (1 mg/kg, p.o.), when administered 60 min prior to PCP, significantly attenuated this effect of PCP. These results suggest that the inhibitory effects of MS-377 on PCP-induced behaviors are partly mediated by inhibition of the increase in dopamine and serotonin release in the rat medial prefrontal cortex caused by PCP.

Interaction of antidepressants with the serotonin and norepinephrine transporters

DEFF Research Database (Denmark)

Sørensen, Lena; Andersen, Jacob; Thomsen, Mette

2012-01-01

The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used...

The short (S) allele of the serotonin transporter polymorphism and acute tryptophan depletion both increase impulsivity in men.

Science.gov (United States)

Walderhaug, Espen; Herman, Aryeh Isaac; Magnusson, Andres; Morgan, Michael John; Landrø, Nils Inge

2010-04-12

Reduced serotonergic neurotransmission is implicated in impulsive behavior. We studied the triallelic system of the serotonin transporter gene linked polymorphic region (5-HTTLPR) and acute manipulation of serotonin together to further delineate the mechanisms by which serotonergic neurotransmission affects impulsivity. Fifty-two healthy participants (38 men and 14 women) underwent acute tryptophan depletion (ATD) or placebo in a randomized, double-blind, parallel group experiment. Impulsive response style was measured on two versions of the Continuous Performance Task (CPT), and calculated using signal detection theory. We observed a dose-dependent effect for the short (S') allele of the 5-HTTLPR on impulsive response style. Individuals who had the S'/S' genotype were more impulsive than individuals with the L/S' genotype. Participants with the L/S' genotype were more impulsive than those with the L/L genotype. ATD increased impulsivity in men, and decreased impulsivity in women. These data demonstrate for the first time that reduced serotonergic tone as a result of either 5-HTTLPR genotype, or experimental ATD, are both independently and additively, associated with elevated impulsive response style in Caucasian men. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Mapping neurotransmitter networks with PET: an example on serotonin and opioid systems.

Science.gov (United States)

Tuominen, Lauri; Nummenmaa, Lauri; Keltikangas-Järvinen, Liisa; Raitakari, Olli; Hietala, Jarmo

2014-05-01

All functions of the human brain are consequences of altered activity of specific neural pathways and neurotransmitter systems. Although the knowledge of "system level" connectivity in the brain is increasing rapidly, we lack "molecular level" information on brain networks and connectivity patterns. We introduce novel voxel-based positron emission tomography (PET) methods for studying internal neurotransmitter network structure and intercorrelations of different neurotransmitter systems in the human brain. We chose serotonin transporter and μ-opioid receptor for this analysis because of their functional interaction at the cellular level and similar regional distribution in the brain. Twenty-one healthy subjects underwent two consecutive PET scans using [(11)C]MADAM, a serotonin transporter tracer, and [(11)C]carfentanil, a μ-opioid receptor tracer. First, voxel-by-voxel "intracorrelations" (hub and seed analyses) were used to study the internal structure of opioid and serotonin systems. Second, voxel-level opioid-serotonin intercorrelations (between neurotransmitters) were computed. Regional μ-opioid receptor binding potentials were uniformly correlated throughout the brain. However, our analyses revealed nonuniformity in the serotonin transporter intracorrelations and identified a highly connected local network (midbrain-striatum-thalamus-amygdala). Regionally specific intercorrelations between the opioid and serotonin tracers were found in anteromedial thalamus, amygdala, anterior cingulate cortex, dorsolateral prefrontal cortex, and left parietal cortex, i.e., in areas relevant for several neuropsychiatric disorders, especially affective disorders. This methodology enables in vivo mapping of connectivity patterns within and between neurotransmitter systems. Quantification of functional neurotransmitter balances may be a useful approach in etiological studies of neuropsychiatric disorders and also in drug development as a biomarker-based rationale for targeted

Serotonin 2A receptor agonist binding in the human brain with [C]Cimbi-36

DEFF Research Database (Denmark)

Ettrup, A.; da Cunha-Bang, S.; McMahon, Barry P.

2014-01-01

[C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely ....... Thus, we here describe [C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT receptors in the human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 April 2014; doi:10.1038/jcbfm.2014.68....... than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT receptors with [C]Cimbi-36 PET. The two-tissue compartment model using arterial input...

Nutrients affecting brain composition and behavior

Science.gov (United States)

Wurtman, R. J.

1987-01-01

This review examines the changes in brain composition and in various brain functions, including behavior, that can follow the ingestion of particular foods or nutrients. It details those that are best understood: the increases in serotonin, catecholamine, or acetylcholine synthesis that can occur subsequent to food-induced increases in brain levels of tryptophan, tyrosine, or choline; it also discusses the various processes that must intervene between the mouth and the synapse, so to speak, in order for a nutrient to affect neurotransmission, and it speculates as to additional brain chemicals that may ultimately be found to be affected by changes in the availability of their nutrient precursors. Because the brain chemicals best known to be nutrient dependent overlap with those thought to underlie the actions of most of the drugs used to treat psychiatric diseases, knowledge of this dependence may help the psychiatrist to understand some of the pathologic processes occurring in his/her patients, particularly those with appetitive symptoms. At the very least, such knowledge should provide the psychiatrist with objective criteria for judging when to take seriously assertions that particular foods or nutrients do indeed affect behavior (e.g., in hyperactive children). If the food can be shown to alter neurotransmitter release, it may be behaviorally-active; however, if it lacks a discernible neurochemical effect, the likelihood that it really alters behavior is small.

(-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain.

Science.gov (United States)

Knoll, J; Yoneda, F; Knoll, B; Ohde, H; Miklya, I

1999-12-01

1. The brain constituents beta-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain ('catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (-)Deprenyl (Selegiline) and (-)1-phenyl-2-propylaminopentane [(-)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property. 2. By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (-)1-(benzofuran-2-yl)-2-propylaminopentane [(-)BPAP] was selected as a potential follower of (-)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain. 3. (-)BPAP significantly enhanced in 0.18 micromol 1(-1) concentration the impulse propagation mediated release of [(3)H]-noradrenaline and [(3)H]-dopamine and in 36 nmol 1(-1) concentration the release of [(3)H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10(-12) - 10(-14) M (-)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(-14) M concentration. In rats (-)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 microg kg(-1) s.c. In the shuttle box, (-)BPAP in rats was about 130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced inhibition of performance.

Variation in serotonin neurotransmission genes affects neural activation during response inhibition in adolescents and young adults with ADHD and healthy controls

NARCIS (Netherlands)

Van Rooij, Daan; Hartman, Catharina A.; Van Donkelaar, Marjolein M. J.; Bralten, Janita; Von Rhein, Daniel; Hakobjan, Marina; Franke, Barbara; Heslenfeld, Dirk J.; Oosterlaan, Jaap; Rommelse, Nanda; Buitelaar, Jan K.; Hoekstra, Pieter J.

2015-01-01

Objectives. Deficits in response inhibition have been associated with attention-deficit/hyperactivity disorder (ADHD). Given the role of serotonin in ADHD and impulsivity, we postulated that genetic variants within the serotonin pathway might influence response inhibition. Methods. We measured

One-step preparation of [18F]FPBM for PET imaging of serotonin transporter (SERT) in the brain

International Nuclear Information System (INIS)

Qiao, Hongwen; Zhang, Yan; Wu, Zehui; Zhu, Lin; Choi, Seok Rye; Ploessl, Karl; Kung, Hank F.

2016-01-01

Serotonin transporters (SERT) in the brain play an important role in normal brain function. Selective serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, escitalopram, etc., specifically target SERT binding in the brain. Development of SERT imaging agents may be useful for studying the function of SERT by in vivo imaging. A one-step preparation of [ 18 F]FPBM, 2-(2′-(dimethylamino)methyl)-4′-(3-([ 18 F]fluoropropoxy)phenylthio) benzenamine, for positron emission tomography (PET) imaging of SERT binding in the brain was achieved. An active OTs intermediate, 9, was reacted with [ 18 F]F − /K 222 to produce [ 18 F]FPBM in one step and in high radiochemical yield. This labeling reaction was evaluated and optimized under different temperatures, bases, solvents, and varying amounts of precursor 9. The radiolabeling reaction led to the desired [ 18 F]FPBM in one step and the crude product was purified by HPLC purification to give no-carrier-added [ 18 F]FPBM (radiochemical yield, 24–33%, decay corrected; radiochemical purity > 99%). PET imaging studies in normal monkeys (n = 4) showed fast, pronounced uptakes in the midbrain and thalamus, regions known to be rich in SERT binding sites. A displacement experiment with escitalopram (5 mg/kg iv injection at 30 min after [ 18 F]FPBM injection) showed a rapid and complete reversal of SERT binding, suggesting that binding by [ 18 F]FPBM was highly specific and reversible. A one-step radiolabeling method coupled with HPLC purification for preparation of [ 18 F]FPBM was developed. Imaging studies suggest that it is feasible to use this method to prepare [ 18 F]FPBM for in vivo PET imaging of SERT binding in the brain.

Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter.

Science.gov (United States)

Neumeister, Alexander; Young, Theresa; Stastny, Juergen

2004-08-01

Serotonin systems appear to play a key role in the pathophysiology of major depressive disorder. Consequently, ongoing research determines whether serotonin related genes account for the very robust differential behavioral and neural mechanisms that discriminate patients with depression from healthy controls. Serotonin type 1(A) receptors and the serotonin transporters are reduced in depression, and recent genetic research in animals and humans has implicated both in depression. Preclinical studies have utilized a variety of animal models that have been used to explain pathophysiological mechanisms in humans, although it is not clear at all whether these models constitute relevant models for depression in humans. However, data from preclinical studies can generate hypotheses that are tested in humans by combining genetic data with behavioral and physiological challenge paradigms and neuroimaging. These studies will enhance our understanding about combined influences from multiple interacting genes, as well as from environmental factors on brain circuits and their function, and about how these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders.

Selective labeling of serotonin uptake sites in rat brain by [3H]citalopram contrasted to labeling of multiple sites by [3H]imipramine

International Nuclear Information System (INIS)

D'Amato, R.J.; Largent, B.L.; Snowman, A.M.; Snyder, S.H.

1987-01-01

Citalopram is a potent and selective inhibitor of neuronal serotonin uptake. In rat brain membranes [ 3 H]citalopram demonstrates saturable and reversible binding with a KD of 0.8 nM and a maximal number of binding sites (Bmax) of 570 fmol/mg of protein. The drug specificity for [ 3 H]citalopram binding and synaptosomal serotonin uptake are closely correlated. Inhibition of [ 3 H]citalopram binding by both serotonin and imipramine is consistent with a competitive interaction in both equilibrium and kinetic analyses. The autoradiographic pattern of [ 3 H]citalopram binding sites closely resembles the distribution of serotonin. By contrast, detailed equilibrium-saturation analysis of [ 3 H]imipramine binding reveals two binding components, i.e., high affinity (KD = 9 nM, Bmax = 420 fmol/mg of protein) and low affinity (KD = 553 nM, Bmax = 8560 fmol/mg of protein) sites. Specific [ 3 H]imipramine binding, defined as the binding inhibited by 100 microM desipramine, is displaced only partially by serotonin. Various studies reveal that the serotonin-sensitive portion of binding corresponds to the high affinity sites of [ 3 H]imipramine binding whereas the serotonin-insensitive binding corresponds to the low affinity sites. Lesioning of serotonin neurons with p-chloroamphetamine causes a large decrease in [ 3 H]citalopram and serotonin-sensitive [ 3 H]imipramine binding with only a small effect on serotonin-insensitive [ 3 H]imipramine binding. The dissociation rate of [ 3 H]imipramine or [ 3 H]citalopram is not altered by citalopram, imipramine or serotonin up to concentrations of 10 microM. The regional distribution of serotonin sensitive [ 3 H]imipramine high affinity binding sites closely resembles that of [ 3 H]citalopram binding

Enhancement of brain serotonin by long term oral administration of tryptophan produces no effect on food intake

International Nuclear Information System (INIS)

Haider, S.; Akhtar, N.; Kidwai, I.M.; Haleem, D.J.

1999-01-01

L-tryptophan (TRP) is widely used to enhance serotonin mediate brain functions. In the Present study effects of oral administration of TRP (100mg/kg) daily for 5 weeks, were investigated on the food intake, growth rate and brain indole amine metabolism in young rats. TRP ingestion significantly increased growth rate but did not alter food intake in rats. The levels of TRP and 5-hydroxytryptamine (5-HT) were higher in the hypothalamus of TRP treated rats. Increases of 5-hydroxyindole acetic acid (5-HIAA) were hot significant. TRP, 5-HT and 5-HIAA all increased in the rest of the brain of TRP treated rats. The present study shows that long term TRP administration thorough increases brain 5-ht metabolism and turnover but functional responses to 5-ht are not necessarily increases. (author)

Ketamine attenuates the glutamatergic neurotransmission in the ventral posteromedial nucleus slices of rats.

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Fu, Bao; Liu, Chengxi; Zhang, Yajun; Fu, Xiaoyun; Zhang, Lin; Yu, Tian

2017-08-23

Ketamine is a frequently used intravenous anesthetic, which can reversibly induce loss of consciousness (LOC). Previous studies have demonstrated that thalamocortical system is critical for information transmission and integration in the brain. The ventral posteromedial nucleus (VPM) is a critical component of thalamocortical system. Glutamate is an important excitatory neurotransmitter in the brain and may be involved in ketamine-induced LOC. The study used whole-cell patch-clamp to observe the effect of ketamine (30 μM-1000 μM) on glutamatergic neurotransmission in VPM slices. Ketamine significantly decreased the amplitude of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs), but only higher concentration of ketamine (300 μM and 1000 μM) suppressed the frequency of sEPSCs. Ketamine (100 μM-1000 μM) also decreased the amplitude of glutamatergic miniature excitatory postsynaptic currents (mEPSCs), without altering the frequency. In VPM neurons, ketamine attenuates the glutamatergic neurotransmission mainly through postsynaptic mechanism and action potential may be involved in the process.

BDNF val66met association with serotonin transporter binding in healthy humans

DEFF Research Database (Denmark)

Fisher, P. M.; Ozenne, B.; Svarer, C.

2017-01-01

The serotonin transporter (5-HTT) is a key feature of the serotonin system, which is involved in behavior, cognition and personality and implicated in neuropsychiatric illnesses including depression. The brain-derived neurotrophic factor (BDNF) val66met and 5-HTTLPR polymorphisms have predicted......-carriers have increased subcortical 5-HTT binding. The small difference suggests limited statistical power may explain previously reported null effects. Our finding adds to emerging evidence that BDNF val66met contributes to differences in the human brain serotonin system, informing how variability in the 5-HTT...

Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder

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Hauser Michael A

2011-05-01

Full Text Available Abstract Background Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD. Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4 have been shown to modulate amygdala and prefrontal cortex (PFC activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined. Methods We investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531 and several downstream single nucleotide polymorphisms (SNPs modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22 and a trauma-exposed control group (n = 20 in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed-response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants. Results In patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD. Conclusions The SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify

A neural population model incorporating dopaminergic neurotransmission during complex voluntary behaviors.

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Stefan Fürtinger

2014-11-01

Full Text Available Assessing brain activity during complex voluntary motor behaviors that require the recruitment of multiple neural sites is a field of active research. Our current knowledge is primarily based on human brain imaging studies that have clear limitations in terms of temporal and spatial resolution. We developed a physiologically informed non-linear multi-compartment stochastic neural model to simulate functional brain activity coupled with neurotransmitter release during complex voluntary behavior, such as speech production. Due to its state-dependent modulation of neural firing, dopaminergic neurotransmission plays a key role in the organization of functional brain circuits controlling speech and language and thus has been incorporated in our neural population model. A rigorous mathematical proof establishing existence and uniqueness of solutions to the proposed model as well as a computationally efficient strategy to numerically approximate these solutions are presented. Simulated brain activity during the resting state and sentence production was analyzed using functional network connectivity, and graph theoretical techniques were employed to highlight differences between the two conditions. We demonstrate that our model successfully reproduces characteristic changes seen in empirical data between the resting state and speech production, and dopaminergic neurotransmission evokes pronounced changes in modeled functional connectivity by acting on the underlying biological stochastic neural model. Specifically, model and data networks in both speech and rest conditions share task-specific network features: both the simulated and empirical functional connectivity networks show an increase in nodal influence and segregation in speech over the resting state. These commonalities confirm that dopamine is a key neuromodulator of the functional connectome of speech control. Based on reproducible characteristic aspects of empirical data, we suggest a number

Effects of fluoxetine on the rat brain in the forced swimming test: a [F-18]FDG micro-PET imaging study.

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Jang, Dong-Pyo; Lee, So-Hee; Park, Chan-Woong; Lee, Sang-Yoon; Kim, Young-Bo; Cho, Zang-Hee

2009-02-13

We used the [F-18]FDG micro-PET neuroimaging to examine the effects of fluoxetine on brain activity in rats and on their behavioral response in the forced swimming test (FST). In the first experiment, the rats were administered doses of fluoxetine (10 or 20mg/kg) 24, 19 and 1h before the rat brains were scanned. Fluoxetine induced strong activation of the dorsal hippocampus and the deactivation of the inferior colliculus, medulla oblongata, and prelimbic cortex in a dose-dependent manner. These results seemed to be related with the changes in 5-HT (5-hydroxytryptamine, serotonin) levels after selective serotonin reuptake-inhibitor treatments. In the second experiment, the changes in glucose metabolism in the test session were measured after fluoxetine was given between pre-test and test sessions of the FST. Fluoxetine administration significantly decreased immobility behavior compared with saline administration. At the same time, the activity of the insular/piriform cortex decreased significantly. In contrast, the extent of cerebellar activation increased. The glucose metabolism of the dorsal hippocampus also increased, which suggests that post-stress changes in the facilitation of hippocampal serotonergic neurotransmission lead to decreased immobilization in the FST.

Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal-glial networks

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Kjell eFuxe

2012-06-01

Full Text Available Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT and histamine striatal afferents, the cholinergic interneurons and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal

Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice.

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Yuan, Zhi-Xin; Rapoport, Stanley I

2015-10-01

Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). Brain 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. Male mice pups were injected i.p. daily with fluoxetine (10mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. Published by Elsevier Ltd.

The gastrointestinal-brain axis in humans as an evolutionary advance of the root-leaf axis in plants: A hypothesis linking quantum effects of light on serotonin and auxin.

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Tonello, Lucio; Gashi, Bekim; Scuotto, Alessandro; Cappello, Glenda; Cocchi, Massimo; Gabrielli, Fabio; Tuszynski, Jack A

2018-01-01

Living organisms tend to find viable strategies under ambient conditions that optimize their search for, and utilization of, life-sustaining resources. For plants, a leading role in this process is performed by auxin, a plant hormone that drives morphological development, dynamics, and movement to optimize the absorption of light (through branches and leaves) and chemical "food" (through roots). Similarly to auxin in plants, serotonin seems to play an important role in higher animals, especially humans. Here, it is proposed that morphological and functional similarities between (i) plant leaves and the animal/human brain and (ii) plant roots and the animal/human gastro-intestinal tract have general features in common. Plants interact with light and use it for biological energy, whereas, neurons in the central nervous system seem to interact with bio-photons and use them for proper brain function. Further, as auxin drives roots "arborescence" within the soil, similarly serotonin seems to facilitate enteric nervous system connectivity within the human gastro-intestinal tract. This auxin/serotonin parallel suggests the root-branches axis in plants may be an evolutionary precursor to the gastro-intestinal-brain axis in humans. Finally, we hypothesize that light might be an important factor, both in gastro-intestinal dynamics and brain function. Such a comparison may indicate a key role for the interaction of light and serotonin in neuronal physiology (possibly in both the central nervous system and the enteric nervous system), and according to recent work, mind and consciousness.

Chemical and radiological effects of chronic ingestion of uranium in the rat brain: biochemical impairment of dopaminergic, serotonergic and cholinergic neuro-transmissions

International Nuclear Information System (INIS)

Bussy, C.

2005-09-01

Uranium is an environmental ubiquitous metal-trace element. It has both chemical and radiological toxicity. After chronic ingestion, uranium can distribute in any part of the body and accumulate in the brain. The aims of this study was 1) to determine and estimate the effects of uranium on dopaminergic, serotoninergic and cholinergic systems and 2) to measure the uranium amount in the brain, after chronic exposure by ingestion of depleted (D.U.) or enriched (E.U.) uranium during 1.5 to 18 months at 40 mg.L -1 (40 ppm) in different rat brain areas. At any time of exposure, the results show that both the neurotransmission alterations and the uranium brain accumulation were moderate, area specific, time-evolutive and depended on uranium specific activity. After D.U. exposure, monoamine perturbations are chronic and progressive. On the contrary, monoamine alterations occurred only after long term of E.U. exposure. These mono-aminergic modifications are not always dependent on uranium accumulation in brain areas. Moreover, although the cholinergic system was not affected at both 1.5 and 9 months of D.U. exposure, the alteration of ChE activity after E.U. exposure are both dependent on uranium accumulation in brain areas and on uranium specific activity. After E.U. exposure, cholinergic modification and uranium accumulation in hippocampus could partially explain the short-term memory disturbances which have been previously reported. (author)

Involvement of high plasma corticosterone status and activation of brain regional serotonin metabolism in long-term erythrosine-induced rearing motor hyper activity in young adult male rats.

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Dalal, Arindam; Poddar, Mrinal K

2010-07-01

Long-term consumption of artificial food color(s) can induce behavioral hyperactivity in human and experimental animals, but no neurobiochemical mechanism is defined. This study investigates the role of brain regional serotonin metabolism including its turnover, MAO-A activity, and plasma corticosterone status in relation to behavioral disturbances due to an artificial food color, erythrosine. Long-term (15 or 30 consecutive days) erythrosine administration with higher dosage (10 or 100 mg/kg/day, p.o.) produced optimal hyperactive state in exploratory behavior (rearing motor activity) after 2 h of last erythrosine administration, in young adult male albino rats. Erythrosine-induced stimulation in brain regional (medulla-pons, hypothalamus, hippocampus, and corpus striatum) serotonin metabolism (measuring steady state levels of 5-HT and 5-HIAA, MAO-A activity), including its turnover (pargyline-induced 5-HT accumulation and 5-HIAA declination rate), as well as plasma corticosterone were also observed depending on dosage(s) and duration(s) of erythrosine administration under similar experimental conditions. The lower dosage of erythrosine (1 mg/kg/day, p.o.) under similar conditions did not affect either of the above. These findings suggests (a) the induction as well as optimal effect of long-term erythrosine (artificial food color) on behavioral hyperactivity in parallel with increase in 5-HT level in brain regions, (b) the activation of brain regional serotonin biosynthesis in accordance with plasma corticosterone status under such behavioral hyperactivity, and (c) a possible inhibitory influence of the enhanced glucocorticoids-serotonin interaction on erythrosine-induced rearing motor hyperactivity in young adult mammals.

Serotonin transporter and dopamine transporter imaging in the canine brain

International Nuclear Information System (INIS)

Peremans, Kathelijne; Goethals, Ingeborg; De Vos, Filip; Dobbeleir, A.; Ham, Hamphrey; Van Bree, Henri; Heeringen, Cees van; Audenaert, Kurt

2006-01-01

The serotonergic and dopaminergic systems are involved in a wide range of emotional and behavioral aspects of animals and humans and are involved in many neuropsychiatric disorders. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are designed to block the 5-HT transporter (SERT), thereby increasing the available 5-HT in the brain. Functional imaging with specific SERT and dopamine transporter (DAT) ligands contributes to the study of the SSRI-transporter interaction. First, we evaluated the feasibility of a canine model in the study of the SERT and DAT with the radioligands [ 123 I]-β-CIT and [ 123 I]-FP-CIT as well as single-photon emission computed tomography imaging. Second, we studied the effect of SSRIs (sertraline, citalopram and escitalopram) on the SERT and DAT in two dogs. The position of the canine model in the study of the SERT and DAT is discussed and compared with other animal models

No effect of C1473G polymorphism in the tryptophan hydroxylase 2 gene on the response of the brain serotonin system to chronic fluoxetine treatment in mice.

Science.gov (United States)

Bazhenova, Ekaterina Y; Sinyakova, Nadezhda A; Kulikova, Elizabeth A; Kazarinova, Irina A; Bazovkina, Daria V; Gainetdinov, Raul R; Kulikov, Alexander V

2017-07-13

Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that block serotonin transporter (SERT) and increase serotonin (5-HT) level in the synaptic cleft. The interaction between SERT and the key enzyme of 5-HT synthesis in the brain, tryptophan hydroxylase 2 (TPH2), is essential to maintain the brain 5-HT level. The G allele of C1473G polymorphism in Tph2 gene decreases enzyme activity by half in mouse brain. Here we studied effect of C1473G polymorphism on the reaction of brain 5-HT system to chronic fluoxetine treatment (120mg/l in drinking water, for 3 weeks) in adult males of the congenic B6-1473C and B6-1473G mouse lines with high and low enzyme activity, respectively. The polymorphism did not affect the levels of 5-HT, its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and Tph2 gene mRNA in the brain. Fluoxetine significantly attenuated 5-HT levels in the cortex and striatum, 5-HIAA concentrations in the cortex, hippocampus, striatum and midbrain, and Tph2 gene expression in the midbrain. However, we did not observed any effect of the genotype x treatment interaction on these neurochemical characteristics. Therefore, C1473G polymorphism does not seem to play an essential role in the reaction of the brain 5-HT system to chronic fluoxetine treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

A PET study of effects of chronic 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") on serotonin markers in Göttingen minipig brain

DEFF Research Database (Denmark)

Cumming, Paul; Møller, Mette; Benda, Kjeld

2007-01-01

The psychostimulant 3,4-methylendioxymethamphetamine (MDMA, "ecstasy") evokes degeneration of telencephalic serotonin innervations in rodents, nonhuman primates, and human recreational drug users. However, there has been no alternative to nonhuman primates for studies of the cognitive and neuroch......The psychostimulant 3,4-methylendioxymethamphetamine (MDMA, "ecstasy") evokes degeneration of telencephalic serotonin innervations in rodents, nonhuman primates, and human recreational drug users. However, there has been no alternative to nonhuman primates for studies of the cognitive...... with MDMA (i.m.), administered at a range of doses. In parallel PET studies, [(11)C]WAY-100635 was used to map the distribution of serotonin 5HT(1A) receptors. The acute MDMA treatment in awake pigs evoked 1 degrees C of hyperthermia. MDMA at total doses greater than 20 mg/kg administered over 2-4 days...... reduced the binding potential (pB) of [(11)C]DASB for serotonin transporters in porcine brain. A mean total dose of 42 mg/kg MDMA in four animals evoked a mean 32% decrease in [(11)C]DASB pB in mesencephalon and diencephalon, and a mean 53% decrease in telencephalic structures. However, this depletion...

Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality.

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Heresco-Levy, Uriel

2003-10-01

this area is bound to bring about a better understanding of the role of glutamatergic neurotransmission manipulation in the pharmacotherapy of psychosis and the development of novel pharmacological strategies targeting GLU brain systems.

Spatial cluster analysis of nanoscopically mapped serotonin receptors for classification of fixed brain tissue

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Sams, Michael; Silye, Rene; Göhring, Janett; Muresan, Leila; Schilcher, Kurt; Jacak, Jaroslaw

2014-01-01

We present a cluster spatial analysis method using nanoscopic dSTORM images to determine changes in protein cluster distributions within brain tissue. Such methods are suitable to investigate human brain tissue and will help to achieve a deeper understanding of brain disease along with aiding drug development. Human brain tissue samples are usually treated postmortem via standard fixation protocols, which are established in clinical laboratories. Therefore, our localization microscopy-based method was adapted to characterize protein density and protein cluster localization in samples fixed using different protocols followed by common fluorescent immunohistochemistry techniques. The localization microscopy allows nanoscopic mapping of serotonin 5-HT1A receptor groups within a two-dimensional image of a brain tissue slice. These nanoscopically mapped proteins can be confined to clusters by applying the proposed statistical spatial analysis. Selected features of such clusters were subsequently used to characterize and classify the tissue. Samples were obtained from different types of patients, fixed with different preparation methods, and finally stored in a human tissue bank. To verify the proposed method, samples of a cryopreserved healthy brain have been compared with epitope-retrieved and paraffin-fixed tissues. Furthermore, samples of healthy brain tissues were compared with data obtained from patients suffering from mental illnesses (e.g., major depressive disorder). Our work demonstrates the applicability of localization microscopy and image analysis methods for comparison and classification of human brain tissues at a nanoscopic level. Furthermore, the presented workflow marks a unique technological advance in the characterization of protein distributions in brain tissue sections.

BDNF Val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels

DEFF Research Database (Denmark)

Fisher, Patrick M; Holst, Klaus K; Adamsen, Dea

2015-01-01

) polymorphism. We applied a linear latent variable model (LVM) using regional 5-HT4 binding values (neocortex, amygdala, caudate, hippocampus, and putamen) from 68 healthy humans, allowing us to explicitly model brain-wide and region-specific genotype effects on 5-HT4 binding. Our data supported an LVM wherein...... specifically affects 5-HT4 binding in the neocortex. These findings implicate serotonin signaling as an important molecular mediator underlying the effects of BDNF val66met and 5-HTTLPR on behavior and related risk for neuropsychiatric illness in humans. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc....

Effect of intranasal manganese administration on neurotransmission and spatial learning in rats

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Blecharz-Klin, Kamilla; Piechal, Agnieszka; Joniec-Maciejak, Ilona; Pyrzanowska, Justyna; Widy-Tyszkiewicz, Ewa, E-mail: etyszkiewicz@wum.edu.pl

2012-11-15

The effect of intranasal manganese chloride (MnCl{sub 2}·4H{sub 2}O) exposure on spatial learning, memory and motor activity was estimated in Morris water maze task in adult rats. Three-month-old male Wistar rats received for 2 weeks MnCl{sub 2}·4H{sub 2}O at two doses the following: 0.2 mg/kg b.w. (Mn0.2) or 0.8 mg/kg b.w. (Mn0.8) per day. Control (Con) and manganese-exposed groups were observed for behavioral performance and learning in water maze. ANOVA for repeated measurements did not show any significant differences in acquisition in the water maze between the groups. However, the results of the probe trial on day 5, exhibited spatial memory deficits following manganese treatment. After completion of the behavioral experiment, the regional brain concentrations of neurotransmitters and their metabolites were determined via HPLC in selected brain regions, i.e. prefrontal cortex, hippocampus and striatum. ANOVA demonstrated significant differences in the content of monoamines and metabolites between the treatment groups compared to the controls. Negative correlations between platform crossings on the previous platform position in Southeast (SE) quadrant during the probe trial and neurotransmitter turnover suggest that impairment of spatial memory and cognitive performance after manganese (Mn) treatment is associated with modulation of the serotonergic, noradrenergic and dopaminergic neurotransmission in the brain. These findings show that intranasally applied Mn can impair spatial memory with significant changes in the tissue level and metabolism of monoamines in several brain regions. -- Highlights: ► Intranasal exposure to manganese in rats impairs spatial memory in the water maze. ► Regional changes in levels of neurotransmitters in the brain have been identified. ► Cognitive disorder correlates with modulation of 5-HT, NA and DA neurotransmission.

Effect of intranasal manganese administration on neurotransmission and spatial learning in rats

International Nuclear Information System (INIS)

Blecharz-Klin, Kamilla; Piechal, Agnieszka; Joniec-Maciejak, Ilona; Pyrzanowska, Justyna; Widy-Tyszkiewicz, Ewa

2012-01-01

The effect of intranasal manganese chloride (MnCl 2 ·4H 2 O) exposure on spatial learning, memory and motor activity was estimated in Morris water maze task in adult rats. Three-month-old male Wistar rats received for 2 weeks MnCl 2 ·4H 2 O at two doses the following: 0.2 mg/kg b.w. (Mn0.2) or 0.8 mg/kg b.w. (Mn0.8) per day. Control (Con) and manganese-exposed groups were observed for behavioral performance and learning in water maze. ANOVA for repeated measurements did not show any significant differences in acquisition in the water maze between the groups. However, the results of the probe trial on day 5, exhibited spatial memory deficits following manganese treatment. After completion of the behavioral experiment, the regional brain concentrations of neurotransmitters and their metabolites were determined via HPLC in selected brain regions, i.e. prefrontal cortex, hippocampus and striatum. ANOVA demonstrated significant differences in the content of monoamines and metabolites between the treatment groups compared to the controls. Negative correlations between platform crossings on the previous platform position in Southeast (SE) quadrant during the probe trial and neurotransmitter turnover suggest that impairment of spatial memory and cognitive performance after manganese (Mn) treatment is associated with modulation of the serotonergic, noradrenergic and dopaminergic neurotransmission in the brain. These findings show that intranasally applied Mn can impair spatial memory with significant changes in the tissue level and metabolism of monoamines in several brain regions. -- Highlights: ► Intranasal exposure to manganese in rats impairs spatial memory in the water maze. ► Regional changes in levels of neurotransmitters in the brain have been identified. ► Cognitive disorder correlates with modulation of 5-HT, NA and DA neurotransmission.

Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods

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Claudia eBarth

2015-02-01

Full Text Available Sex hormones have been implicated in neurite outgrowth, synaptogenesis, dendritic branching, myelination and other important mechanisms of neural plasticity. Here we review the evidence from animal experiments and human studies reporting interactions between sex hormones and the dominant neurotransmitters, such as serotonin, dopamine, GABA and glutamate. We provide an overview of accumulating data during physiological and pathological conditions and discuss currently conceptualized theories on how sex hormones potentially trigger neuroplasticity changes through these four neurochemical systems. Many brain regions have been demonstrated to express high densities for estrogen- and progesterone receptors, such as the amygdala, the hypothalamus, and the hippocampus. As the hippocampus is of particular relevance in the context of mediating structural plasticity in the adult brain, we put particular emphasis on what evidence could be gathered thus far that links differences in behavior, neurochemical patterns and hippocampal structure to a changing hormonal environment. Finally, we discuss how physiologically occurring hormonal transition periods in humans can be used to model how changes in sex hormones influence functional connectivity, neurotransmission and brain structure in vivo.

The importance of serotonin in the gastrointestinal tract

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Jarosław Koza

2017-12-01

Description of the current knowledge and conclusions. Serotonin is responsible for some symptoms of carcinoid syndrome. It is the result of higher 5-hydroxytryptamine content in the body. Moreover disrupted serotonin system is found in different gastrointestinal disorders e.g. in gastroesophageal reflux disease, functional heartburn, hypersensitive esophagus, functional dyspepsia, irritable bowel syndrome (both diarrhoea predominant and constipation predominant as well as in inflammatory bowel diseases. Knowledge of changed mechanisms in particular diseases facilitates the optimal choice of treatment. Drugs affecting the serotonin system in gastroenterological clinical practice are useful especially in the case of abnormalities in the brain - gut axis.

Serotonin transporter and dopamine transporter imaging in the canine brain

Energy Technology Data Exchange (ETDEWEB)

Peremans, Kathelijne [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Goethals, Ingeborg [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); De Vos, Filip [Laboratory of Radiopharmacy, Pharmaceutical Sciences, Ghent University, B-9000 Ghent (Belgium); Dobbeleir, A. [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Ham, Hamphrey [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); Van Bree, Henri [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Heeringen, Cees van [Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium); Audenaert, Kurt [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium) and Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium)]. E-mail: kurt.audenaert@ugent.be

2006-10-15

The serotonergic and dopaminergic systems are involved in a wide range of emotional and behavioral aspects of animals and humans and are involved in many neuropsychiatric disorders. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are designed to block the 5-HT transporter (SERT), thereby increasing the available 5-HT in the brain. Functional imaging with specific SERT and dopamine transporter (DAT) ligands contributes to the study of the SSRI-transporter interaction. First, we evaluated the feasibility of a canine model in the study of the SERT and DAT with the radioligands [{sup 123}I]-{beta}-CIT and [{sup 123}I]-FP-CIT as well as single-photon emission computed tomography imaging. Second, we studied the effect of SSRIs (sertraline, citalopram and escitalopram) on the SERT and DAT in two dogs. The position of the canine model in the study of the SERT and DAT is discussed and compared with other animal models.

Brain Aromatase Modulates Serotonergic Neuron by Regulating Serotonin Levels in Zebrafish Embryos and Larvae

Directory of Open Access Journals (Sweden)

Zulvikar Syambani Ulhaq

2018-05-01

Full Text Available Teleost fish are known to express two isoforms of P450 aromatase, a key enzyme for estrogen synthesis. One of the isoforms, brain aromatase (AroB, cyp19a1b, is highly expressed during early development of zebrafish, thereby suggesting its role in brain development. On the other hand, early development of serotonergic neuron, one of the major monoamine neurons, is considered to play an important role in neurogenesis. Therefore, in this study, we investigated the role of AroB in development of serotonergic neuron by testing the effects of (1 estradiol (E2 exposure and (2 morpholino (MO-mediated AroB knockdown. When embryos were exposed to E2, the effects were biphasic. The low dose of E2 (0.005 µM significantly increased serotonin (5-HT positive area at 48 hour post-fertilization (hpf detected by immunohistochemistry and relative mRNA levels of tryptophan hydroxylase isoforms (tph1a, tph1b, and tph2 at 96 hpf measured by semi-quantitative PCR. To test the effects on serotonin transmission, heart rate and thigmotaxis, an indicator of anxiety, were analyzed. The low dose also significantly increased heart rate at 48 hpf and decreased thigmotaxis. The high dose of E2 (1 µM exhibited opposite effects in all parameters. The effects of both low and high doses were reversed by addition of estrogen receptor (ER blocker, ICI 182,780, thereby suggesting that the effects were mediated through ER. When AroB MO was injected to fertilized eggs, 5-HT-positive area was significantly decreased, while the significant decrease in relative tph mRNA levels was found only with tph2 but not with two other isoforms. AroB MO also decreased heart rate and increased thigmotaxis. All the effects were rescued by co-injection with AroB mRNA and by exposure to E2. Taken together, this study demonstrates the role of brain aromatase in development of serotonergic neuron in zebrafish embryos and larvae, implying that brain-formed estrogen is an important factor to

Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

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Patrick, Rhonda P; Ames, Bruce N

2014-06-01

Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder. © FASEB.

The postirradiation effect of noradrenaline, serotonin and dopamine on Na-K-pump activity in rat brain sections

International Nuclear Information System (INIS)

Dvoretskij, A.I.; Kulikova, I.A.

1993-01-01

Whole-body X-irradiation with doses of 0.155 and 0.310 C/kg was shown to modify in different ways the activating effects of noradrenaline and serotonin, as well as a biphase effect of dopamine of neuronal membranes. The resulting effect was a function of a combination of radiation doses and neurotransmitter concentrations and thus showed different modes of interaction between neurotransmitter and ion-transport systems of brain cells in radiation sickness

Serotonin transporter (SERT and translocator protein (TSPO expression in the obese ob/ob mouse

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Santini Ferruccio

2011-02-01

Full Text Available Abstract Background An ever growing body of evidences is emerging concerning metabolism hormones, neurotransmitters or stress-related biomarkers as effective modulators of eating behavior and body weight in mammals. The present study sought at examining the density and affinity of two proteins related to neurotransmission and cell metabolism, the serotonin transporter SERT and the cholesterol import-benzodiazepine site TSPO (translocator protein, in a rodent leptin-lacking mutant, the obese ob/ob mouse. Binding studies were thus carried out in brain or peripheral tissues, blood platelets (SERT and kidneys (TSPO, of ob/ob and WT mice supplied with a standard diet, using the selective radiochemical ligands [3H]-paroxetine and [3H]-PK11195. Results We observed comparable SERT number or affinity in brain and platelets of ob/ob and WT mice, whilst a significantly higher [3H]-PK11195 density was reported in the brain of ob/ob animals. TSPO binding parameters were similar in the kidneys of all tested mice. By [3H]-PK11195 autoradiography of coronal hypothalamic-hippocampal sections, an increased TSPO signal was detected in the dentate gyrus (hippocampus and choroids plexus of ob/ob mice, without appreciable changes in the cortex or hypothalamic-thalamic regions. Conclusions These findings show that TSPO expression is up-regulated in cerebral regions of ob/ob leptin-deficient mice, suggesting a role of the translocator protein in leptin-dependent CNS trophism and metabolism. Unchanged SERT in mutant mice is discussed herein in the context of previous literature as the forerunner to a deeper biochemical investigation.

Action potential-independent and pharmacologically unique vesicular serotonin release from dendrites

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Colgan, Lesley A.; Cavolo, Samantha L.; Commons, Kathryn G.; Levitan, Edwin S.

2012-01-01

Serotonin released within the dorsal raphe nucleus (DR) induces feedback inhibition of serotonin neuron activity and consequently regulates mood-controlling serotonin release throughout the forebrain. Serotonin packaged in vesicles is released in response to action potentials by the serotonin neuron soma and terminals, but the potential for release by dendrites is unknown. Here three-photon (3P) microscopy imaging of endogenous serotonin in living rat brain slice, immunofluorescence and immuno-gold electron microscopy detection of VMAT2 (vesicular monoamine transporter 2) establish the presence of vesicular serotonin within DR dendrites. Furthermore, activation of glutamate receptors is shown to induce vesicular serotonin release from dendrites. However, unlike release from the soma and terminals, dendritic serotonin release is independent of action potentials, relies on L-type Ca2+ channels, is induced preferentially by NMDA, and displays distinct sensitivity to the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. The unique control of dendritic serotonin release has important implications for DR physiology and the antidepressant action of SSRIs, dihydropyridines and NMDA receptor antagonists. PMID:23136413

In vivo quantification by SPECT of [123I] ADAM bound to serotonin transporters in the brains of rabbits

International Nuclear Information System (INIS)

Ye, X.-X.; Hwang, J.-J.; Hsieh, J.-F.; Chen, J.-C.; Chou, Y.-T.; Tu, K.-Y.; Wey, S.-P.; Ting Gann

2004-01-01

Background: A novel radioiodine ligand [ 123 I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [ 123 I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. Methods: SPECT imaging was performed on female rabbits postinjection of 185 MBq [ 123 I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [ 123 I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. Results: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89±0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [ 123 I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. Conclusion: SPECT imaging of the rabbit brain with [ 123 I] ADAM showed

(−)1-(Benzofuran-2-yl)-2-propylaminopentane, [(−)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain

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Knoll, Joseph; Yoneda, Fumio; Knoll, Berta; Ohde, Hironori; Miklya, Ildikó

1999-01-01

The brain constituents β-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain (‘catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (−)Deprenyl (Selegiline) and (−)1-phenyl-2-propylaminopentane [(−)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property.By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (−)1-(benzofuran-2-yl)-2-propylaminopentane [(−)BPAP] was selected as a potential follower of (−)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain.(−)BPAP significantly enhanced in 0.18 μmol 1−1 concentration the impulse propagation mediated release of [3H]-noradrenaline and [3H]-dopamine and in 36 nmol 1−1 concentration the release of [3H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10−12–10−14 M (−)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of β-amyloid in 10−14 M concentration. In rats (−)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 μg kg−1 s.c. In the shuttle box, (−)BPAP in rats was about 130 times more potent than (−)deprenyl in antagonizing tetrabenazine induced inhibition of performance. PMID:10588928

Peripheral Serotonin: a New Player in Systemic Energy Homeostasis

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Namkung, Jun; Kim, Hail; Park, Sangkyu

2015-01-01

Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment. PMID:26628041

Serotonin: A mediator of the gut-brain axis in multiple sclerosis.

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Malinova, Tsveta S; Dijkstra, Christine D; de Vries, Helga E

2017-11-01

The significance of the gut microbiome for the pathogenesis of multiple sclerosis (MS) has been established, although the underlying signaling mechanisms of this interaction have not been sufficiently explored. We address this point and use serotonin (5-hydroxytryptamine (5-HT))-a microbial-modulated neurotransmitter (NT) as a showcase to demonstrate that NTs regulated by the gut microbiome are potent candidates for mediators of the gut-brain axis in demyelinating disorders. Methods, Results, and Conclusion: Our comprehensive overview of literature provides evidence that 5-HT levels in the gut are controlled by the microbiome, both via secretion and through regulation of metabolites. In addition, we demonstrate that the gut microbiome can influence the formation of the serotonergic system (SS) in the brain. We also show that SS alterations have been related to MS directly-altered expression of 5-HT transporters in central nervous system (CNS) and indirectly-beneficial effects of 5-HT modulating drugs on the course of the disease and higher prevalence of depression in patients with MS. Finally, we discuss briefly the role of other microbiome-modulated NTs such as γ-aminobutyric acid and dopamine in MS to highlight a new direction for future research aiming to relate microbiome-regulated NTs to demyelinating disorders.

Inhibition of serotonin transport by (+)McN5652 is noncompetitive

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Hummerich, Rene [Biochemical Laboratory, Central Institute of Mental Health, 68159 Mannheim (Germany); Schulze, Oliver [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Raedler, Thomas [Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Mikecz, Pal [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Reimold, Matthias [Department of Nuclear Medicine, University Hospital Tuebingen, D-72076 Tuebingen (Germany); Brenner, Winfried [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Clausen, Malte [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Schloss, Patrick [Biochemical Laboratory, Central Institute of Mental Health, 68159 Mannheim (Germany); Buchert, Ralph [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany)]. E-mail: buchert@uke.uni-hamburg.de

2006-04-15

Introduction: Imaging of the serotonergic innervation of the brain using positron emission tomography (PET) with the serotonin transporter (SERT) ligand [{sup 11C}] (+)McN5652 might be affected by serotonin in the synaptic cleft if there is relevant interaction between [{sup 11}C] (+)McN5652 and serotonin at the SERT. The aim of the present study therefore was to pharmacologically characterize the interaction of [{sup 11}C] (+)McN5652 and serotonin at the SERT. Methods: In vitro saturation analyses of [{sup 3}H]serotonin uptake into HEK293 cells stably expressing the human SERT were performed in the absence and presence of unlabelled (+)McN5652. Data were evaluated assuming Michaelis-Menten kinetics. Results: Unlabelled (+)McN5652 significantly reduced the maximal rate of serotonin transport V {sub max} of SERT without affecting the Michaelis-Menten constant K {sub M}. Conclusions: This finding indicates that (+)McN5652 inhibits serotonin transport through the SERT in a noncompetitive manner. This might suggest that [{sup 11}C] (+)McN5652 PET is not significantly affected by endogenous serotonin.

Inhibition of serotonin transport by (+)McN5652 is noncompetitive

International Nuclear Information System (INIS)

Hummerich, Rene; Schulze, Oliver; Raedler, Thomas; Mikecz, Pal; Reimold, Matthias; Brenner, Winfried; Clausen, Malte; Schloss, Patrick; Buchert, Ralph

2006-01-01

Introduction: Imaging of the serotonergic innervation of the brain using positron emission tomography (PET) with the serotonin transporter (SERT) ligand [ 11C ] (+)McN5652 might be affected by serotonin in the synaptic cleft if there is relevant interaction between [ 11 C] (+)McN5652 and serotonin at the SERT. The aim of the present study therefore was to pharmacologically characterize the interaction of [ 11 C] (+)McN5652 and serotonin at the SERT. Methods: In vitro saturation analyses of [ 3 H]serotonin uptake into HEK293 cells stably expressing the human SERT were performed in the absence and presence of unlabelled (+)McN5652. Data were evaluated assuming Michaelis-Menten kinetics. Results: Unlabelled (+)McN5652 significantly reduced the maximal rate of serotonin transport V max of SERT without affecting the Michaelis-Menten constant K M . Conclusions: This finding indicates that (+)McN5652 inhibits serotonin transport through the SERT in a noncompetitive manner. This might suggest that [ 11 C] (+)McN5652 PET is not significantly affected by endogenous serotonin

Synthesis and evaluation of racemic [11C]NS2456 and its enantiomers as selective serotonin reuptake radiotracers for PET

International Nuclear Information System (INIS)

Smith, D.F.; Bender, D.; Marthi, K.; Cumming, P.; Hansen, S.B.; Peters, D.; Oestergaard Nielsen, E.; Scheel-Krueger, J.; Gjedde, A.

2001-01-01

Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1RS,5SR)-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes; their IC 50 values were 3000-fold lower for [ 3 H]serotonin than for either [ 3 H]dopamine or [ 3 H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N-methylation with C-11, yielding [ 11 C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood-brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [ 11 C]NS2456 nor its [ 11 C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites

Serotonin Modulation of Prefronto-Hippocampal Rhythms in Health and Disease.

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Puig, M Victoria; Gener, Thomas

2015-07-15

There is mounting evidence that most cognitive functions depend upon the coordinated activity of neuronal networks often located far from each other in the brain. Ensembles of neurons synchronize their activity, generating oscillations at different frequencies that may encode behavior by allowing an efficient communication between brain areas. The serotonin system, by virtue of the widespread arborisation of serotonergic neurons, is in an excellent position to exert strong modulatory actions on brain rhythms. These include specific oscillatory activities in the prefrontal cortex and the hippocampus, two brain areas essential for many higher-order cognitive functions. Psychiatric patients show abnormal oscillatory activities in these areas, notably patients with schizophrenia who display psychotic symptoms as well as affective and cognitive impairments. Synchronization of neural activity between the prefrontal cortex and the hippocampus seems to be important for cognition and, in fact, reduced prefronto-hippocampal synchrony has been observed in a genetic mouse model of schizophrenia. Here, we review recent advances in the field of neuromodulation of brain rhythms by serotonin, focusing on the actions of serotonin in the prefrontal cortex and the hippocampus. Considering that the serotonergic system plays a crucial role in cognition and mood and is a target of many psychiatric treatments, it is surprising that this field of research is still in its infancy. In that regard, we point to future investigations that are much needed in this field.

The influence of serotonin on fear learning.

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Catherine Hindi Attar

Full Text Available Learning of associations between aversive stimuli and predictive cues is the basis of Pavlovian fear conditioning and is driven by a mismatch between expectation and outcome. To investigate whether serotonin modulates the formation of such aversive cue-outcome associations, we used functional magnetic resonance imaging (fMRI and dietary tryptophan depletion to reduce brain serotonin (5-HT levels in healthy human subjects. In a Pavlovian fear conditioning paradigm, 5-HT depleted subjects compared to a non-depleted control group exhibited attenuated autonomic responses to cues indicating the upcoming of an aversive event. These results were closely paralleled by reduced aversive learning signals in the amygdala and the orbitofrontal cortex, two prominent structures of the neural fear circuit. In agreement with current theories of serotonin as a motivational opponent system to dopamine in fear learning, our data provide first empirical evidence for a role of serotonin in representing formally derived learning signals for aversive events.

Potential of [11C]DASB for measuring endogenous serotonin with PET: binding studies

International Nuclear Information System (INIS)

Lundquist, Pinelopi; Wilking, Helena; Hoeglund, A. Urban; Sandell, Johan; Bergstroem, Mats; Hartvig, Per; Langstroem, Bengt

2005-01-01

The serotonin transporter radioligand [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, or [ 11 C]DASB, was examined in order to assess its potential for measuring fluctuations in endogenous serotonin concentrations with positron emission tomography. Binding characteristics of [ 11 C]DASB and the propensity for serotonin to displace the tracer were explored in rat brain homogenates. Experiments showed that serotonin displaced [ 11 C]DASB in vitro. Ex vivo experiments performed after tranylcypromine injection (3 or 15 mg/kg) showed a dose-dependent trend in radioactivity uptake and suggested that serotonin may compete with [ 11 C]DASB for transporter binding

Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities

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Janušonis Skirmantas

2005-07-01

Full Text Available Abstract Background A wide range of abnormalities has been reported in autistic brains, but these abnormalities may be the result of an earlier underlying developmental alteration that may no longer be evident by the time autism is diagnosed. The most consistent biological finding in autistic individuals has been their statistically elevated levels of 5-hydroxytryptamine (5-HT, serotonin in blood platelets (platelet hyperserotonemia. The early developmental alteration of the autistic brain and the autistic platelet hyperserotonemia may be caused by the same biological factor expressed in the brain and outside the brain, respectively. Unlike the brain, blood platelets are short-lived and continue to be produced throughout the life span, suggesting that this factor may continue to operate outside the brain years after the brain is formed. The statistical distributions of the platelet 5-HT levels in normal and autistic groups have characteristic features and may contain information about the nature of this yet unidentified factor. Results The identity of this factor was studied by using a novel, quantitative approach that was applied to published distributions of the platelet 5-HT levels in normal and autistic groups. It was shown that the published data are consistent with the hypothesis that a factor that interferes with brain development in autism may also regulate the release of 5-HT from gut enterochromaffin cells. Numerical analysis revealed that this factor may be non-functional in autistic individuals. Conclusion At least some biological factors, the abnormal function of which leads to the development of the autistic brain, may regulate the release of 5-HT from the gut years after birth. If the present model is correct, it will allow future efforts to be focused on a limited number of gene candidates, some of which have not been suspected to be involved in autism (such as the 5-HT4 receptor gene based on currently available clinical and

In vivo binding of 125I-LSD to serotonin 5-HT2 receptors in mouse brain

International Nuclear Information System (INIS)

Hartig, P.R.; Scheffel, U.; Frost, J.J.; Wagner, H.N. Jr.

1985-01-01

The binding of 125 I-LSD (2-[ 125 I]-lysergic acid diethylamide) was studied in various mouse brain regions following intravenous injection of the radioligand. The high specific activity of 125 I-LSD enabled the injection of low mass doses (14ng/kg), which are well below the threshold for induction of any known physiological effect of the probe. The highest levels of 125 I-LSD binding were found in the frontal cortex, olfactory tubercles, extra-frontal cortex and striatum while the lowest level was found in the cerebellum. Binding was saturable in the frontal cortex but increased linearly in the cerebellum with increasing doses of 125 I-LSD. Serotonergic compounds potently inhibited 125 I-LSD binding in cortical regions, olfactory tubercles, and hypothalamus but had no effect in the cerebellum. Dopaminergic compounds caused partial inhibition of binding in the striatum while adrenergic compounds were inactive. From these studies the authors conclude that 125 I-LSD labels serotonin 5-HT 2 receptor sites in cortical regions with no indication that other receptor sites are labeled. In the olfactory tubercles and hypothalamus, 125 I-LSD labeling occurs predominantly or entirely at serotonic 5-HT 2 sites. In the striatum, 125 I-LSD labels approximately equal proportions of serotonergic and dopaminergic sites. These data indicate that 125 I-LSD labels serotonin receptors in vivo and suggests that appropriate derivatives of 2I-LSD may prove useful for tomographic imaging of serotonin 5-HT 2 receptors in the mammalian cortex

Tryptophan Research in Panic Disorder

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Eduard Maron

2008-01-01

Full Text Available A considerable body of evidence suggests the involvement of serotonin neurotransmission in the pathogenesis of panic disorder. Research on pathways and functions of tryptophan, an essential amino acid converted into serotonin, may advance our understanding of serotonergic actions in panic disorder and related phenomena. The investigative approaches in this field include manipulations of tryptophan availability as well as genetic association and functional brain imaging studies. In this review we examine the principle findings of these studies and propose further research directions.

Serotonin depletion induces pessimistic-like behavior in a cognitive bias paradigm in pigs.

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Stracke, Jenny; Otten, Winfried; Tuchscherer, Armin; Puppe, Birger; Düpjan, Sandra

2017-05-15

Cognitive and affective processes are highly interrelated. This has implications for neuropsychiatric disorders such as major depressive disorder in humans but also for the welfare of non-human animals. The brain serotonergic system might play a key role in mediating the relationship between cognitive functions and affective regulation. The aim of our study was to examine the influence of serotonin depletion on the affective state and cognitive processing in pigs, an important farm animal species but also a potential model species for biomedical research in humans. For this purpose, we modified a serotonin depletion model using para-chlorophenylalanine (pCPA) to decrease serotonin levels in brain areas involved in cognitive and affective processing (part 1). The consequences of serotonin depletion were then measured in two behavioral tests (part 2): the spatial judgement task (SJT), providing information about the effects of the affective state on cognitive processing, and the open field/novel object (OFNO) test, which measures behavioral reactions to novelty that are assumed to reflect affective state. In part 1, 40 pigs were treated with either pCPA or saline for six consecutive days. Serotonin levels were assessed in seven different brain regions 4, 5, 6, 11 and 13days after the first injection. Serotonin was significantly depleted in all analyzed brain regions up to 13days after the first application. In part 2, the pCPA model was applied to 48 animals in behavioral testing. Behavioral tests, the OFNO test and the SJT, were conducted both before and after pCPA/saline injections. While results from the OFNO tests were inconclusive, an effect of treatment as well as an effect of the phase (before and after treatment) was observed in the SJT. Animals treated with pCPA showed more pessimistic-like behavior, suggesting a more negative affective state due to serotonin depletion. Thus, our results confirm that the serotonergic system is a key player in cognitive

Brain serotonin 4 receptor binding is associated with the cortisol awakening response

DEFF Research Database (Denmark)

Jakobsen, Gustav R; Fisher, Patrick M; Dyssegaard, Agnete

2016-01-01

Serotonin signalling is considered critical for an appropriate and dynamic adaptation to stress. Previously, we have shown that prefrontal serotonin transporter (SERT) binding is positively associated with the cortisol awakening response (CAR) (Frokjaer et al., 2013), which is an index of hypotha...

Characterization of bromine-76-labelled 5-bromo-6-nitroquipazine for PET studies of the serotonin transporter

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Lundkvist, Camilla E-mail: Lundkvis@shfj.cea.fr; Loc' h, Christian; Halldin, Christer; Bottlaender, Michel; Ottaviani, Michele; Coulon, Christine; Fuseau, Chantal; Mathis, Chester; Farde, Lars; Maziere, Bernard

1999-07-01

The development of suitable radioligands for brain imaging of the serotonin transporter is of great importance for the study of depression and other affective disorders. The potent and selective serotonin transporter ligand, 5-iodo-6-nitro-2-piperazinylquinoline, has been labelled with iodine-123 and used as a radioligand for single photon emission computerized tomography. To evaluate the potential of the bromine-76-labelled analogue, 5-bromo-6-nitroquipazine, as a radioligand for positron emission tomography (PET), its brain distribution and binding characteristics were examined in rats. In vivo brain distribution and ex vivo autoradiography demonstrated that [{sup 76}Br]5-bromo-6-nitroquipazine enters the brain rapidly. The regional brain distribution of [{sup 76}Br]5-bromo-6-nitroquipazine was consistent with the known distribution of serotonin transporters in the midbrain, pons, thalamus, striatum, and neocortex. Specific binding was inhibited by the selective serotonin reuptake inhibitor citalopram. The peripheral metabolism in plasma was rapid, but more than 90% of the radioactivity in brain represented unchanged radioligand 2 h postinjection (p.i.). A preliminary PET study was also performed in a baboon. Following the intravenous injection of [{sup 76}Br]5-bromo-6-nitroquipazine in a baboon, there was a conspicuous accumulation of radioactivity in thalamus, striatum, and pons. The radioactivity in these brain regions was 1.5 times higher than in the cerebellum at 3 h and 2.5-4 times higher at 24 h. A rapid metabolism of the radioligand in plasma was observed (38% unchanged after 5 min). The results indicate that [{sup 76}Br]5-bromo-6-nitroquipazine has potential for PET imaging of the serotonin transporter.

β adrenergic receptor modulation of neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

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Bateman, R J; Boychuk, C R; Philbin, K E; Mendelowitz, D

2012-05-17

β-adrenergic receptors are a class of G protein-coupled receptors that have essential roles in regulating heart rate, blood pressure, and other cardiorespiratory functions. Although the role of β adrenergic receptors in the peripheral nervous system is well characterized, very little is known about their role in the central nervous system despite being localized in many brain regions involved in autonomic activity and regulation. Since parasympathetic activity to the heart is dominated by cardiac vagal neurons (CVNs) originating in the nucleus ambiguus (NA), β adrenergic receptors localized in the NA represent a potential target for modulating cardiac vagal activity and heart rate. This study tests the hypothesis that activation of β adrenergic receptors alters the membrane properties and synaptic neurotransmission to CVNs. CVNs were identified in brainstem slices, and membrane properties and synaptic events were recorded using the whole-cell voltage-clamp technique. The nonselective β agonist isoproterenol significantly decreased inhibitory GABAergic and glycinergic as well as excitatory glutamatergic neurotransmission to CVNs. In addition, the β(1)-selective receptor agonist dobutamine, but not β(2) or β(3) receptor agonists, significantly decreased inhibitory GABAergic and glycinergic and excitatory glutamatergic neurotransmission to CVNs. These decreases in neurotransmission to CVNs persisted in the presence of tetrodotoxin (TTX). These results provide a mechanism by which activation of adrenergic receptors in the brainstem can alter parasympathetic activity to the heart. Likely physiological roles for this adrenergic receptor activation are coordination of parasympathetic-sympathetic activity and β receptor-mediated increases in heart rate upon arousal. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

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Kode, Aruna; Mosialou, Ioanna; Silva, Barbara C.; Rached, Marie-Therese; Zhou, Bin; Wang, Ji; Townes, Tim M.; Hen, Rene; DePinho, Ronald A.; Guo, X. Edward; Kousteni, Stavroula

2012-01-01

Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element–binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation. PMID:22945629

Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.

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Baumann, Michael H; Bulling, Simon; Benaderet, Tova S; Saha, Kusumika; Ayestas, Mario A; Partilla, John S; Ali, Syed F; Stockner, Thomas; Rothman, Richard B; Sandtner, Walter; Sitte, Harald H

2014-05-01

Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [(3)H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [(3)H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.

[{sup 14}C]Serotonin uptake and [O-methyl-{sup 11}C]venlafaxine kinetics in porcine brain

Energy Technology Data Exchange (ETDEWEB)

Smith, D.F. E-mail: dfsmith@inet.uni2.dk; Hansen, S.B.; Oestergaard, L.; Gee, A.D.; Danielsen, E.; Ishizu, K.; Bender, D.; Poulsen, P.H.; Gjedde, A

2001-08-01

As part of our program of developing PET tracers for neuroimaging of psychotropic compounds, venlafaxine, an antidepressant drug, was evaluated. First, we measured in vitro rates of serotonin uptake in synaptosomes prepared from selected regions of porcine brain. Then, we determined the pharmacokinetics of venlafaxine, [O-methyl-{sup 11}C]-labeled for PET. Synaptosomal studies showed that the active uptake of [{sup 14}C]5-HT differed markedly between brain regions, with highest rates in hypothalamus, raphe region, and thalamus, and lowest rates in cortex and cerebellum. PET studies showed that the unidirectional rate of uptake of [O-methyl-{sup 11}C]venlafaxine from blood to brain was highest in the hypothalamus, raphe region, thalamus and basal ganglia and lowest in the cortex and cerebellum. Under normal physiological conditions, the capillary permeability-surface area (PS) product for [O-methyl-{sup 11}C]venlafaxine could not be estimated, because of complete flow-limitation of the cerebral uptake. Nevertheless, a correlation occurred between the apparent partition volume of the radiotracer and the rate of active uptake of 5-HT in selected regions of the porcine brain. During hypercapnia, limitations of blood-brain transfer were observed, giving PS-products for water that were only ca. 50% higher than those of venlafaxine. Thus, under normal physiological conditions, the rate of uptake of venlafaxine from blood into brain is completely flow-limited.

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites

International Nuclear Information System (INIS)

Battaglia, G.; Yeh, S.Y.; O'Hearn, E.; Molliver, M.E.; Kuhar, M.J.; De Souza, E.B.

1987-01-01

This study examines the effects of repeated systemic administration (20 mg/kg s.c., twice daily for 4 days) of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on levels of brain monoamines, their metabolites and on the density of monoamine uptake sites in various regions of rat brain. Marked reductions (30-60%) in the concentration of 5-hydroxyindoleacetic acid were observed in cerebral cortex, hippocampus, striatum, hypothalamus and midbrain at 2 weeks after a 4-day treatment regimen of MDMA or MDA; less consistent reductions in serotonin (5-HT) content were observed in these brain regions. In addition, both MDMA and MDA caused comparable and substantial reductions (50-75%) in the density of [ 3 H]paroxetine-labeled 5-HT uptake sites in all brain regions examined. In contrast, neither MDMA nor MDA caused any widespread or long-term changes in the content of the catecholaminergic markers (i.e., norepinephrine, dopamine, 3,4 dihydroxyphenylacetic acid and homovanillic acid) or in the number of [ 3 H]mazindol-labeled norepinephrine or dopamine uptake sites in the brain regions examined. These data demonstrate that MDMA and MDA cause long-lasting neurotoxic effects with respect to both the functional and structural integrity of serotonergic neurons in brain. Furthermore, our measurement of reductions in the density of 5-HT uptake sites provides a means for quantification of the neurodegenerative effects of MDMA and MDA on presynaptic 5-HT terminals

Exercise and sleep in aging: emphasis on serotonin.

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Melancon, M O; Lorrain, D; Dionne, I J

2014-10-01

Reductions in central serotonin activity with aging might be involved in sleep-related disorders in later life. Although the beneficial effects of aerobic exercise on sleep are not new, sleep represents a complex recurring state of unconsciousness involving many lines of transmitters which remains only partly clear despite intense ongoing research. It is known that serotonin released into diencephalon and cerebrum might play a key inhibitory role to help promote sleep, likely through an active inhibition of supraspinal neural networks. Several lines of evidence support the stimulatory effects of exercise on higher serotonergic pathways. Hence, exercise has proved to elicit acute elevations in forebrain serotonin concentrations, an effect that waned upon cessation of exercise. While adequate exercise training might lead to adaptations in higher serotonergic networks (desensitization of forebrain receptors), excessive training has been linked to serious brain serotonergic maladaptations accompanied by insomnia. Dietary supplementation of tryptophan (the only serotonin precursor) is known to stimulate serotonergic activity and promote sleep, whereas acute tryptophan depletion causes deleterious effects on sleep. Regarding sleep-wake regulation, exercise has proved to accelerate resynchronization of the biological clock to new light-dark cycles following imposition of phase shifts in laboratory animals. Noteworthy, the effect of increased serotonergic transmission on wake state appears to be biphasic, i.e. promote wake and thereafter drowsiness. Therefore, it might be possible that acute aerobic exercise would act on sleep by increasing activity of ascending brain serotonergic projections, though additional work is warranted to better understand the implication of serotonin in the exercise-sleep axis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1.

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Seillier, Lenka; Lorenz, Corinna; Kawaguchi, Katsuhisa; Ott, Torben; Nieder, Andreas; Pourriahi, Paria; Nienborg, Hendrikje

2017-11-22

Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus ("noise-correlation"). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms. SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This

No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

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Dea Siggaard Stenbæk

Full Text Available Serotonin (5-HT brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R brain availability, which has recently become possible to image with Positron Emission Tomography (PET. This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females, the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17 or the latent construct of global 5-HT4R levels (all p-values > .37. Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits.

No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

Science.gov (United States)

Stenbæk, Dea Siggaard; Dam, Vibeke Høyrup; Fisher, Patrick MacDonald; Hansen, Nanna; Hjordt, Liv Vadskjær; Frokjaer, Vibe Gedsoe

2017-01-01

Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R) brain availability, which has recently become possible to image with Positron Emission Tomography (PET). This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17) or the latent construct of global 5-HT4R levels (all p-values > .37). Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits.

In vivo quantification by SPECT of [{sup 123}I] ADAM bound to serotonin transporters in the brains of rabbits

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Ye, X.-X. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hwang, J.-J. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hsieh, J.-F. [Department of Nuclear Medicine, Chi-Mei Foundation Medical Center, Yungkang City 710, Taiwan (China); Chen, J.-C. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China)]. E-mail: jcchen@ym.edu.tw; Chou, Y.-T. [Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan (China); Tu, K.-Y. [Department of Nuclear Medicine, Mackey Memorial Hospital, Taipei, Taiwan 104 (China); Wey, S.-P. [Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Taoyuan, Taiwan 333 (China); Ting Gann [Institute of Nuclear Energy Research, Tao- Yuan 335, Taiwan (China)

2004-11-01

Background: A novel radioiodine ligand [{sup 123}I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [{sup 123}I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. Methods: SPECT imaging was performed on female rabbits postinjection of 185 MBq [{sup 123}I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [{sup 123}I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. Results: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89{+-}0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [{sup 123}I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. Conclusion: SPECT imaging of the rabbit brain with

Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

Science.gov (United States)

Miller, Jeffrey M; Hesselgrave, Natalie; Ogden, R Todd; Sullivan, Gregory M; Oquendo, Maria A; Mann, J John; Parsey, Ramin V

2013-08-15

Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [(11)C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed nonattempters, and healthy controls using PET and a superior radiotracer, [(11)C]DASB. Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [(11)C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification. Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed nonattempters (p = .031) and control subjects (p = .0093). There was no difference in serotonin transporter binding comparing all depressed subjects with healthy control subjects considering six a priori regions of interest simultaneously (p = .41). Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD and determine the cause of low binding. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

The evolution of violence in men: the function of central cholesterol and serotonin.

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Wallner, Bernard; Machatschke, Ivo H

2009-04-30

Numerous studies point to central serotonin as an important modulator of maladaptive behaviors. In men, for instance, low concentrations of this neurotransmitter are related to hostile aggression. A key player in serotonin metabolism seems to be central cholesterol. It plays a fundamental role in maintaining the soundness of neuron membranes, especially in the exocytosis transport of serotonin vesicles into the synaptic cleft. In this review, we attempt an evolutionary approach to the neurobiological basis of human male violence. Hominid evolution was shaped by periods of starvation but also by energy demands of an increasingly complex brain. A lack of food resources reduces uptake of glucose and results in a decreased energy-supply for autonomous brain cholesterol synthesis. Consequently, concentrations of neuromembrane cholesterol decrease, which lead to a failure of the presynaptic re-uptake mechanism of serotonin and ultimately to low central serotonin. We propose that starvation might have affected the larger male brains earlier than those of females. Furthermore, this neurophysiological process diminished the threshold for hostile aggression, which in effect represented a prerequisite for being a successful hunter or scavenger. In a Darwinian sense, the odds to acquire reliable energetic resources made those males to attractive spouses in terms of paternal care and mate support. To underpin these mechanisms, a hypothetical four-stage model of synaptic membrane destabilization effected by a prolonged shortage of high-energy, cholesterol-containing food is illustrated.

Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior.

Science.gov (United States)

Patrick, Rhonda P; Ames, Bruce N

2015-06-01

Serotonin regulates a wide variety of brain functions and behaviors. Here, we synthesize previous findings that serotonin regulates executive function, sensory gating, and social behavior and that attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior all share in common defects in these functions. It has remained unclear why supplementation with omega-3 fatty acids and vitamin D improve cognitive function and behavior in these brain disorders. Here, we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction. © FASEB.

Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

DEFF Research Database (Denmark)

Haahr, M. E.; Rasmussen, Peter Mondrup; Madsen, K.

2012-01-01

in food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake.Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT4Rs and common obesity.We found in humans a strong positive association......The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT4 receptor (5-HT4R) is involved......'s food intake. They also suggest that pharmacological stimulation of the cerebral 5-HT4R may reduce reward-related overeating in humans....

Brain serotonin synthesis in adult males characterized by physical aggression during childhood: a 21-year longitudinal study.

Directory of Open Access Journals (Sweden)

Linda Booij

2010-06-01

Full Text Available Adults exhibiting severe impulsive and aggressive behaviors have multiple indices of low serotonin (5-HT neurotransmission. It remains unclear though whether low 5-HT mediates the behavior or instead reflects a pre-existing vulnerability trait.In the present study, positron emission tomography with the tracer alpha-[(11C]methyl-L-tryptophan ((11C-AMT was used to compare 5-HT synthesis capacity in two groups of adult males from a 21-year longitudinal study (mean age +/- SD: 27.1+/-0.7: individuals with a history of childhood-limited high physical aggression (C-LHPA; N = 8 and individuals with normal (low patterns of physical aggression (LPA; N = 18. The C-LHPA males had significantly lower trapping of (11C-AMT bilaterally in the orbitofrontal cortex and self-reported more impulsiveness. Despite this, in adulthood there were no group differences in plasma tryptophan levels, genotyping, aggression, emotional intelligence, working memory, computerized measures of impulsivity, psychosocial functioning/adjustment, and personal and family history of mood and substance abuse disorders.These results force a re-examination of the low 5-HT hypothesis as central in the biology of violence. They suggest that low 5-HT does not mediate current behavior and should be considered a vulnerability factor for impulsive-aggressive behavior that may or may not be expressed depending on other biological factors, experience, and environmental support during development.

Voltammetric and Mathematical Evidence for Dual Transport Mediation of Serotonin Clearance In Vivo

Science.gov (United States)

Wood, Kevin M.; Zeqja, Anisa; Nijhout, H. Frederik; Reed, Michael C.; Best, Janet; Hashemi, Parastoo

2014-01-01

The neurotransmitter serotonin underlies many of the brain’s functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters (SERTs) and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry (FSCV) is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle (MFB) to provoke and detect terminal serotonin in the substantia nigra reticulata (SNr). In response to MFB stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants. PMID:24702305

Serotonin and Blood Pressure Regulation

Science.gov (United States)

Morrison, Shaun F.; Davis, Robert Patrick; Barman, Susan M.

2012-01-01

5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension. PMID:22407614

Evening dietary tryptophan improves post-sleep behavioral and brain measures of memory function in healthy subjects

NARCIS (Netherlands)

Markus, C.R.; Jonkman, L.M.; Lammers, J.H.C.M.; Deutz, N.E.P.

2006-01-01

Brain serotonin function has been implicated in the control of sleep and sleep related memory dysfunctions are attributed to deficient brain serotonin activity. Depletion of the serotonin precursor tryptophan reduces brain serotonin function and is found to cause sleep abnormalities and cognitive

From Blood to Brain: Adult-Born Neurons in the Crayfish Brain Are the Progeny of Cells Generated by the Immune System

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Barbara S. Beltz

2017-12-01

Full Text Available New neurons continue to be born and integrated into the brains of adult decapod crustaceans. Evidence in crayfish indicates that the 1st-generation neural precursors that generate these adult-born neurons originate in the immune system and travel to the neurogenic niche via the circulatory system. These precursors are attracted to the niche, become integrated amongst niche cells, and undergo mitosis within a few days; both daughters of this division migrate away from the niche toward the brain clusters where they will divide again and differentiate into neurons. In the crustacean brain, the rate of neuronal production is highly sensitive to serotonin (5-hydroxytryptamine, 5-HT levels. These effects are lineage-dependent, as serotonin's influence is limited to late 2nd-generation neural precursors and their progeny. Experiments indicate that serotonin regulates adult neurogenesis in the crustacean brain by multiple mechanisms: via direct effects of serotonin released from brain neurons into the hemolymph or by local release onto target cells, or by indirect influences via a serotonin-mediated release of agents from other regions, such as hormones from the sinus gland and cytokines from hematopoietic tissues. Evidence in crayfish also indicates that serotonin mediates the attraction of neural precursors generated by the immune system to the neurogenic niche. Thus, studies in the crustacean brain have revealed multiple roles for this monoamine in adult neurogenesis, and identified several pathways by which serotonin influences the generation of new neurons.

Expression analysis for inverted effects of serotonin transporter inactivation

International Nuclear Information System (INIS)

Ichikawa, Manabu; Okamura-Oho, Yuko; Shimokawa, Kazuro; Kondo, Shinji; Nakamura, Sakiko; Yokota, Hideo; Himeno, Ryutaro; Lesch, Klaus-Peter; Hayashizaki, Yoshihide

2008-01-01

Inactivation of serotonin transporter (HTT) by pharmacologically in the neonate or genetically increases risk for depression in adulthood, whereas pharmacological inhibition of HTT ameliorates symptoms in depressed patients. The differing role of HTT function during early development and in adult brain plasticity in causing or reversing depression remains an unexplained paradox. To address this we profiled the gene expression of adult Htt knockout (Htt KO) mice and HTT inhibitor-treated mice. Inverted profile changes between the two experimental conditions were seen in 30 genes. Consistent results of the upstream regulatory element search and the co-localization search of these genes indicated that the regulation may be executed by Pax5, Pax7 and Gata3, known to be involved in the survival, proliferation, and migration of serotonergic neurons in the developing brain, and these factors are supposed to keep functioning to regulate downstream genes related to serotonin system in the adult brain

SPECT imaging of dopamine and serotonin transporters with [[sup 123]I][beta]-CIT. Binding kinetics in the human brain

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Bruecke, T; Asenbaum, S; Frassine, H; Podreka, I [Vienna Univ. (Austria). Neurologische Klinik; Kornhuber, J [Wuerzburg Univ. (Germany); Angelberger, P [Oesterreichisches Forschungszentrum Seibersdorf GmbH (Austria)

1993-01-01

Single photon emission computerized tomography (SPECT) studies in non-human primates have previously shown that the cocaine derivative [[sup 123]I]-2-[beta]-carbomethoxy-3-[beta]-(4-iodophenyl)-tropane ([[sup 123]I][beta]-CIT) labels dopamine transporters in the striatum and serotonin transporters in the hypothalamus-midbrain area. Here, we report on the regional kinetic uptake of [[sup 123]I][beta]-CIT in the brain of 4 normal volunteers and 2 patients with Parkinson's disease. In healthy subjects striatal activity increased slowly to reach peak values at about 20 hours post injection. In the hypothalamus-midbrain area peak activities were observed at about 4 hours with a slow decrease thereafter. Low activity was observed in cortical and cerebellar areas. The striatal to cerebellar ratio was about 4 after 5 hours and 9 after 20 hours. In 2 patients with idiopathic Parkinson's disease striatal activity was markedly decreased while the activity in hypothalamus-midbrain areas was only diminished. Uptake into cortical and cerebellar areas appeared to be unchanged in Parkinson's disease. Consequently, in Parkinson's disease the striatal to cerebellar ratio was decreased to values around 2.5 after 20 hours. These preliminary methodological studies suggest that [[sup 123]I][beta]-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.

Different components of 3H-imipramine binding in rat brain membranes: relation to serotonin uptake sites

International Nuclear Information System (INIS)

Gobbi, M.; Taddei, C.; Mennini, T.

1988-01-01

In the present paper, the authors confirm and extend previous studies showing heterogeneous 3 H-imipramine ( 3 H-IMI) binding sites. Inhibition curves of various drugs (serotonin, imipramine, desmethyl-imipramine, d-fenfluramine, d-norfenfluramine and indalpine, a potent serotonin uptake inhibitor) obtained using 2 nM 3 H-IMI and in presence of 120 mM NaCl, confirmed the presence of at least three 3 H-IMI binding sites: two of these were serotonin-insensitive while the third one was selectively inhibited by serotonin and indalpine with nanomolar affinities. Moreover this last component was found to be selectively modulated by chronic imipramine treatment thus suggesting a close relation to serontonin uptake mechanism. These data indicate that the use of a more selective inhibitors of the serotonin-sensitive component (like indalpine or serotonin itself) to define non specific 3 H-IMI, may be of help in understanding its relation with serotonin uptake system. 22 references, 2 figures, 2 tables

Effects of ageing on serotonin transporters in healthy females

International Nuclear Information System (INIS)

Kuikka, J.T.; Tammela, L.; Karhunen, L.; Uusitupa, M.; Bergstroem, K.A.; Tiihonen, J.

2001-01-01

The effect of ageing on brain serotonin transporters was evaluated in 19 healthy female volunteers (age range 22-74 years) using single-photon emission tomography and [ 123 I] nor-β-CIT. The study subjects were scanned 0.3, 3, 6 and 23 h after injection of 185 MBq of [ 123 I] nor-β-CIT. The ratio of the distribution volume for tracer in the midbrain to that in the cerebellum minus 1 was used as an index for serotonin transporter binding. An age-related decline of 2% per decade (r=-0.47; P 123 I] nor-β-CIT binding in the serotonin transporter-rich area is much less than that in dopamine transporters in the striatum (6% per decade). (orig.)

The Gain-of-Function Integrin β3 Pro33 Variant Alters the Serotonin System in the Mouse Brain.

Science.gov (United States)

Dohn, Michael R; Kooker, Christopher G; Bastarache, Lisa; Jessen, Tammy; Rinaldi, Capria; Varney, Seth; Mazalouskas, Matthew D; Pan, Hope; Oliver, Kendra H; Velez Edwards, Digna R; Sutcliffe, James S; Denny, Joshua C; Carneiro, Ana M D

2017-11-15

Engagement of integrins by the extracellular matrix initiates signaling cascades that drive a variety of cellular functions, including neuronal migration and axonal pathfinding in the brain. Multiple lines of evidence link the ITGB3 gene encoding the integrin β3 subunit with the serotonin (5-HT) system, likely via its modulation of the 5-HT transporter (SERT). The ITGB3 coding polymorphism Leu33Pro (rs5918, Pl A2 ) produces hyperactive αvβ3 receptors that influence whole-blood 5-HT levels and may influence the risk for autism spectrum disorder (ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant, male-specific associations between the Pro33 allele and attention-deficit hyperactivity disorder and ASDs. Here, we used knock-in (KI) mice expressing an Itgb3 variant that phenocopies the human Pro33 variant to elucidate the consequences of constitutively enhanced αvβ3 signaling to the 5-HT system in the brain. KI mice displayed deficits in multiple behaviors, including anxiety, repetitive, and social behaviors. Anatomical studies revealed a significant decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT activity and reduced localization of SERTs to integrin adhesion complexes in synapses of KI mice. Inhibition of focal adhesion kinase (FAK) rescued SERT function in synapses of KI mice, demonstrating that constitutive active FAK signaling downstream of the Pro32Pro33 integrin αvβ3 suppresses SERT activity. Our studies identify a complex regulation of 5-HT homeostasis and behaviors by integrin αvβ3, revealing an important role for integrins in modulating risk for neuropsychiatric disorders. SIGNIFICANCE STATEMENT The integrin β3 Leu33Pro coding polymorphism has been associated with autism spectrum disorders (ASDs) within a subgroup of patients with elevated blood 5-HT levels, linking integrin β3, 5-HT, and ASD risk. We capitalized on these interactions to demonstrate that the Pro33 coding variation in the murine

Chemical and radiological effects of chronic ingestion of uranium in the rat brain: biochemical impairment of dopaminergic, serotonergic and cholinergic neuro-transmissions; Effets chimique et radiologique d'une ingestion chronique d'uranium sur le cerveau du rat. Effets sur les neurotransmissions dopaminergique, serotoninergique et cholinergique

Energy Technology Data Exchange (ETDEWEB)

Bussy, C

2005-09-15

Uranium is an environmental ubiquitous metal-trace element. It has both chemical and radiological toxicity. After chronic ingestion, uranium can distribute in any part of the body and accumulate in the brain. The aims of this study was 1) to determine and estimate the effects of uranium on dopaminergic, serotoninergic and cholinergic systems and 2) to measure the uranium amount in the brain, after chronic exposure by ingestion of depleted (D.U.) or enriched (E.U.) uranium during 1.5 to 18 months at 40 mg.L{sup -1} (40 ppm) in different rat brain areas. At any time of exposure, the results show that both the neurotransmission alterations and the uranium brain accumulation were moderate, area specific, time-evolutive and depended on uranium specific activity. After D.U. exposure, monoamine perturbations are chronic and progressive. On the contrary, monoamine alterations occurred only after long term of E.U. exposure. These mono-aminergic modifications are not always dependent on uranium accumulation in brain areas. Moreover, although the cholinergic system was not affected at both 1.5 and 9 months of D.U. exposure, the alteration of ChE activity after E.U. exposure are both dependent on uranium accumulation in brain areas and on uranium specific activity. After E.U. exposure, cholinergic modification and uranium accumulation in hippocampus could partially explain the short-term memory disturbances which have been previously reported. (author)

Mutational Mapping and Modeling of the Binding Site for (S)-Citalopram in the Human Serotonin Transporter

DEFF Research Database (Denmark)

Andersen, Jacob; Olsen, Lars; Hansen, Kasper B.

2010-01-01

The serotonin transporter (SERT) regulates extracellular levels of the neurotransmitter serotonin (5-hydroxytryptamine) in the brain by facilitating uptake of released 5-hydroxytryptamine into neuronal cells. SERT is the target for widely used antidepressant drugs, including imipramine, fluoxetine...

Altered serotonin transporter availability in patients with multiple sclerosis

International Nuclear Information System (INIS)

Hesse, Swen; Sabri, Osama; Moeller, Franziska; Thomae, Eva; Then Bergh, Florian; Petroff, David; Lobsien, Donald; Luthardt, Julia; Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Meyer, Philipp M.; Regenthal, Ralf

2014-01-01

Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [ 11 C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS. (orig.)

Altered serotonin transporter availability in patients with multiple sclerosis

Energy Technology Data Exchange (ETDEWEB)

Hesse, Swen; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig (Germany); Moeller, Franziska; Thomae, Eva; Then Bergh, Florian [University of Leipzig, Department of Neurology, Leipzig (Germany); Petroff, David [University of Leipzig, Coordinating Centre for Clinical Studies, Leipzig (Germany); Lobsien, Donald [University of Leipzig, Department of Neuroradiology, Leipzig (Germany); Luthardt, Julia; Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Meyer, Philipp M. [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Regenthal, Ralf [University of Leipzig, Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig (Germany)

2014-05-15

Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [{sup 11}C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS. (orig.)

5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function.

Science.gov (United States)

Wang, Xin; Dergacheva, Olga; Kamendi, Harriet; Gorini, Christopher; Mendelowitz, David

2007-08-01

Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and gamma-aminobutyric acid (GABA) neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The mu-opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4alpha agonist BIMU-8 did not by itself change inspiratory activity but prevented the mu-opioid-mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic neurotransmission. In contrast, BIMU-8 did not alter GABAergic neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin, the inhibition of GABAergic inhibitory postsynaptic currents with fentanyl is prevented by coapplication of BIMU-8, indicating that BIMU-8 acts at presynaptic GABAergic terminals to prevent fentanyl-induced depression. These results suggest that activation of 5

Serotonin synthesis studied with positron emission tomography, (PET)

DEFF Research Database (Denmark)

Honoré, Per Gustaf Hartvig; Lundquist, Pinelopi

Positron emission tomography (PET) has the potential to study the biosynthesis and release of serotonin (5HT) at brain serotonergic neurons. PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes. This section focuses on probes to measure...

How the cerebral serotonin homeostasis predicts environmental changes

DEFF Research Database (Denmark)

Kalbitzer, Jan; Kalbitzer, Urs; Knudsen, Gitte Moos

2013-01-01

Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which...... has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment...... of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes...

Neuroticism and serotonin 5-HT_1A receptors in healthy subjects

DEFF Research Database (Denmark)

Hirvonen, Jussi; Tuominen, Lauri; Någren, Kjell

2015-01-01

subjects is unclear. We measured brain serotonin 5-HT1A receptor in 34 healthy subjects in vivo using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635. Binding potential (BPP) was determined using the golden standard of kinetic compartmental modeling using arterial blood samples...... and radiometabolite determination. Personality traits were assessed using the Karolinska Scales of Personality. We found a strong negative association between serotonin 5-HT1A receptor BPP and neuroticism. That is, individuals with high neuroticism tended to have lower 5-HT1A receptor binding than individuals...... with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may...

Brain SPECT in childhood

International Nuclear Information System (INIS)

Tranquart, F.; Saliba, E.; Prunier, C.; Baulieu, F.; Besnard, J.C.; Guilloteau, D.; Baulieu, J.L.

2001-01-01

The modalities and the indications of perfusion and neurotransmission SPECT in childhood are presented. The perfusion as well as neurotransmission tracers have not yet authorization for use in children; they have to be used by prescription of magistral preparation or in research protocols. The radioprotection rules have to be strictly respected. The most frequent indication of perfusion SPECT is pharmacologically resistant epilepsy; the ictal SPECT before surgery allows the localization of the epileptogenic focus. Other indications are relevant in the prognosis of neonatal anoxia and encephalitis. In psychiatric disorders, especially in autism, the interest is the physiopathological approach of the brain dysfunctions. The neurotransmission SPECT is emerging as a consequence of the development of new radiotracer, as the dopaminergic system ligands. The decrease of the dopamine D2 receptors in the striatum can be imaged and quantified in the neonate. The lesions of dopamine system seem to be a consequence of the neonatal hypoxia-ischemia and it is predictive of motor sequelae. Brain SPECT should become a routine examination in child neurologic and psychiatric disorders. (authors)

Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication.

Science.gov (United States)

Benton, Tami; Lynch, Kevin; Dubé, Benoit; Gettes, David R; Tustin, Nancy B; Ping Lai, Jian; Metzger, David S; Blume, Joshua; Douglas, Steven D; Evans, Dwight L

2010-11-01

To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection. Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition. The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status. These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.

Reaching Out to Send a Message: Proteins Associated with Neurite Outgrowth and Neurotransmission are Altered with Age in the Long-Lived Naked Mole-Rat.

Science.gov (United States)

Triplett, Judy C; Swomley, Aaron M; Kirk, Jessime; Grimes, Kelly M; Lewis, Kaitilyn N; Orr, Miranda E; Rodriguez, Karl A; Cai, Jian; Klein, Jon B; Buffenstein, Rochelle; Butterfield, D Allan

2016-07-01

Aging is the greatest risk factor for developing neurodegenerative diseases, which are associated with diminished neurotransmission as well as neuronal structure and function. However, several traits seemingly evolved to avert or delay age-related deterioration in the brain of the longest-lived rodent, the naked mole-rat (NMR). The NMR remarkably also exhibits negligible senescence, maintaining an extended healthspan for ~75 % of its life span. Using a proteomic approach, statistically significant changes with age in expression and/or phosphorylation levels of proteins associated with neurite outgrowth and neurotransmission were identified in the brain of the NMR and include: cofilin-1; collapsin response mediator protein 2; actin depolymerizing factor; spectrin alpha chain; septin-7; syntaxin-binding protein 1; synapsin-2 isoform IIB; and dynamin 1. We hypothesize that such changes may contribute to the extended lifespan and healthspan of the NMR.

Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification.

Directory of Open Access Journals (Sweden)

Lise Gutknecht

Full Text Available Brain serotonin (5-HT is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2. Tph2 inactivation (Tph2-/- resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT(1A and 5-HT(1B receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.

Radioenzymatic microassay for picogram quantities of serotonin or acetylserotonin in biological fluids and tissues

International Nuclear Information System (INIS)

Hussain, M.N.; Benedict, C.R.

1987-01-01

This paper describes several modifications of the original radioenzymatic assay for serotonin which increase the sensitivity of the assay 20-fold as well as enhance its reliability. Using this method serotonin concentrations can be directly measured in biological examples without precleaning the sample. When compared to currently available methods this assay is specific and sensitive to approximately 1 pg of serotonin and can be used to measure serotonin levels in individual brain nuclei or microliter quantities of biological fluids. This assay can be easily adapted for the direct measurement of N-acetylserotonin. A large number of samples can be assayed in a single working day

Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine.

Science.gov (United States)

Banerjee, S; Poddar, M K

2016-04-05

Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. The aging-induced changes in [(3)H]-5-HT receptor binding with carnosine (2.0 μg/kg/day, intrathecally, for 21 consecutive days) attenuated in (a) 24-month-aged rats irrespective of the brain regions with the attenuation of its Bmax except hypothalamus where both Bmax and KD were significantly attenuated, (b) hippocampus and hypothalamus of 18-month-aged rats with the attenuation of its Bmax, and restored toward the [(3)H]-5-HT receptor binding that observed in 4-month-young rats. The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

[3H]WB4101 labels the 5-HT1A serotonin receptor subtype in rat brain. Guanine nucleotide and divalent cation sensitivity

International Nuclear Information System (INIS)

Norman, A.B.; Battaglia, G.; Creese, I.

1985-01-01

In the presence of a 30 nM prazosin mask, [ 3 H]-2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane ([ 3 H]WB4101) can selectively label 5-HT1 serotonin receptors. Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for [ 3 H] WB4101 binding in cerebral cortex. We have found a significant correlation (r = 0.96) between the affinities of a number of serotonergic and nonserotonergic compounds at [ 3 H]WB4101-binding sites in the presence of 30 nM prazosin and [ 3 H] lysergic acid diethylamide ([ 3 H]LSD)-labeled 5-HT1 serotonin receptors in homogenates of rat cerebral cortex. Despite similar pharmacological profiles, distribution studies indicate that, in the presence of 5 mM MgSO4, the Bmax of [ 3 H]WB4101 is significantly lower than the Bmax of [ 3 H]LSD in various brain regions. WB4101 competition for [ 3 H] LSD-labeled 5-HT1 receptors fits best to a computer-derived model assuming two binding sites, with the KH for WB4101 being similar to the KD of [ 3 H]WB4101 binding derived from saturation experiments. This suggests that [ 3 H]WB4101 labels only one of the subtypes of the 5-HT1 serotonin receptors labeled by [ 3 H]LSD. The selective 5-HT1A serotonin receptor antagonist, spiperone, and the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetraline, exhibit high affinity and monophasic competition for [ 3 H]WB4101 but compete for multiple [ 3 H]LSD 5-HT1 binding sites. These data indicate that [ 3 H]WB4101 selectively labels the 5-HT1A serotonin receptor, whereas [ 3 H] LSD appears to label both the 5-HT1A and the 5-HT1B serotonin receptor subtypes. The divalent cations, Mn2+, Mg2+, and Ca2+ were found to markedly increase the affinity and Bmax of [ 3 H]WB4101 binding in cerebral cortex. Conversely, the guanine nucleotides guanylylimidodiphosphate and GTP, but not the adenosine nucleotide ATP, markedly reduce the Bmax of [ 3 H]WB4101 binding

Imaging of nitric oxide in nitrergic neuromuscular neurotransmission in the gut.

Directory of Open Access Journals (Sweden)

Hemant S Thatte

Full Text Available Numerous functional studies have shown that nitrergic neurotransmission plays a central role in peristalsis and sphincter relaxation throughout the gut and impaired nitrergic neurotransmission has been implicated in clinical disorders of all parts of the gut. However, the role of nitric oxide (NO as a neurotransmitter continues to be controversial because: 1 the cellular site of production during neurotransmission is not well established; 2 NO may interacts with other inhibitory neurotransmitter candidates, making it difficult to understand its precise role.Imaging NO can help resolve many of the controversies regarding the role of NO in nitrergic neurotransmission. Imaging of NO and its cellular site of production is now possible. NO forms quantifiable fluorescent compound with diaminofluorescein (DAF and allows imaging of NO with good specificity and sensitivity in living cells. In this report we describe visualization and regulation of NO and calcium (Ca(2+ in the myenteric nerve varicosities during neurotransmission using multiphoton microscopy. Our results in mice gastric muscle strips provide visual proof that NO is produced de novo in the nitrergic nerve varicosities upon nonadrenergic noncholinergic (NANC nerve stimulation. These studies show that NO is a neurotransmitter rather than a mediator. Changes in NO production in response to various pharmacological treatments correlated well with changes in slow inhibitory junction potential of smooth muscles.Dual imaging and electrophysiologic studies provide visual proof that during nitrergic neurotransmission NO is produced in the nerve terminals. Such studies may help define whether NO production or its signaling pathway is responsible for impaired nitrergic neurotransmission in pathological states.

Chemical and radiological effects of chronic ingestion of uranium in the rat brain: biochemical impairment of dopaminergic, serotonergic and cholinergic neuro-transmissions; Effets chimique et radiologique d'une ingestion chronique d'uranium sur le cerveau du rat. Effets sur les neurotransmissions dopaminergique, serotoninergique et cholinergique

Energy Technology Data Exchange (ETDEWEB)

Bussy, C

2005-09-15

Uranium is an environmental ubiquitous metal-trace element. It has both chemical and radiological toxicity. After chronic ingestion, uranium can distribute in any part of the body and accumulate in the brain. The aims of this study was 1) to determine and estimate the effects of uranium on dopaminergic, serotoninergic and cholinergic systems and 2) to measure the uranium amount in the brain, after chronic exposure by ingestion of depleted (D.U.) or enriched (E.U.) uranium during 1.5 to 18 months at 40 mg.L{sup -1} (40 ppm) in different rat brain areas. At any time of exposure, the results show that both the neurotransmission alterations and the uranium brain accumulation were moderate, area specific, time-evolutive and depended on uranium specific activity. After D.U. exposure, monoamine perturbations are chronic and progressive. On the contrary, monoamine alterations occurred only after long term of E.U. exposure. These mono-aminergic modifications are not always dependent on uranium accumulation in brain areas. Moreover, although the cholinergic system was not affected at both 1.5 and 9 months of D.U. exposure, the alteration of ChE activity after E.U. exposure are both dependent on uranium accumulation in brain areas and on uranium specific activity. After E.U. exposure, cholinergic modification and uranium accumulation in hippocampus could partially explain the short-term memory disturbances which have been previously reported. (author)

Quantitative accuracy of serotonergic neurotransmission imaging with high-resolution 123I SPECT

International Nuclear Information System (INIS)

Kuikka, J.T.

2004-01-01

Aim: Serotonin transporter (SERT) imaging can be used to study the role of regional abnormalities of neurotransmitter release in various mental disorders and to study the mechanism of action of therapeutic drugs or drugs' abuse. We examine the quantitative accuracy and reproducibility that can be achieved with high-resolution SPECT of serotonergic neurotransmission. Method: Binding potential (BP) of 123 I labeled tracer specific for midbrain SERT was assessed in 20 healthy persons. The effects of scatter, attenuation, partial volume, misregistration and statistical noise were estimated using phantom and human studies. Results: Without any correction, BP was underestimated by 73%. The partial volume error was the major component in this underestimation whereas the most critical error for the reproducibility was misplacement of region of interest (ROI). Conclusion: The proper ROI registration, the use of the multiple head gamma camera with transmission based scatter correction introduce more relevant results. However, due to the small dimensions of the midbrain SERT structures and poor spatial resolution of SPECT, the improvement without the partial volume correction is not great enough to restore the estimate of BP to that of the true one. (orig.) [de

Brain serotonin signaling does not determine sexual preference in male mice.

Directory of Open Access Journals (Sweden)

Mariana Angoa-Pérez

Full Text Available It was reported recently that male mice lacking brain serotonin (5-HT lose their preference for females (Liu et al., 2011, Nature, 472, 95-100, suggesting a role for 5-HT signaling in sexual preference. Regulation of sex preference by 5-HT lies outside of the well established roles in this behavior established for the vomeronasal organ (VNO and the main olfactory epithelium (MOE. Presently, mice with a null mutation in the gene for tryptophan hydroxylase 2 (TPH2, which are depleted of brain 5-HT, were tested for sexual preference. When presented with inanimate (urine scents from male or estrous female or animate (male or female mouse in estrus sexual stimuli, TPH2-/- males show a clear preference for female over male stimuli. When a TPH2-/- male is offered the simultaneous choice between an estrous female and a male mouse, no sexual preference is expressed. However, when confounding behaviors that are seen among 3 mice in the same cage are controlled, TPH2-/- mice, like their TPH2+/+ counterparts, express a clear preference for female mice. Female TPH2-/- mice are preferred by males over TPH2+/+ females but this does not lead to increased pregnancy success. In fact, if one or both partners in a mating pair are TPH2-/- in genotype, pregnancy success rates are significantly decreased. Finally, expression of the VNO-specific cation channel TRPC2 and of CNGA2 in the MOE of TPH2-/- mice is normal, consistent with behavioral findings that sexual preference of TPH2-/- males for females is intact. In conclusion, 5-HT signaling in brain does not determine sexual preference in male mice. The use of pharmacological agents that are non-selective for the 5-HT neuronal system and that have serious adverse effects may have contributed historically to the stance that 5-HT regulates sexual behavior, including sex partner preference.

Music improves dopaminergic neurotransmission: demonstration based on the effect of music on blood pressure regulation.

Science.gov (United States)

Sutoo, Den'etsu; Akiyama, Kayo

2004-08-06

The mechanism by which music modifies brain function is not clear. Clinical findings indicate that music reduces blood pressure in various patients. We investigated the effect of music on blood pressure in spontaneously hypertensive rats (SHR). Previous studies indicated that calcium increases brain dopamine (DA) synthesis through a calmodulin (CaM)-dependent system. Increased DA levels reduce blood pressure in SHR. In this study, we examined the effects of music on this pathway. Systolic blood pressure in SHR was reduced by exposure to Mozart's music (K.205), and the effect vanished when this pathway was inhibited. Exposure to music also significantly increased serum calcium levels and neostriatal DA levels. These results suggest that music leads to increased calcium/CaM-dependent DA synthesis in the brain, thus causing a reduction in blood pressure. Music might regulate and/or affect various brain functions through dopaminergic neurotransmission, and might therefore be effective for rectification of symptoms in various diseases that involve DA dysfunction.

Individual differences in emotion-cognition interactions: Emotional valence interacts with serotonin transporter genotype to influence brain systems involved in emotional reactivity and cognitive control

Directory of Open Access Journals (Sweden)

Melanie eStollstorff

2013-07-01

Full Text Available The serotonin transporter gene (5-HTTLPR influences emotional reactivity and attentional bias towards or away from emotional stimuli and has been implicated in psychopathological states, such as depression and anxiety disorder. The short allele is associated with increased reactivity and attention towards negatively-valenced emotional information, whereas the long allele is associated with that towards positively-valenced emotional information. The neural basis for individual differences in the ability to exert cognitive control over these bottom-up biases in emotional reactivity and attention is unknown, an issue investigated in the present study. Two groups, homozygous 5-HTTLPR long allele carriers or homozygous short allele carriers, underwent functional magnetic resonance imaging (fMRI while completing an Emotional Stroop-like task that varied with regards to the congruency of task-relevant and task-irrelevant information and the emotional valence of the task-irrelevant information. Behaviorally, participants demonstrated the classic Stroop effect (slower responses for incongruent than congruent trials, which did not differ by 5-HTTLPR genotype. However, fMRI results revealed that genotype influenced the degree to which neural systems were engaged depending on the valence of the conflicting task-irrelevant information. While the Long group recruited prefrontal control regions and superior temporal sulcus during conflict when task-irrelevant information was positively-valenced, the "Short" group recruited these regions when task-irrelevant information was negatively-valenced. Thus, participants successfully engaged cognitive control to overcome conflict in an emotional context using similar neural circuitry, but the engagement of this circuitry depended on emotional valence and 5-HTTLPR status. These results suggest that the interplay between emotion and cognition is modulated, in part, by a genetic polymorphism that influences serotonin

Dual-isotope single-photon emission computed tomography for dopamine and serotonin transporters in normal and parkinsonian monkey brains

International Nuclear Information System (INIS)

Li, I-H.; Huang, W.-S.; Yeh, C.-B.; Liao, M.-H.; Chen, C.-C.; Shen, L.-H.; Liu, J.-C.; Ma, K.-H.

2009-01-01

Introduction: Parkinson's disease (PD) affects both dopaminergic and serotonergic systems. In this study, we simultaneously evaluated dopamine and serotonin transporters in primates using dual-isotope single-photon emission computed tomography (SPECT) imaging and compared the results with traditional single-isotope imaging. Methods: Four healthy and one 6-OHDA-induced PD monkeys were used for this study. SPECT was performed over 4 h after individual or simultaneous injection of [ 99m Tc]TRODAT-1 (a dopamine transporter imaging agent) and [ 123 I]ADAM (a serotonin transporter imaging agent). Results: The results showed that the image quality and uptake ratios in different brain regions were comparable between single- and dual-isotope studies. The striatal [ 99m Tc]TRODAT-1 uptake in the PD monkey was markedly lower than that in normal monkeys. The uptake of [ 123 I]ADAM in the midbrain of the PD monkey was comparable to that in the normal monkeys, but there were decreased uptakes in the thalamus and striatum of the PD monkey. Conclusions: Our results suggest that dual-isotope SPECT using [ 99m Tc]TRODAT-1 and [ 123 I]ADAM can simultaneously evaluate changes in dopaminergic and serotonergic systems in a PD model.

The role of cortical and hypothalamic histamine-3 receptors in the modulation of central histamine neurotransmission : an in vivo electrophysiology and microdialysis study

NARCIS (Netherlands)

Flik, Gunnar; Dremencov, Eliyahu; Cremers, Thomas I. H. F.; Folgering, Joost H. A.; Westerink, Ben H. C.

2011-01-01

The current study aimed to investigate the effect of histamine-3 (H3) receptors, expressed in the tuberomammillary nucleus (TMN) of the hypothalamus and in the prefrontal cortex (PFC), on histamine neurotransmission in the rat brain. The firing activity of histamine neurons in the TMN was measured

Action of naftopidil on spinal serotonergic neurotransmission for inhibition of the micturition reflex in rats.

Science.gov (United States)

Sugaya, Kimio; Nishijima, Saori; Kadekawa, Katsumi; Ashitomi, Katsuhiro; Ueda, Tomoyuki; Yamamoto, Hideyuki; Hattori, Tsuyoshi

2017-03-01

We examined the mechanism of action of naftopidil, an α1D/A blocker, on spinal descending serotonergic neurotransmission for the micturition reflex. We examined (1) urinary 5-hydroxyindole acetic acid (5-HIAA) after intraperitoneal administration of saline, para-chlorophenylalanine (PCPA; a serotonin synthetic enzyme inhibitor), and/or 5-hydroxytryptophan (5-HTP; a serotonin precursor); (2) isovolumetric cystometry after intraperitoneal administration of saline, PCPA, and/or 5-HTP and intravenous injection of naftopidil; and (3) isovolumetric cystometry before and after intrathecal administration of serotonin (5-HT) receptor antagonists and intravenous injection of naftopidil. PCPA decreased and 5-HTP increased urinary 5-HIAA/creatinine. Intraperitoneal injection of PCPA did not influence cystometric parameters. Intraperitoneal injection of 5-HTP significantly shortened the interval between bladder contractions. Intravenous injection of naftopidil transiently abolished bladder contractions. However, the duration of abolishment of bladder contractions after injection of naftopidil in rats given PCPA was significantly shorter than that in rats given vehicle, but significantly longer than that in rats given PCPA and 5-HTP. Intrathecal injection of 5-HT1B, 5-HT3, or 5-HT7 receptor antagonists significantly prolonged the interval between bladder contractions. Intrathecal injection of 5-HT1D or 5-HT2B receptor antagonists significantly shortened the interval between bladder contractions. Combined administration of the maximum non-effective dose of 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, or 5-HT3 receptor antagonists and intravenous injection of naftopidil significantly shortened the duration of abolishment of bladder contraction compared to intravenous injection of naftopidil alone. Naftopidil may inhibit the micturition reflex via 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT3 receptors in the spinal cord. Neurourol. Urodynam. 36:604-609, 2017. © 2016 Wiley Periodicals, Inc. �

Gender differences in alpha-[(11)C]MTrp brain trapping, an index of serotonin synthesis, in medication-free individuals with major depressive disorder: a positron emission tomography study.

Science.gov (United States)

Frey, Benicio N; Skelin, Ivan; Sakai, Yojiro; Nishikawa, Masami; Diksic, Mirko

2010-08-30

Women are at higher risk than men for developing major depressive disorder (MDD), but the mechanisms underlying this higher risk are unknown. Here, we report proportionally normalized alpha-[(11)C]methyl-L-tryptophan brain trapping constant (alpha-[(11)C]MTrp K*(N)), an index of serotonin synthesis, in 25 medication-free individuals with MDD and in 25 gender- and age-matched healthy subjects who were studied using positron emission tomography (PET). Comparisons of alpha-[(11)C]MTrp K*(N) values between the men and women were conducted at the voxel and cluster levels using Statistical Parametric Mapping 2 (SPM2) analysis. In addition, the alpha-[(11)C]MTrp K*(N) values on both sides of the brain were extracted and compared to identify the left to right differences, as well as the gender differences. Women with MDD displayed higher alpha-[(11)C]MTrp K*(N) than men in the inferior frontal gyrus, anterior cingulate cortex (ACC), parahippocampal gyrus, precuneus, superior parietal lobule, and occipital lingual gyrus. In a matched group of normal subjects the gender differences were opposite from those found in MDD patients. Significant hemispheric differences in fronto-limbic structures between men and women with MDD were also observed. The K*(N) extracted from the volumes identified in MDD patients and in male and female normal subjects suggested no significant differences between males and females. In conclusion, depressed women have higher serotonin synthesis in multiple regions of the prefrontal cortex and limbic system involved with mood regulation, as compared with depressed men. Gender differences in brain serotonin synthesis may be related to higher risk for MDD in women. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Changes in EEG indices and serotonin concentrations in depression and anxiety disorders

Directory of Open Access Journals (Sweden)

I. V. Kichuk

2016-01-01

Full Text Available Electroencephalogram (EEG is an important tool to study brain function. EEG can evaluate the current functional state of the brain with high temporal resolution and identify metabolic and ion disorders that cannot be detected by magnetic resonance imaging.Objective: to analyze the relationship between some neurophysiological and biochemical parameters with a Neuro-KM hardware-software complex for the topographic mapping of brain electrical activity.Patients and methods. 75 patients with depression, 101 with anxiety disorders (AD, and 86 control individuals were examined. EEG spectrum and coherence changes were estimated in the depression and AD groups versus the control group. Correlation analysis of EEG indices and blood serotonin concentrations was carried out.Results and discussion. The patients with depression and those with AD as compared to the controls were observed to have similar EEG spectral changes in the beta band. Coherence analysis in the beta-band showed that both disease groups versus the control group had oppositely directed changes: a reduction in intra- and interhemispheric coherence for depression and its increase for AD (p < 0.001. That in the theta and alpha bands revealed that both disease groups had unidirectional interhemispheric coherence changes: a decrease in integration in the alpha band and its increase in the theta and delta bands in the depression and AD groups (p < 0.05 and multidirectional changes in intrahemispheric coherence: its reduction in the depression group and an increase in the AD group (p < 0.05. Correlation analysis of EEG parameters and platelet serotonin concentrations showed opposite correlations of serotonin concentrations and EEG percentage power in the theta and beta bands. When there were higher serotonin concentrations in the patients with depression, EEG demonstrated a preponderance of a synchronization pattern; when these were in the patients with AD, there was a predominance

Contribution to the study of the radioprotective effect of serotonin on brain spontaneous and evoked electrical activities in the adult rabbit following whole-body lethal $gamma$-irradiation

Energy Technology Data Exchange (ETDEWEB)

Fatome, M; Court, L

1973-11-01

Thesis. Submitted to Paris Univ., (France). A 1 to 12 mg/kg serotonin- creatine-sulfate intravenous injection seems to act only slightly on the chronic implanted rabbit CNS except for an increase in latencies and delays of the fast components of evoked potentials and a generalized decrease in the total energy of the signal occurring 20 to 60 min after the injection. The CNS is given a real protection by a 10 mg/kg serotonin injec, tion 20 min before a 650 R whole-body exposure, the spontaneous or induced electrical activity being slightly disturbed. In the hours following irradiation the total energy increase is less important than in the unprotected animal, and there is no clear variation towards the low frequencies. Serotonin could act on the brain structures and the total energy of the signal through its depressing effect. Its radioprotective effect could act, at least partly, through the CNS. (auth)

Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

Energy Technology Data Exchange (ETDEWEB)

Visser, Anniek K.D.; Waarde, Aren van; Willemsen, Antoon T.M. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Bosker, Fokko J. [University of Groningen, University Medical Center Groningen, University Center of Psychiatry, Groningen (Netherlands); Luiten, Paul G.M. [University of Groningen, Center for Behavior and Neurosciences, Department of Molecular Neurobiology, Haren (Netherlands); Boer, Johan A. den [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University of Groningen, University Medical Center Groningen, University Center of Psychiatry, Groningen (Netherlands); Kema, Ido P. [University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen (Netherlands); Dierckx, Rudi A.J.O. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University Hospital Ghent, Department of Nuclear Medicine, Ghent (Belgium)

2011-03-15

The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are {alpha}-[{sup 11}C]methyltryptophan ([{sup 11}C]AMT) and 5-hydroxy-L-[{beta}-{sup 11}C]tryptophan ([{sup 11}C]5-HTP). Both tracers have advantages and disadvantages. [{sup 11}C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [{sup 11}C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain. (orig.)

No evidence for a role of the serotonin 4 receptor in five-factor personality traits

DEFF Research Database (Denmark)

Stenbæk, Dea Siggaard; Dam, Vibeke Høyrup; Fisher, Patrick MacDonald

2017-01-01

Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo...... serotonin 4 receptor (5-HT4R) brain availability, which has recently become possible to image with Positron Emission Tomography (PET). This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone...... in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated...

Co-treatment with imipramine averted haloperidol-instigated tardive dyskinesia: Association with serotonin in brain regions.

Science.gov (United States)

Samad, Noreen; Yasmin, Farzana; Haleem, Darakhshan Jabeen

2016-11-01

Outcome of imipramine (IMI) treatment was scrutinized on progression of haloperidol instigated tardive dyskinesia (TD). 0.2 mg/kg/rat dosage of haloperidol provided orally to rats for 2 weeks enhanced vacuous chewing movements that escalated when the process proceeded for 5 weeks. Following 2 weeks co-injection 5 mg/kg dosage of IMI was diminished haloperidol-instigated VCMs and fully averted following five weeks. The potency of 8-OH-DPAT-instigated locomotor activity exhibited higher in saline+haloperidol treated rats while not observed in IMI+ haloperidol treated rats. 8-OH-DPAT-instigated low 5-hydroxytryptamine (5-HT; serotonin) metabolism was higher in saline+ haloperidol treated rats when compare to IMI+ haloperidol treated rats in both regions of brain (striatum and midbrain). It is recommended that IMI possibly competent in averting TD, in cases receiving treatment to antipsychotics.

Cortical enlargement in autism is associated with a functional VNTR in the monoamine oxidase A gene.

Science.gov (United States)

Davis, Lea K; Hazlett, Heather C; Librant, Amy L; Nopoulos, Peggy; Sheffield, Val C; Piven, Joesph; Wassink, Thomas H

2008-10-05

Monoamine oxidase A (MAOA) is an enzyme expressed in the brain that metabolizes dopamine, norepinephrine, epinephrine, and serotonin. Abnormalities of serotonin neurotransmission have long been implicated in the psychopathology of autism. A polymorphism exists within the promoter region of the MAOA gene that influences MAOA expression levels so that "low activity" alleles are associated with increased neurotransmitter levels in the brain. Individuals with autism often exhibit elevated serotonin levels. Additional studies indicate that the "low activity" allele may be associated with lower IQ and more severe autistic symptoms. In this study we genotyped the MAOA promoter polymorphism in a group of 29 males (age 2-3 years) with autism and a group of 39 healthy pediatric controls for whom brain MRI data was available. We found a consistent association between the "low activity" allele and larger brain volumes for regions of the cortex in children with autism but not in controls. We did not find evidence for over-transmission of the "low activity" allele in a separate sample of 114 affected sib pair families. Nor did we find any unknown SNPs in yet another sample of 96 probands. Future studies will determine if there is a more severe clinical phenotype associated with both the "low activity" genotype and the larger brain volumes in our sample.

Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET.

Science.gov (United States)

Vanicek, Thomas; Kutzelnigg, Alexandra; Philippe, Cecile; Sigurdardottir, Helen L; James, Gregory M; Hahn, Andreas; Kranz, Georg S; Höflich, Anna; Kautzky, Alexander; Traub-Weidinger, Tatjana; Hacker, Marcus; Wadsak, Wolfgang; Mitterhauser, Markus; Kasper, Siegfried; Lanzenberger, Rupert

2017-02-01

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP ND ) in patients with ADHD and to assess associations of SERT BP ND between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [ 11 C]DASB. SERT BP ND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP ND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP ND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R 2  = 0.284, R 2  = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley

Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress

Institute of Scientific and Technical Information of China (English)

De-guo Jiang; Shi-li Jin; Gong-ying Li; Qing-qing Li; Zhi-ruo Li; Hong-xia Ma; Chuan-jun Zhuo; Rong-huan Jiang; Min-jie Ye

2016-01-01

Previous studies suggest that serotonin (5-HT) might interact with brain-derived neurotrophic factor (BDNF) during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry andin situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no signiifcant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our ifndings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.

Investigation of the GPR39 zinc receptor following inhibition of monoaminergic neurotransmission and potentialization of glutamatergic neurotransmission

DEFF Research Database (Denmark)

Młyniec, Katarzyna; Gaweł, Magdalena; Librowski, Tadeusz

2015-01-01

Zinc can regulate neural function in the brain via the GPR39 receptor. In the present study we investigated whether inhibition of serotonin, noradrenaline and dopamine synthesis and potentialization of glutamate, via administration of p-chlorophenylalanine (pCPA), α-methyl-p-tyrosine (αMT) and N......-methyl-d-aspartatic acid (NMDA), respectively, would cause changes in GPR39 levels. Western blot analysis showed GPR39 up-regulation following 3-day administration of αMT and NMDA in the frontal cortex, and GPR39 down-regulation following 10-day administration of pCPA, αMT, and NMDA in the hippocampus of CD-1 mice....... There were no changes in serum zinc levels. Additionally, we investigated tryptophan, tyrosine and glutamate concentrations in the hippocampus and frontal cortex of GPR39 knockout (GPR39 KO) mice. Liquid chromatography-mass spectrometry (LC-MS) showed a significant decrease in tryptophan and tyrosine...

Thermodynamic laws apply to brain function.

Science.gov (United States)

Salerian, Alen J

2010-02-01

Thermodynamic laws and complex system dynamics govern brain function. Thus, any change in brain homeostasis by an alteration in brain temperature, neurotransmission or content may cause region-specific brain dysfunction. This is the premise for the Salerian Theory of Brain built upon a new paradigm for neuropsychiatric disorders: the governing influence of neuroanatomy, neurophysiology, thermodynamic laws. The principles of region-specific brain function thermodynamics are reviewed. The clinical and supporting evidence including the paradoxical effects of various agents that alter brain homeostasis is demonstrated.

Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.

Science.gov (United States)

Miyazaki, Kayoko W; Miyazaki, Katsuhiko; Tanaka, Kenji F; Yamanaka, Akihiro; Takahashi, Aki; Tabuchi, Sawako; Doya, Kenji

2014-09-08

Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14]. However, the therapeutic effects of serotonin signal-enhancing medications have been difficult to reconcile with this theory [15, 16]. In contrast, a more recent theory states that serotonin facilitates long-term optimal behaviors and suppresses impulsive behaviors [17-21]. To test these theories, we developed optogenetic mice that selectively express channelrhodopsin in serotonin neurons and tested how the activation of serotonergic neurons in the DRN affects animal behavior during a delayed reward task. The activation of serotonin neurons reduced the premature cessation of waiting for conditioned cues and food rewards. In reward omission trials, serotonin neuron stimulation prolonged the time animals spent waiting. This effect was observed specifically when the animal was engaged in deciding whether to keep waiting and was not due to motor inhibition. Control experiments showed that the prolonged waiting times observed with optogenetic stimulation were not due to behavioral inhibition or the reinforcing effects of serotonergic activation. These results show, for the first time, that the timed activation of serotonin neurons during waiting promotes animals' patience to wait for a delayed reward. Copyright © 2014 Elsevier Ltd. All rights reserved.

Alteration of neurotransmission and skeletogenesis in sea urchin Arbacia lixula embryos exposed to copper oxide nanoparticles.

Science.gov (United States)

Cappello, Tiziana; Vitale, Valeria; Oliva, Sabrina; Villari, Valentina; Mauceri, Angela; Fasulo, Salvatore; Maisano, Maria

2017-09-01

The extensive use of copper oxide nanoparticles (CuO NPs) in many applications has raised concerns over their toxicity on environment and human health. Herein, the embryotoxicity of CuO NPs was assessed in the black sea urchin Arbacia lixula, an intertidal species commonly present in the Mediterranean. Fertilized eggs were exposed to 0.7, 10 and 20ppb of CuO NPs, until pluteus stage. Interferences with the normal neurotransmission pathways were observed in sea urchin embryos. In detail, evidence of cholinergic and serotoninergic systems affection was revealed by dose-dependent decreased levels of choline and N-acetyl serotonin, respectively, measured by nuclear magnetic resonance (NMR)-based metabolomics, applied for the first time to our knowledge on sea urchin embryos. The metabolic profile also highlighted a significant CuO NP dose-dependent increase of glycine, a component of matrix proteins involved in the biomineralization process, suggesting perturbed skeletogenesis accordingly to skeletal defects in spicule patterning observed previously in the same sea urchin embryos. However, the expression of skeletogenic genes, i.e. SM30 and msp130, did not differ among groups, and therefore altered primary mesenchyme cell (PMC) migration was hypothesized. Other unknown metabolites were detected from the NMR spectra, and their concentrations found to be reflective of the CuO NP exposure levels. Overall, these findings demonstrate the toxic potential of CuO NPs to interfere with neurotransmission and skeletogenesis of sea urchin embryos. The integrated use of embryotoxicity tests and metabolomics represents a highly sensitive and effective tool for assessing the impact of NPs on aquatic biota. Copyright © 2017 Elsevier Inc. All rights reserved.

Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder

DEFF Research Database (Denmark)

Mc Mahon, Brenda; Andersen, Sofie B.; Madsen, Martin K.

2016-01-01

controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding...... between summer and winter (Psex-(P = 0.02) and genotype-(P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom...

Dual-isotope single-photon emission computed tomography for dopamine and serotonin transporters in normal and parkinsonian monkey brains

Energy Technology Data Exchange (ETDEWEB)

Li, I-H. [Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan (China); Huang, W.-S. [Department of Nuclear Medicine, Tri-Service General Hospital, Taipei, 114, Taiwan (China); Yeh, C.-B. [Department of Psychiatry, Tri-Service General Hospital, Taipei, 114, Taiwan (China); Liao, M.-H.; Chen, C.-C.; Shen, L.-H. [Division of Isotope Application, Institute of Nuclear Energy Research, Taoyaun, 325 Taiwan (China); Liu, J.-C. [Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan (China); Ma, K.-H. [Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan (China)], E-mail: kuohsing91@yahoo.com.tw

2009-08-15

Introduction: Parkinson's disease (PD) affects both dopaminergic and serotonergic systems. In this study, we simultaneously evaluated dopamine and serotonin transporters in primates using dual-isotope single-photon emission computed tomography (SPECT) imaging and compared the results with traditional single-isotope imaging. Methods: Four healthy and one 6-OHDA-induced PD monkeys were used for this study. SPECT was performed over 4 h after individual or simultaneous injection of [{sup 99m}Tc]TRODAT-1 (a dopamine transporter imaging agent) and [{sup 123}I]ADAM (a serotonin transporter imaging agent). Results: The results showed that the image quality and uptake ratios in different brain regions were comparable between single- and dual-isotope studies. The striatal [{sup 99m}Tc]TRODAT-1 uptake in the PD monkey was markedly lower than that in normal monkeys. The uptake of [{sup 123}I]ADAM in the midbrain of the PD monkey was comparable to that in the normal monkeys, but there were decreased uptakes in the thalamus and striatum of the PD monkey. Conclusions: Our results suggest that dual-isotope SPECT using [{sup 99m}Tc]TRODAT-1 and [{sup 123}I]ADAM can simultaneously evaluate changes in dopaminergic and serotonergic systems in a PD model.

Serotonin 2A receptor agonist binding in the human brain with [¹¹C]Cimbi-36

DEFF Research Database (Denmark)

Ettrup, Anders; Svarer, Claus; McMahon, Brenda

2016-01-01

INTRODUCTION: [(11)C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test-retest variability of cerebral [(11)C]Cimbi-36 PET and compare [(11)C...... test-retest variability in [(11)C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [(18)F]altanserin. Regional differences in the brain distribution of [(11)C]Cimbi-36 and [(18)F]altanserin were assessed with a correlation of regional binding measures...... and with voxel-based analysis. RESULTS: Test-retest variability of [(11)C]Cimbi-36 non-displaceable binding potential (BPND) was consistently correlation between regional...

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

Science.gov (United States)

Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

2016-01-01

Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID

Transient Serotonin Syndrome by Concurrent Use of Electroconvulsive Therapy and Selective Serotonin Reuptake Inhibitor: A Case Report and Review of the Literature

Directory of Open Access Journals (Sweden)

Nagahisa Okamoto

2012-01-01

Full Text Available The serotonin syndrome, which is characterized by psychiatric, autonomic nervous and neurological symptoms, is considered to be caused by excessive stimulation of the 5-HT1A and 5-HT2 receptors in the gray matter and spinal cord of the central nervous system, after the start of dosing or increase of the dose of a serotoninergic drug. There have been hardly any reports of induction of serotonin syndrome by electroconvulsive therapy (ECT in combination with antidepressant. We present the case of a female patient with major depressive disorder (MDD who developed transient serotonin syndrome soon after the first session of ECT in combination with paroxetine. Paroxetine was discontinued, and her psychiatric, autonomic nervous and neurological symptoms were gradually relieved and disappeared within 2 days. We performed the second ECT session 5 days after the initial session and performed 12 sessions of ECT without any changes in the procedure of ECT and anesthesia, but no symptoms of SS were observed. Finally, her MDD remitted. ECT might cause transiently increased blood-brain barrier (BBB permeability and enhance the transmissivity of the antidepressant in BBB. Therefore, it is necessary to pay attention to rare side effect of serotonin syndrome by ECT in combination with antidepressant.

Transient serotonin syndrome by concurrent use of electroconvulsive therapy and selective serotonin reuptake inhibitor: a case report and review of the literature.

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Okamoto, Nagahisa; Sakamoto, Kota; Yamada, Maki

2012-01-01

The serotonin syndrome, which is characterized by psychiatric, autonomic nervous and neurological symptoms, is considered to be caused by excessive stimulation of the 5-HT1A and 5-HT2 receptors in the gray matter and spinal cord of the central nervous system, after the start of dosing or increase of the dose of a serotoninergic drug. There have been hardly any reports of induction of serotonin syndrome by electroconvulsive therapy (ECT) in combination with antidepressant. We present the case of a female patient with major depressive disorder (MDD) who developed transient serotonin syndrome soon after the first session of ECT in combination with paroxetine. Paroxetine was discontinued, and her psychiatric, autonomic nervous and neurological symptoms were gradually relieved and disappeared within 2 days. We performed the second ECT session 5 days after the initial session and performed 12 sessions of ECT without any changes in the procedure of ECT and anesthesia, but no symptoms of SS were observed. Finally, her MDD remitted. ECT might cause transiently increased blood-brain barrier (BBB) permeability and enhance the transmissivity of the antidepressant in BBB. Therefore, it is necessary to pay attention to rare side effect of serotonin syndrome by ECT in combination with antidepressant.

Effects of Postnatal Serotonin Agonism on Fear Response and Memory

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The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter the development of the serotonergic circuitry, altering behaviors mediated by 5-HT signaling, such as memory, fear and aggression. White leghorn chicks...

Differential effects of chronic partial sleep deprivation and stress on serotonin-1A and muscarinic acetylcholine receptor sensitivity

NARCIS (Netherlands)

Roman, Viktor; Hagewoud, Roelina; Luiten, Paul G. M.; Meerlo, Peter

2006-01-01

Disrupted sleep and stress are often linked to each other, and considered as predisposing factors for psychopathologies such as depression. The depressed brain is associated with reduced serotonergic and enhanced cholinergic neurotransmission. In an earlier study, we showed that chronic sleep

Serotonin: A mediator of the gut-brain axis in multiple sclerosis

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Malinova, Tsveta S.; Dijkstra, Christine D.; de Vries, Helga E.

2017-01-01

The significance of the gut microbiome for the pathogenesis of multiple sclerosis (MS) has been established, although the underlying signaling mechanisms of this interaction have not been sufficiently explored. We address this point and use serotonin (5-hydroxytryptamine (5-HT))-a

Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review.

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Gillman, P Ken

2010-02-01

The US Food and Drug Administration (FDA) have suggested that fatal serotonin syndrome (SS) is possible with selective serotonin reuptake inhibitors (SSRIs) and triptans: this warning affects millions of patients as these drugs are frequently given simultaneously. SS is a complex topic about which there is much misinformation. The misconception that 5-HT1A receptors can cause serious SS is still widely perpetuated, despite quality evidence that it is activation of the 5-HT2A receptor that is required for serious SS. This review considers SS involving serotonin agonists: ergotamine, lysergic acid diethylamide, bromocriptine, and buspirone, as well as triptans, and reviews the experimental foundation underpinning the latest understanding of SS. It is concluded that there is neither significant clinical evidence, nor theoretical reason, to entertain speculation about serious SS from triptans and SSRIs. The misunderstandings about SS exhibited by the FDA, and shared by the UK Medicines and Healthcare products Regulatory Agency (in relation to methylene blue), are an important issue with wide ramifications.

Revisiting the tryptophan-serotonin deficiency and the inflammatory hypotheses of major depression in a biopsychosocial approach

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Andreas Baranyi

2017-11-01

Full Text Available Background The aim of this cross-sectional study was to identify important biopsychosocial correlates of major depression. Biological mechanisms, including the inflammatory and the tryptophan-serotonin deficiency hypotheses of major depression, were investigated alongside health-related quality of life, life satisfaction, and social support. Methods The concentrations of plasma tryptophan, plasma kynurenine, plasma kynurenic acid, serum quinolinic acid, and the tryptophan breakdown to kynurenine were determined alongside health-related quality of life (Medical Outcome Study Form, SF-36, life satisfaction (Life Satisfaction Questionnaire, FLZ, and social support (Social Support Survey, SSS in 71 depressive patients at the time of their in-patient admittance and 48 healthy controls. Results Corresponding with the inflammatory hypothesis of major depression, our study results suggest a tryptophan breakdown to kynurenine in patients with major depression, and depressive patients had a lower concentration of neuroprotective kynurenic acid in comparison to the healthy controls (Mann–Whitney-U: 1315.0; p = 0.046. Contradicting the inflammatory theory, the concentrations of kynurenine (t: −0.945; df = 116; p = 0.347 and quinolinic acid (Mann-Whitney-U: 1376.5; p = 0.076 in depressive patients were not significantly different between depressed and healthy controls. Our findings tend to support the tryptophan-serotonin deficiency hypothesis of major depression, as the deficiency of the serotonin precursor tryptophan in depressive patients (t: −3.931; df = 116; p < 0.001 suggests dysfunction of serotonin neurotransmission. A two-step hierarchical linear regression model showed that low tryptophan concentrations, low social support (SSS, occupational requirements (FLZ, personality traits (FLZ, impaired physical role (SF-36, and impaired vitality (SF-36 predict higher Beck Depression Inventory (BDI-II scores. Discussion Our study results

Emotional voice processing: investigating the role of genetic variation in the serotonin transporter across development.

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Tobias Grossmann

Full Text Available The ability to effectively respond to emotional information carried in the human voice plays a pivotal role for social interactions. We examined how genetic factors, especially the serotonin transporter genetic variation (5-HTTLPR, affect the neurodynamics of emotional voice processing in infants and adults by measuring event-related brain potentials (ERPs. The results revealed that infants distinguish between emotions during an early perceptual processing stage, whereas adults recognize and evaluate the meaning of emotions during later semantic processing stages. While infants do discriminate between emotions, only in adults was genetic variation associated with neurophysiological differences in how positive and negative emotions are processed in the brain. This suggests that genetic association with neurocognitive functions emerges during development, emphasizing the role that variation in serotonin plays in the maturation of brain systems involved in emotion recognition.

Brain neurotransmitters and hippocampal proteome in pigs under stress and environmental enrichment

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Laura Arroyo

2017-06-01

Full Text Available Stress and wellbeing are psychological conditions that are mediated by the central nervous system. In the brain, stress is mediated mainly by the hypothalamus, which will activate the hypothalamic-pituitary-adrenal (HPA axis, leading to the secretion of cortisol, the paradigmatic stress hormone. Other brain areas as the amygdala, the hippocampus or the prefrontal cortex (PFC are involved in emotions such as happiness, anxiety and fear. Communication between brain areas is achieved by chemical neurotransmitters (NTs, which are secreted by presynaptic neurons to reach postsynaptic neurons, where they will cause a variation in membrane polarization and other cell signaling actions, leading to physiological responses. Amongst these NTs, catecholamines (noradrenaline and dopamine and serotonin play an important role. On the other hand, the adverse effects of stress may be counteracted by housing the individuals under environmental enrichment conditions. This long-term situation should have an effect, not only on NTs, but also on the brain proteome. Under the hypothesis that different stress situations will lead to changes in NT composition that will be specific for crucial brain areas, we have tested the effects of transport stress, handling stress at the slaughterhouse, and the stress-susceptible genotype (Ryr1 on the amine NT concentration in amygdala, hippocampus, PFC and hypothalamus of pigs. The effects of living under environmentally enriched or control conditions on the NT concentration in several brain regions and on the hippocampus proteome has been also analyzed. In conclusion, genetic factors as well as management conditions related to housing, transport and slaughterhouse alter in different degree the catecholaminergic and the serotoninergic neurotransmission in the brain, and give clues about how different individual types are able to react to external challenges. Likewise, environmental enrichment leads to changes in the proteome

Effects of Early Serotonin Programming on Fear Response, Memory and Aggression

Science.gov (United States)

The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter development of serotonergic circuitry, altering behaviors mediated by 5-HT signaling, including memory, fear and aggression. The present study was desi...

Regionally Selective Requirement for D[subscript 1]/D[subscript 5] Dopaminergic Neurotransmission in the Medial Prefrontal Cortex in Object-in-Place Associative Recognition Memory

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Savalli, Giorgia; Bashir, Zafar I.; Warburton, E. Clea

2015-01-01

Object-in-place (OiP) memory is critical for remembering the location in which an object was last encountered and depends conjointly on the medial prefrontal cortex, perirhinal cortex, and hippocampus. Here we examined the role of dopamine D[subscript 1]/D[subscript 5] receptor neurotransmission within these brain regions for OiP memory. Bilateral…

Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

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Belmer, Arnauld; Quentin, Emily; Diaz, Silvina L; Guiard, Bruno P; Fernandez, Sebastian P; Doly, Stéphane; Banas, Sophie M; Pitychoutis, Pothitos M; Moutkine, Imane; Muzerelle, Aude; Tchenio, Anna; Roumier, Anne; Mameli, Manuel; Maroteaux, Luc

2018-06-01

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT 2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT 2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT 2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT 2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT 2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT 2B -receptor stimulation by BW723C86 counteracted 5-HT 1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT 2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT 2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT 1A -autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT 2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT 2B receptor acts as a direct positive modulator of serotonin Pet1

Abnormal serotonin transporter availability in the brains of adults with conduct disorder.

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Chang, Chieh; Gau, Susan Shur-Fen; Huang, Wen-Sheng; Shiue, Chyng-Yann; Yeh, Chin-Bin

2017-06-01

The aims of the current study were to determine whether patients with conduct disorder (CD) showed an abnormal availability of serotonin reuptake transporter (SERT), and if their hyperkinetic symptoms, impulsivity, and quality of life were correlated with the availability of SERT. We recruited 14 drug-naïve patients with CD and eight age-matched healthy controls (HCs). The adult attention-deficit/hyperactivity disorder (ADHD) self-report scale (ASRS), Barrett impulsivity scale (BIS), and the World Health Organization quality of life-brief version (WHOQOL-BREF) scale were administered. Positron emission tomography (PET) of the brain with 4-[ 18 F]-ADAM was arranged for SERT imaging. SERT availability was significantly reduced in the striatum and midbrain of patients with CD. Quality of life and inattention symptoms were also significantly correlated with the availability of SERT in the prefrontal cortex. The study suggested that a reduction in the availability of SERT might be associated with CD and could potentially predict poor quality of life or symptoms of inattention for these patients. The implications of our results might be limited to individuals with CD; a future study with a larger sample to validate our preliminary results is warranted. Copyright © 2016. Published by Elsevier B.V.

Expression of brain derived neurotrophic factor, activity-regulated cytoskeleton protein mRNA, and enhancement of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensine

DEFF Research Database (Denmark)

Larsen, Marianne Hald; Rosenbrock, Holger; Sams-Dodd, Frank

2007-01-01

The changes of gene expression resulting from long-term exposure to monoamine antidepressant drugs in experimental animals are key to understanding the mechanisms of action of this class of drugs in man. Many of these genes and their products are either relevant biomarkers or directly involved...... in structural changes that are perhaps necessary for the antidepressant effect. Tesofensine is a novel triple monoamine reuptake inhibitor that acts to increase noradrenaline, serotonin, and dopamine neurotransmission. This study was undertaken to examine the effect of sub-chronic (5 days) and chronic (14 days......) administration of Tesofensine on the expression of brain derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton protein (Arc) in the rat hippocampus. Furthermore, hippocampi from the same animals were used to investigate the effect on cell proliferation by means of Ki-67- and Neuro...

[Synergistic application of zinc and vitamin C to support memory, attention and the reduction of the risk of the neurological diseases].

Science.gov (United States)

Gromova, O A; Torshin, I Yu; Pronin, A V; Kilchevsky, M A

Zinc and vitamin C supplementation of the body is important for CNS functioning. Zinc ions are involved in the neurotransmission (signal transmission from acetylcholine, catecholamine, serotonin, prostaglandin receptors) and in ubiquitin-related protein degradation. Zinc deficits are associated with Alzheimer's disease and depression. Zinc supplementation (10-30 mg daily) improves neurologic recovery rate in patients with stroke and brain injury, has a positive impact on memory and reduces hyperactivity in children. Vitamin C, a zinc synergist, maintains antioxidant resources of the brain, synaptic activity and detoxification. Vitamin C in dose 130-500 mg daily should be used to prevent dementia and neurodegenerative pathology.

Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration.

NARCIS (Netherlands)

Matondo, R.B.; Punt, C.J.A.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; Bruin, A. de

2009-01-01

The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver

Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration

NARCIS (Netherlands)

Matondo, R.B.; Punt, C.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; de Bruin, A.

2009-01-01

The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver

Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice.

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Kyzar, Evan J; Stewart, Adam Michael; Kalueff, Allan V

2016-01-01

Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert(+/-) mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert(+/-) mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert(+/+) and Sert(+/-) mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert(+/-) mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice. Copyright © 2015 Elsevier B.V. All rights reserved.

Omega-3 polyunsaturated fatty acids and brain aging.

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Denis, Isabelle; Potier, Brigitte; Heberden, Christine; Vancassel, Sylvie

2015-03-01

The literature on the influence of dietary omega-3 polyunsaturated fatty acid (ω-3 PUFA) on brain aging has grown exponentially during the last decade. Many avenues have been explored but no global picture or clear evidence has emerged. Experimental studies have shown that ω-3 PUFA is involved in many neurobiological processes that are involved in neurotransmission and neuroprotection, indicating that these PUFAs may prevent age-related brain damage. Human studies have revealed only a weak link between ω-3 PUFA status and cognitive aging, whereas interventional studies have yet to confirm it. The purpose of this review is to analyze the developments in the area during the last 2 years. Human brain MRI studies have confirmed previous findings that ω-3 PUFA can protect the brain during aging; two intervention studies obtained clear evidence. We also analyzed the experimental data clarifying the involvement of ω-3 PUFA in neurotransmission, neuroprotection (including prevention of peroxidation, inflammation, and excitotoxicity), and neurogenesis, thereby helping the brain cope with aging. These recent human and experimental studies provide support for and clarification of how ω-3 PUFA protect against brain aging and highlight the main lines for future research.

Biodistribution and dosimetry of 123I-mZIENT: a novel ligand for imaging serotonin transporters

International Nuclear Information System (INIS)

Nicol, Alice; Krishnadas, Rajeev; Champion, Sue; Tamagnan, Gilles; Stehouwer, Jeffrey S.; Goodman, Mark M.; Hadley, Donald M.; Pimlott, Sally L.

2012-01-01

123 I-labelled mZIENT (2β-carbomethoxy-3β-(3'-((Z)-2-iodoethenyl)phenyl)nortropane) has been developed as a radioligand for the serotonin transporter. The aim of this preliminary study was to assess its whole-body biodistribution in humans and estimate dosimetry. Three healthy controls and three patients receiving selective serotonin reuptake inhibitor (SSRI) therapy for depression were included (two men, four women, age range 41-56 years). Whole-body imaging, brain SPECT imaging and blood and urine sampling were performed. Whole-body images were analysed using regions of interest (ROIs), time-activity curves were derived using compartmental analysis and dosimetry estimated using OLINDA software. Brain ROI analysis was performed to obtain specific-to-nonspecific binding ratios in the midbrain, thalamus and striatum. Initial high uptake in the lungs decreased in later images. Lower uptake was seen in the brain, liver and intestines. Excretion was primarily through the urinary system. The effective dose was estimated to be of the order of 0.03 mSv/MBq. The organ receiving the highest absorbed dose was the lower large intestine wall. Uptake in the brain was consistent with the known SERT distribution with higher specific-to-nonspecific binding in the midbrain, thalamus and striatum in healthy controls compared with patients receiving SSRI therapy. 123 I-mZIENT may be a promising radioligand for imaging the serotonin transporters in humans with acceptable dosimetry. (orig.)

Cocaine Dysregulates Opioid Gating of GABA Neurotransmission in the Ventral Pallidum

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Scofield, Michael D.; Rice, Kenner C.; Cheng, Kejun; Roques, Bernard P.

2014-01-01

The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a δ and μ opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in reward-related behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-dependent long-term depression of GABA neurotransmission in the VP was lost in cocaine-extinguished rats. Last, GABA neurotransmission was found to be tonically suppressed in cocaine-extinguished rats. These substantial synaptic changes indicated that cocaine was increasing tone on MOR receptors. Accordingly, increasing endogenous tone by blocking the enzymatic degradation of enkephalin inhibited GABA neurotransmission in yoked saline rats but not in cocaine-extinguished rats. In conclusion, our results indicate that following withdrawal from cocaine self-administration enkephalin levels in the VP are elevated and the opioid modulation of GABA neurotransmission is impaired. This may contribute to the difficulties withdrawn addicts experience when trying to resist relapse. PMID:24431463

Serotonin-induced down-regulation of cell surface serotonin transporter

DEFF Research Database (Denmark)

Jørgensen, Trine Nygaard; Christensen, Peter Møller; Gether, Ulrik

2014-01-01

The serotonin transporter (SERT) terminates serotonergic signaling and enables refilling of synaptic vesicles by mediating reuptake of serotonin (5-HT) released into the synaptic cleft. The molecular and cellular mechanisms controlling SERT activity and surface expression are not fully understood...

Compositions and methods related to serotonin 5-HT1A receptors

Science.gov (United States)

Mukherjee, Jogeshwar [Irvine, CA; Saigal, Neil [Fresno, CA; Saigal, legal representative, Harsh

2012-09-25

Contemplated substituted arylpiperazinyl compounds, and most preferably .sup.18F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with .sup.18F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

Brain SPECT in childhood; Temp cerebrale chez l'enfant

Energy Technology Data Exchange (ETDEWEB)

Tranquart, F; Saliba, E; Prunier, C; Baulieu, F; Besnard, J C; Guilloteau, D; Baulieu, J L [Hopital Bretonneau, Service de Medecine Nucleaire, Unite Inserm 316, 37 - Tours (France)

2001-04-01

The modalities and the indications of perfusion and neurotransmission SPECT in childhood are presented. The perfusion as well as neurotransmission tracers have not yet authorization for use in children; they have to be used by prescription of magistral preparation or in research protocols. The radioprotection rules have to be strictly respected. The most frequent indication of perfusion SPECT is pharmacologically resistant epilepsy; the ictal SPECT before surgery allows the localization of the epileptogenic focus. Other indications are relevant in the prognosis of neonatal anoxia and encephalitis. In psychiatric disorders, especially in autism, the interest is the physiopathological approach of the brain dysfunctions. The neurotransmission SPECT is emerging as a consequence of the development of new radiotracer, as the dopaminergic system ligands. The decrease of the dopamine D2 receptors in the striatum can be imaged and quantified in the neonate. The lesions of dopamine system seem to be a consequence of the neonatal hypoxia-ischemia and it is predictive of motor sequelae. Brain SPECT should become a routine examination in child neurologic and psychiatric disorders. (authors)

Serotonergic modulation of face-emotion recognition

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C.M. Del-Ben

2008-04-01

Full Text Available Facial expressions of basic emotions have been widely used to investigate the neural substrates of emotion processing, but little is known about the exact meaning of subjective changes provoked by perceiving facial expressions. Our assumption was that fearful faces would be related to the processing of potential threats, whereas angry faces would be related to the processing of proximal threats. Experimental studies have suggested that serotonin modulates the brain processes underlying defensive responses to environmental threats, facilitating risk assessment behavior elicited by potential threats and inhibiting fight or flight responses to proximal threats. In order to test these predictions about the relationship between fearful and angry faces and defensive behaviors, we carried out a review of the literature about the effects of pharmacological probes that affect 5-HT-mediated neurotransmission on the perception of emotional faces. The hypothesis that angry faces would be processed as a proximal threat and that, as a consequence, their recognition would be impaired by an increase in 5-HT function was not supported by the results reviewed. In contrast, most of the studies that evaluated the behavioral effects of serotonin challenges showed that increased 5-HT neurotransmission facilitates the recognition of fearful faces, whereas its decrease impairs the same performance. These results agree with the hypothesis that fearful faces are processed as potential threats and that 5-HT enhances this brain processing.

Clinical results of neurotransmission SPECT in extra-pyramidal diseases; Resultats cliniques de la TEMP de la neurotransmission en pathologie extra-pyramidale

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Baulieu, J.L.; Prunier, C.; Tranquart, F.; Guilloteau, D. [Centre Hospitalier Universitaire Bretonneau, Service de Medecine Nucleaire in vitro, INSERM U316, 37 - Tours (France)

1999-12-01

We present some methodological aspects and clinical applications of dopamine D2 receptor and transporter SPECT using new radiotracers radiolabeled with iodine 123. The gamma camera quality control and standardisation has to be adapted to the small volume and deep location of striata, where receptors and transporters are present. Phantom containing hollow spheres of different diameters which can be filled with different amounts of {sup 99m}Tc or {sup 123}I. The semi quantitation of receptor and transporter molecular concentration is based on an equilibrium binding model. According to this model, the binding potential (Bmax. Ka) is equal to the ratio between specific binding in the striatum and circulating activity in a reference region of interest in the occipital cortex. By comparing ECD and ILIS SPECT, it has been shown that striatal ILIS binding does not depend on the local perfusion. The clinical applications mainly concern the extra-pyramidal pathology: ILIS and IBZM SPECT are able to differentiate pre- and post-synaptic lesions. In Parkinson disease the nigrostriatal pathway is damaged and D2 receptors are normal or increased, as shown by normal or elevated IBZM or ILIS uptake. In other extra pyramidal degenerative diseases as progressive supra nuclear palsy or multiple system atrophy striatal D2 receptors are damaged as shown by decreased IBZM or ILIS uptake. In our experience, 88 per cent of patients are correctly classified by ILIS SPECT and 86 per cent with IBZM SPECT. Dopamine transporter SPECT with {beta}CIT and PE2I provides an evaluation of the presynaptic neuronal density in the striatum. One can expect an help for the early diagnosis and the evaluation of Parkinson disease. Another potential application of dopaminergic neurotransmission SPECT is the evaluation of neuronal loss after hypoxo-ischemia. We conclude that dopaminergic neurotransmission SPECT using specific ligands should become a useful diagnosis tool to study a large number of brain

The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia

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Jennifer S. Yokoyama

2015-01-01

Full Text Available The serotonin transporter length polymorphism (5-HTTLPR short allele (5-HTTLPR-s has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD, a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2 of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03 and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01. These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease-related compensation for altered serotonergic activity.

Biodistribution and dosimetry of {sup 123}I-mZIENT: a novel ligand for imaging serotonin transporters

Energy Technology Data Exchange (ETDEWEB)

Nicol, Alice [NHS Greater Glasgow and Clyde, Department of Nuclear Medicine, Southern General Hospital, Glasgow (United Kingdom); Krishnadas, Rajeev [University of Glasgow, Sackler Institute of Psychobiological Research, Glasgow (United Kingdom); Champion, Sue [University of Glasgow, Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, Glasgow (United Kingdom); Tamagnan, Gilles [Institute for Neurodegenerative Disorders, New Haven, CT (United States); Stehouwer, Jeffrey S.; Goodman, Mark M. [Emory University, Department of Radiology and Imaging Sciences, Atlanta, GA (United States); Hadley, Donald M. [NHS Greater Glasgow and Clyde, Department of Neuro-Radiology, Institute of Neurological Sciences, Glasgow (United Kingdom); Pimlott, Sally L. [NHS Greater Glasgow and Clyde, West of Scotland Radionuclide Dispensary, Glasgow (United Kingdom)

2012-05-15

{sup 123}I-labelled mZIENT (2{beta}-carbomethoxy-3{beta}-(3'-((Z)-2-iodoethenyl)phenyl)nortropane) has been developed as a radioligand for the serotonin transporter. The aim of this preliminary study was to assess its whole-body biodistribution in humans and estimate dosimetry. Three healthy controls and three patients receiving selective serotonin reuptake inhibitor (SSRI) therapy for depression were included (two men, four women, age range 41-56 years). Whole-body imaging, brain SPECT imaging and blood and urine sampling were performed. Whole-body images were analysed using regions of interest (ROIs), time-activity curves were derived using compartmental analysis and dosimetry estimated using OLINDA software. Brain ROI analysis was performed to obtain specific-to-nonspecific binding ratios in the midbrain, thalamus and striatum. Initial high uptake in the lungs decreased in later images. Lower uptake was seen in the brain, liver and intestines. Excretion was primarily through the urinary system. The effective dose was estimated to be of the order of 0.03 mSv/MBq. The organ receiving the highest absorbed dose was the lower large intestine wall. Uptake in the brain was consistent with the known SERT distribution with higher specific-to-nonspecific binding in the midbrain, thalamus and striatum in healthy controls compared with patients receiving SSRI therapy. {sup 123}I-mZIENT may be a promising radioligand for imaging the serotonin transporters in humans with acceptable dosimetry. (orig.)

Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation*

Science.gov (United States)

Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

2015-01-01

The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu406 is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. PMID:25903124

Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats

NARCIS (Netherlands)

Homberg, J.R.; Nijman, I.J.; Kuijpers, S.; Cuppen, E.

2010-01-01

BACKGROUND: Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4) has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain

Opposite effect of phencyclidine on activity-regulated cytoskeleton-associated protein (Arc) in juvenile and adult limbic rat brain regions

DEFF Research Database (Denmark)

Thomsen, Morten S; Hansen, Henrik H; Mikkelsen, Jens D

2010-01-01

-regulated cytoskeleton-associated protein (Arc) and parvalbumin mRNA expression in juvenile and adult rats. Arc is a marker for excitatory neurotransmission. Parvalbumin is a marker for GABAergic neurotransmission, known to be reduced in postmortem brains of schizophrenics. PCP reduced parvalbumin mRNA expression...

Impaired dopaminergic neurotransmission in patients with traumatic brain injury: a SPECT study using 123I-beta-CIT and 123I-IBZM.

Science.gov (United States)

Donnemiller, E; Brenneis, C; Wissel, J; Scherfler, C; Poewe, W; Riccabona, G; Wenning, G K

2000-09-01

Structural imaging suggests that traumatic brain injury (TBI) may be associated with disruption of neuronal networks, including the nigrostriatal dopaminergic pathway. However, to date deficits in pre- and/or postsynaptic dopaminergic neurotransmission have not been demonstrated in TBI using functional imaging. We therefore assessed dopaminergic function in ten TBI patients using [123I]2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane (beta-CIT) and [123I]iodobenzamide (IBZM) single-photon emission tomography (SPET). Average Glasgow Coma Scale score (+/-SD) at the time of head trauma was 5.8+/-4.2. SPET was performed on average 141 days (SD +/-92) after TBI. The SPET images were compared with structural images using cranial computerised tomography (CCT) and magnetic resonance imaging (MRI). SPET was performed with an ADAC Vertex dual-head camera. The activity ratios of striatal to cerebellar uptake were used as a semiquantitative parameter of striatal dopamine transporter (DAT) and D2 receptor (D2R) binding. Compared with age-matched controls, patients with TBI had significantly lower striatal/cerebellar beta-CIT and IBZM binding ratios (PTBI despite relative structural preservation of the striatum. Further investigations of possible clinical correlates and efficacy of dopaminergic therapy in patients with TBI seem justified.

Autoradiographic imaging of the serotonin transporter, using S-[18F](fluoromethyl)-(+)-McN5652 ([18F]Me-McN) in the brains of several animal species

International Nuclear Information System (INIS)

Kretzschmar, M.; Zessin, J.; Brust, P.; Cumming, P.; Bergmann, R.

2002-01-01

The [ 18 F]fluoromethyl analogue of (+)-McN5652 ([ 18 F]Me-McN) was recently proposed as a new potential PET tracer [1]. To further validate its use in PET, we studied the binding of [ 18 F]Me-McN in the brains of rats and pigs using autoradiography. The binding was compared with the uptake of the known 5-HT uptake inhibitor [ 3 H] citalopram [2] and the radioligand (+)-[ 11 C]McN5652. The binding of the three compounds was qualitatively identical in the autoradiograms of the individual brains. Intense labelling was observed in regions known to be serotonin uptake sites. The binding was specifically inhibited, using the 5-HT uptake inhibitors citalopram and fluoxetine. (orig.)

Brain SPECT in childhood; Temp cerebrale chez l'enfant

Energy Technology Data Exchange (ETDEWEB)

Tranquart, F.; Saliba, E.; Prunier, C.; Baulieu, F.; Besnard, J.C.; Guilloteau, D.; Baulieu, J.L. [Hopital Bretonneau, Service de Medecine Nucleaire, Unite Inserm 316, 37 - Tours (France)

2001-04-01

The modalities and the indications of perfusion and neurotransmission SPECT in childhood are presented. The perfusion as well as neurotransmission tracers have not yet authorization for use in children; they have to be used by prescription of magistral preparation or in research protocols. The radioprotection rules have to be strictly respected. The most frequent indication of perfusion SPECT is pharmacologically resistant epilepsy; the ictal SPECT before surgery allows the localization of the epileptogenic focus. Other indications are relevant in the prognosis of neonatal anoxia and encephalitis. In psychiatric disorders, especially in autism, the interest is the physiopathological approach of the brain dysfunctions. The neurotransmission SPECT is emerging as a consequence of the development of new radiotracer, as the dopaminergic system ligands. The decrease of the dopamine D2 receptors in the striatum can be imaged and quantified in the neonate. The lesions of dopamine system seem to be a consequence of the neonatal hypoxia-ischemia and it is predictive of motor sequelae. Brain SPECT should become a routine examination in child neurologic and psychiatric disorders. (authors)

Serotonin 6 receptor controls Alzheimer's disease and depression.

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Yun, Hyung-Mun; Park, Kyung-Ran; Kim, Eun-Cheol; Kim, Sanghyeon; Hong, Jin Tae

2015-09-29

Alzheimer's disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R antagonist, SB271036 rescued memory impairment by attenuating the generation of Aβ via the inhibition of γ-secretase activity and the inactivation of astrocytes and microglia in the AD mouse model. It was found that the reduction of serotonin level was significantly recovered by SB271036, which was mediated by an indirect regulation of serotonergic neurons via GABA. Selective serotonin reuptake inhibitor (SSRI), fluoxetine significantly improved cognitive impairment and behavioral changes. In human brain of depression patients, we then identified the potential genes, amyloid beta (A4) precursor protein-binding, family A, member 2 (APBA2), well known AD modulators by integrating datasets from neuropathology, microarray, and RNA seq. studies with correlation analysis tools. And also, it was demonstrated in mouse models and patients of AD. These data indicate functional network of 5-HT6R between AD and depression.

Characterization of the effects of serotonin on the release of [3H]dopamine from rat nucleus accumbens and striatal slices

International Nuclear Information System (INIS)

Nurse, B.; Russell, V.A.; Taljaard, J.J.

1988-01-01

The effect of serotonin agonists on the depolarization (K+)-induced, calcium-dependent, release of [ 3 H]dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal 3 H overflow and reduced K+-induced release of [ 3 H]DA from nucleus accumbens slices. The effect of serotonin on basal 3 H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K+-induced release of [ 3 H]DA in the nucleus accumbens or striatum. The serotonin agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K+-induced release of [ 3 H]DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens

Memory function and serotonin transporter promoter gene polymorphism in ecstasy (MDMA) users

NARCIS (Netherlands)

Reneman, Liesbeth; Schilt, T.; de Win, Maartje M.; Booij, Jan; Schmand, Ben; van den Brink, Wim; Bakker, Onno

2006-01-01

Although 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) has been shown to damage brain serotonin (5-HT) neurons in animals and possibly humans, little is known about the long-term consequences of MDMA-induced 5-HT neurotoxic lesions on functions in which 5-HT is involved, such as cognitive

A blunted anxiolytic like effect of curcumin against acute lead induced anxiety in rat: involvement of serotonin.

Science.gov (United States)

Benammi, Hind; El Hiba, Omar; Romane, Abderrahmane; Gamrani, Halima

2014-06-01

Anxiety is one of the most common mental disorders sharing extreme or pathological anxiety states as the primary disturbance in mood or emotional tone, with increased fear and exaggerated acute stress responses. Medicinal plants are very variable, but some of them are used as a spice such as curcumin (Curcuma longa). Curcumin shows a wide range of pharmacological potentialities, however, little is known about its anxiolytic properties. The aim of our study was to assess the anti-anxiety potential of curcumin extract against experimental lead induced-anxiety in rats. Experiments were carried out on male Wistar rats intoxicated acutely with an intraperitoneal injection of Pb (25mg/kg B.W.) and/or concomitantly with administration of curcumin (30 mg/kg B.W.) for 3 days. Using immunohistochemistry and anxiety assessment tests (dark light box and elevated plus maze), we evaluated, respectively, the expression of serotonin (5HT) in the dorsal raphe nucleus (DRN) and the anxiety state in our animals. Our results showed, for the first time, a noticeable anxiolytic effect of curcumin against lead induced anxiety in rats and this may possibly result from modulation of central neuronal monoaminergic neurotransmission, especially serotonin, which has shown a significant reduction of the immunoreactivity within the DRN. Copyright © 2014 Elsevier GmbH. All rights reserved.

Preclinical pharmacological study on I-ADAM as a serotonin transporter ligand

International Nuclear Information System (INIS)

Wu Chunying; Lu Chunxiong; Jiang Quanfu; Zou Meifen; Chen Zhengping; Wang Songpei; Li Xiaomin; Zhang Tongxing; Zhu Junqing; Lin Xiangtong

2004-01-01

Objective: To evaluate the new ligand: I-2-( (22( (dimethylamino) methyl) phenyl) thio)-5- iodophenylamine (ADAM) as a serotonin imaging agent. Methods: Biological evaluations were performed in rats and mice. Results: Biodistribution studies in rats showed that the initial uptake of 131 I-ADAM in the brain was high (1.087%ID/organ at 2 min postinjection), and consistently displayed the highest binding (between 60-240 min postinjection) in hypothalamus, a region with the highest density of serotonin transporter (SERT). The specific binding [(TPCB)-1] of 131 I-ADAM in hypothalamus was 2.94, 3.03 and 3.09 at 60, 120 and 240 min postinjection, respectively. The (TPCB)-1 was significantly blocked by pretreatment with Paroxetine, which is known as a serotonin site reuptake inhibitor, while another nonselective competing drug, Ketanserin, showed no blocking effect. The rat brain autoradiography and analysis showed that there was high 131 I-ADAM uptake in hypothalamus, the ratio of hypothalamus/cerebellum was significantly reduced from 7.94 ± 0.39 to 1.30 ± 0.56 by pretreatment with Paroxetine at 60 min postinjection. Blood clearance kinetics was studied in rats, and the initial half-life of 13.79 min and late half-life of 357.14 min were obtained. The kinetic equation was: C=3.6147·e -0.0725t + 1.0413 e -0.0028t . The thyroid uptake was 0.009 and 1.421% ID/organ at 2 min and 120 min postinjection, respectively, suggesting that in vivo deiodination maybe the major route of metabolism. Toxicity trial showed that the dose per kilogram administered to mice was 1000 times greater than that to human beings, assuming a body-weight of 50 kg. Conclusion: These data suggest that 131 I-ADAM may be useful for SPECT imaging of SERT binding sits in the brain. (authors)

SEROTONIN METABOLISM FOLLOWING PLATINUM-BASED CHEMOTHERAPY COMBINED WITH THE SEROTONIN TYPE-3 ANTAGONIST TROPISETRON

NARCIS (Netherlands)

SCHRODER, CP; VANDERGRAAF, WTA; KEMA, IP; GROENEWEGEN, A; SLEIJFER, DT; DEVRIES, EGE

1995-01-01

The administration of platinum-based chemotherapy induces serotonin release from the enterochromaffin cells, causing nausea and vomiting. This study was conducted to evaluate parameters of serotonin metabolism following platinum-based chemotherapy given in combination with the serotonin type-3

Mind Over Matter: The Brain's Response to Drugs. Teacher's Guide.

Science.gov (United States)

National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.

This teacher's guide aims to develop an understanding among students grades 5 through 9 of the physical reality of drug use. Contents include: (1) "Brain Anatomy"; (2) "Nerve Cells and Neurotransmission"; (3) "Effects of Drugs on the Brain"; (4) "Marijuana"; (5) "Opiates"; (6) "Inhalants"; (7) "Hallucinogens"; (8) "Steroids"; (9) "Stimulants";…

Serotonin manipulations and social behavior : Studies in individuals at familial risk for depression

NARCIS (Netherlands)

Hogenelst, Koen

2016-01-01

Interactions with others affect our mood, and vice versa. Unsurprisingly, people with a mood disorder such as depression often have difficulties in their social relationships. Depression is often thought to be associated with a decreased availability of serotonin, a signaling molecule in the brain

Serotonin and noradrenaline reuptake inhibitors improve micturition control in mice.

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Marco Redaelli

Full Text Available Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg, to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition.

Sonic Hedgehog (SHH) pathway in the adult brain: key signaling for astrocyte reactivation and brain repair

OpenAIRE

Bermúdez-Muñoz, Olga M

2016-01-01

While neurons play a key role in neurotransmission in the nervous central system (CNS) of animals, glial cells are crucial for neuron support and brain maintenance. Recent studies reveal that glial cells regulate the release and reuptake of neurotransmitters, pyruvate and glutathione metabolism, ion buffering, the organization of blood brain barrier and ensures the production of myelin and cerebrospinal fluid. The activity of glial cells is coordinated by the communication between neurons and...

Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin.

Science.gov (United States)

Bernasconi, Fosco; Schmidt, André; Pokorny, Thomas; Kometer, Michael; Seifritz, Erich; Vollenweider, Franz X

2014-12-01

Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168-189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211-242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168-189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211-242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Design of a serotonin 4 receptor radiotracer with decreased lipophilicity for single photon emission computed tomography.

Science.gov (United States)

Fresneau, Nathalie; Dumas, Noé; Tournier, Benjamin B; Fossey, Christine; Ballandonne, Céline; Lesnard, Aurélien; Millet, Philippe; Charnay, Yves; Cailly, Thomas; Bouillon, Jean-Philippe; Fabis, Frédéric

2015-04-13

With the aim to develop a suitable radiotracer for the brain imaging of the serotonin 4 receptor subtype (5-HT4R) using single photon emission computed tomography (SPECT), we synthesized and evaluated a library of di- and triazaphenanthridines with lipophilicity values which were in the range expected to favour brain penetration, and which demonstrated specific binding to the target of interest. Adding additional nitrogen atoms to previously described phenanthridine ligands exhibiting a high unspecific binding, we were able to design a radioiodinated compound [(125)I]14. This compound exhibited a binding affinity value of 0.094 nM toward human 5-HT4R and a high selectivity over other serotonin receptor subtypes (5-HTR). In vivo SPECT imaging studies and competition experiments demonstrated that the decreased lipophilicity (in comparison with our previously reported compounds 4 and 5) allowed a more specific labelling of the 5-HT4R brain-containing regions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Depressed patients have decreased binding of tritiated imipramine to platelet serotonin ''transporter''

International Nuclear Information System (INIS)

Paul, S.M.; Rehavi, M.; Skolnick, P.; Ballenger, J.C.; Goodwin, F.K.

1981-01-01

The high-affinity tritiated (3H) imipramine binding sites are functionally (and perhaps structurally) associated with the presynaptic neuronal and platelet uptake sites for serotonin. Since there is an excellent correlation between the relative potencies of a series of antidepressants in displacing 3H-imipramine from binding sites in human brain and platelet, we have examined the binding of 3H-imipramine to platelets from 14 depressed patients and 28 age- and sex-matched controls. A highly significant decrease in the number of 3H-imipramine binding sites, with no significant change in the apparent affinity constants, was observed in platelets from the depressed patients compared with the controls. These results, coupled with previous studies showing a significant decrease in the maximal uptake of serotonin in platelets from depressed patients, suggest that an inherited or acquired deficiency of the serotonin transport protein or proteins may be involved in the pathogenesis of depression

Epigenetic regulation of enteric neurotransmission by gut bacteria.

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Tor eSavidge

2016-01-01

Full Text Available The Human Microbiome Project defined microbial community interactions with the human host, and provided important molecular insight into how epigenetic factors can influence intestinal ecosystems. Given physiological context, changes in gut microbial community structure are increasingly found to associate with alterations in enteric neurotransmission and disease. At present, it is not known whether shifts in microbial community dynamics represent cause or consequence of disease pathogenesis. The discovery of bacterial-derived neurotransmitters suggests further studies are needed to establish their role in enteric neuropathy. This mini-review highlights recent advances in bacterial communications to the autonomic nervous system and discusses emerging epigenetic data showing that diet, probiotic and antibiotic use may regulate enteric neurotransmission through modulation of microbial communities. Because of its limited scope, a particular emphasis is placed on bacterial regulation of enteric nervous system function in the intestine.

Disruption of Transient Serotonin Accumulation by Non-Serotonin-Producing Neurons Impairs Cortical Map Development

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Xiaoning Chen

2015-01-01

Full Text Available Polymorphisms that alter serotonin transporter SERT expression and functionality increase the risks for autism and psychiatric traits. Here, we investigate how SERT controls serotonin signaling in developing CNS in mice. SERT is transiently expressed in specific sets of glutamatergic neurons and uptakes extrasynaptic serotonin during perinatal CNS development. We show that SERT expression in glutamatergic thalamocortical axons (TCAs dictates sensory map architecture. Knockout of SERT in TCAs causes lasting alterations in TCA patterning, spatial organizations of cortical neurons, and dendritic arborization in sensory cortex. Pharmacological reduction of serotonin synthesis during the first postnatal week rescues sensory maps in SERTGluΔ mice. Furthermore, knockdown of SERT expression in serotonin-producing neurons does not impair barrel maps. We propose that spatiotemporal SERT expression in non-serotonin-producing neurons represents a determinant in early life genetic programming of cortical circuits. Perturbing this SERT function could be involved in the origin of sensory and cognitive deficits associated with neurodevelopmental disorders.

Central fatigue and nycthemeral change of serum tryptophan and serotonin in the athletic horse

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Percipalle Maurizio

2005-04-01

Full Text Available Abstract Background The serotonergic system is associated with numerous brain functions, including the resetting of the mammalian circadian clock. The synthesis and metabolism of 5-HT in the brain increases in response to exercise and is correlated with high levels of blood-borne tryptophan (TRP. The present investigation was aimed at testing the existence of a daily rhythm of TRP and 5-HT in the blood of athletic horses. Methods Blood samples from 5 Thoroughbred mares were collected at 4-hour intervals for 48 hours (starting at 08:00 hours on day 1 and finishing at 4:00 on day 2 via an intravenous cannula inserted into the jugular vein. Tryptophan and serotonin concentrations were assessed by HPLC. Data analysis was conducted by one-way repeated measures analysis of variance (ANOVA and by the single cosinor method. Results ANOVA showed a highly significant influence of time both on tryptophan and on serotonin, in all horses, on either day, with p values Conclusion The results showed that serotonin and tryptophan blood levels undergo nycthemeral variation with typical evening acrophases. These results enhance the understanding of the athlete horse's chronoperformance and facilitate the establishment of training programs that take into account the nycthemeral pattern of aminoacids deeply involved in the onset of central fatigue.

Microautoradiography of [123I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors

International Nuclear Information System (INIS)

Ye, X.-X.; Chen, J.-C.; Liu, R.-S.; Wey, S.-P.; Lee, J.-S.; Chen, C.-C.; Fu, Y.-K.; Ting, Gann; Hwang, J.-J.

2004-01-01

A radiopharmaceutical, 123 I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([ 123 I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [ 123 I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [ 123 I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [ 123 I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [ 123 I]ADAM. Significant and selective accumulation of [ 123 I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [ 131 I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [ 123 I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine

Positron Emission Tomography Quantification of Serotonin1A Receptor Binding in Suicide Attempters With Major Depressive Disorder

Science.gov (United States)

Sullivan, Gregory M.; Oquendo, Maria A.; Milak, Matthew; Miller, Jeffrey M.; Burke, Ainsley; Ogden, R. Todd; Parsey, Ramin V.; Mann, J. John

2015-01-01

IMPORTANCE Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin1A autoreceptor in the brainstem raphe of individuals who die by suicide. OBJECTIVES To determine the relationships between brain serotonin1A binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin1A antagonist radiotracer carbon C 11 [11C]–labeled WAY-100635. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin1A binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. MAIN OUTCOMES AND MEASURES The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. RESULTS Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin1A BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin1A BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin1A BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in

Glutamatergic neurotransmission from melanopsin retinal ganglion cells is required for neonatal photoaversion but not adult pupillary light reflex.

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Anton Delwig

Full Text Available Melanopsin-expressing retinal ganglion cells (mRGCs in the eye play an important role in many light-activated non-image-forming functions including neonatal photoaversion and the adult pupillary light reflex (PLR. MRGCs rely on glutamate and possibly PACAP (pituitary adenylate cyclase-activating polypeptide to relay visual signals to the brain. However, the role of these neurotransmitters for individual non-image-forming responses remains poorly understood. To clarify the role of glutamatergic signaling from mRGCs in neonatal aversion to light and in adult PLR, we conditionally deleted vesicular glutamate transporter (VGLUT2 selectively from mRGCs in mice. We found that deletion of VGLUT2 in mRGCs abolished negative phototaxis and light-induced distress vocalizations in neonatal mice, underscoring a necessary role for glutamatergic signaling. In adult mice, loss of VGLUT2 in mRGCs resulted in a slow and an incomplete PLR. We conclude that glutamatergic neurotransmission from mRGCs is required for neonatal photoaversion but is complemented by another non-glutamatergic signaling mechanism for the pupillary light reflex in adult mice. We speculate that this complementary signaling might be due to PACAP neurotransmission from mRGCs.

Mitochondria and Neurotransmission: Evacuating the Synapse

OpenAIRE

Hollenbeck, Peter J.

2005-01-01

An abundance of mitochondria has been the hallmark of synapses since their first ultrastructural description 50 years ago. Mitochondria have been shown to be essential for synaptic form and function in many systems, but until recently it has not been clear exactly what role(s) they play in neurotransmission. Now, evidence from the nervous system of Drosophila identifies the specific subcellular events that are most dependent upon nearby mitochondria.

Salivary serotonin does not correlate with central serotonin turnover in adult phenylketonuria (PKU patients

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Joseph Leung

2018-06-01

Full Text Available Introduction: Phenylketonuria (PKU is an inborn error of metabolism associated with an increased risk of behavioural and mood disorders. There are currently no reliable markers for monitoring mood in PKU. The purpose of this study was to evaluate salivary serotonin as a possible non-invasive marker of long-term mood symptoms and central serotonin activity in patients with PKU. Methods: 20 patients were recruited from our Adult Metabolic Diseases Clinic. Age, sex, plasma phenylalanine (Phe level, DASS (Depression Anxiety Stress Scales depression score, DASS anxiety score, BMI, salivary serotonin, salivary cortisol, 2-year average Phe, 2-year average tyrosine (Tyr, and 2-year average Phe:Tyr ratio were collected for each patient. Spearman's ρ correlation analysis was used to determine if there was any relationship between any of the parameters. Results: There were positive correlations between DASS anxiety and DASS depression scores (Spearman's ρ = 0.8708, p-value < 0.0001, BMI and plasma Phe level (Spearman's ρ = 0.6228, p-value = .0034, and 2-year average Phe and BMI (Spearman's ρ = 0.5448, p-value = .0130. There was also a negative correlation between salivary cortisol and plasma Phe level (Spearman's ρ = −0.5018, p-value = .0338. All other correlations were not statistically significant. Conclusion: Salivary serotonin does not correlate with peripheral phenylalanine levels, DASS depression scale scores, or DASS anxiety scale scores, implying that salivary serotonin does not reflect central serotonin turnover. Additionally, this study suggests that salivary serotonin is not a suitable marker for monitoring dietary control, mood, or anxiety in PKU. Synopsis: Salivary serotonin does not correlate with peripheral phenylalanine levels, DASS depression scale scores, or DASS anxiety scale scores, suggesting that salivary serotonin is not a suitable marker for monitoring dietary control, mood, or anxiety in PKU

Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation.

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Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

2015-06-05

The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu(406) is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Altered cortical GABA neurotransmission in schizophrenia: insights into novel therapeutic strategies.

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Stan, Ana D; Lewis, David A

2012-06-01

Altered markers of cortical GABA neurotransmission are among the most consistently observed abnormalities in postmortem studies of schizophrenia. The altered markers are particularly evident between the chandelier class of GABA neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons. For example, in the dorsolateral prefrontal cortex of subjects with schizophrenia immunoreactivity for the GABA membrane transporter is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABAA receptor α2 subunit is increased in postsynaptic AIS. Both of these molecular changes appear to be compensatory responses to a presynaptic deficit in GABA synthesis, and thus could represent targets for novel therapeutic strategies intended to augment the brain's own compensatory mechanisms. Recent findings that GABA inputs from neocortical chandelier neurons can be powerfully excitatory provide new ideas about the role of these neurons in the pathophysiology of cortical dysfunction in schizophrenia, and consequently in the design of pharmacological interventions.

Functional significance of brain glycogen in sustaining glutamatergic neurotransmission

DEFF Research Database (Denmark)

Sickmann, Helle M; Walls, Anne B; Schousboe, Arne

2009-01-01

The involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present u...

[11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

International Nuclear Information System (INIS)

Zessin, Joerg; Deuther-Conrad, Winnie; Kretzschmar, Marion; Wuest, Frank; Pawelke, Beate; Brust, Peter; Steinbach, Joerg; Bergmann, Ralf

2006-01-01

N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [ 11 C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [ 11 C]S Me-Adam. The radiochemical yield was 27±5%, and the specific radioactivity was 26-40 GBq/μmol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59±0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74±0.95 at 60 min postinjection. The [ 11 C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38±11% of the control value. Furthermore, no metabolites of [ 11 C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [ 11 C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain

[11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats.

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Zessin, Jörg; Deuther-Conrad, Winnie; Kretzschmar, Marion; Wüst, Frank; Pawelke, Beate; Brust, Peter; Steinbach, Jörg; Bergmann, Ralf

2006-01-01

N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (SMe-ADAM, 1) is a highly potent and selective inhibitor of the serotonin transporter (SERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [(11)C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [(11)C]SMe-ADAM. The radiochemical yield was 27 +/- 5%, and the specific radioactivity was 26-40 GBq/micromol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SERT, such as the thalamus/hypothalamus region (3.59 +/- 0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74 +/- 0.95 at 60 min postinjection. The [(11)C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38 +/- 11% of the control value. Furthermore, no metabolites of [(11)C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [(11)C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

The endocannabinoid system in brain reward processes.

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Solinas, M; Goldberg, S R; Piomelli, D

2008-05-01

Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.

Interactive effects of genetic polymorphisms and childhood adversity on brain morphologic changes in depression.

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Kim, Yong-Ku; Ham, Byung-Joo; Han, Kyu-Man

2018-03-10

The etiology of depression is characterized by the interplay of genetic and environmental factors and brain structural alteration. Childhood adversity is a major contributing factor in the development of depression. Interactions between childhood adversity and candidate genes for depression could affect brain morphology via the modulation of neurotrophic factors, serotonergic neurotransmission, or the hypothalamus-pituitary-adrenal (HPA) axis, and this pathway may explain the subsequent onset of depression. Childhood adversity is associated with structural changes in the hippocampus, amygdala, anterior cingulate cortex (ACC), and prefrontal cortex (PFC), as well as white matter tracts such as the corpus callosum, cingulum, and uncinate fasciculus. Childhood adversity showed an interaction with the brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism, serotonin transporter-linked promoter region (5-HTTLPR), and FK506 binding protein 51 (FKBP5) gene rs1360780 in brain morphologic changes in patients with depression and in a non-clinical population. Individuals with the Met allele of BDNF Val66Met and a history of childhood adversity had reduced volume in the hippocampus and its subfields, amygdala, and PFC and thinner rostral ACC in a study of depressed patients and healthy controls. The S allele of 5-HTTLPR combined with exposure to childhood adversity or a poorer parenting environment was associated with a smaller hippocampal volume and subsequent onset of depression. The FKBP5 gene rs160780 had a significant interaction with childhood adversity in the white matter integrity of brain regions involved in emotion processing. This review identified that imaging genetic studies on childhood adversity may deepen our understanding on the neurobiological background of depression by scrutinizing complicated pathways of genetic factors, early psychosocial environments, and the accompanying morphologic changes in emotion-processing neural circuitry. Copyright

The Effects of Serotonin in Immune Cells

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Herr, Nadine; Bode, Christoph; Duerschmied, Daniel

2017-01-01

Serotonin [5-hydroxytryptamine (5-HT)] plays an important role in many organs as a peripheral hormone. Most of the body’s serotonin is circulating in the bloodstream, transported by blood platelets and is released upon activation. The functions of serotonin are mediated by members of the 7 known mammalian serotonin receptor subtype classes (15 known subtypes), the serotonin transporter (SERT), and by covalent binding of serotonin to different effector proteins. Almost all immune cells express...

Serotonin transporter density in binge eating disorder and pathological gambling: A PET study with [11C]MADAM.

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Majuri, Joonas; Joutsa, Juho; Johansson, Jarkko; Voon, Valerie; Parkkola, Riitta; Alho, Hannu; Arponen, Eveliina; Kaasinen, Valtteri

2017-12-01

Behavioral addictions, such as pathological gambling (PG) and binge eating disorder (BED), appear to be associated with specific changes in brain dopamine and opioid function, but the role of other neurotransmitter systems is less clear. Given the crucial role of serotonin in a number of psychiatric disorders, we aimed to compare brain serotonergic function among individuals with BED, PG and healthy controls. Seven BED patients, 13 PG patients and 16 healthy controls were scanned with high-resolution positron emission tomography (PET) using the serotonin transporter (SERT) tracer [ 11 C]MADAM. Both region-of-interest and voxel-wise whole brain analyses were performed. Patients with BED showed increased SERT binding in the parieto-occipital cortical regions compared to both PG and healthy controls, with parallel decreases in binding in the nucleus accumbens, inferior temporal gyrus and lateral orbitofrontal cortex. No differences between PG patients and controls were observed. None of the subjects were on SSRI medications at the time of imaging, and there were no differences in the level of depression between PG and BED patients. The results highlight differences in brain SERT binding between individuals with BED and PG and provide further evidence of different neurobiological underpinnings in behavioral addictions that are unrelated to the co-existing mood disorder. The results aid in the conceptualization of behavioral addictions by characterizing the underlying serotonin changes and provide a framework for additional studies to examine syndrome-specific pharmaceutical treatments. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains.

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Naumenko, V S; Kondaurova, E M; Bazovkina, D V; Tsybko, A S; Tikhonova, M A; Kulikov, A V; Popova, N K

2012-07-12

The effect of brain-derived neurotrophic factor (BDNF) on depressive-like behavior and serotonin (5-HT) system in the brain of antidepressant sensitive cataleptics (ASC)/Icg mouse strain, characterized by depressive-like behavior, in comparison with the parental nondepressive CBA/Lac mouse strain was examined. Significant decrease of catalepsy and tail suspension test (TST) immobility was shown 17days after acute central BDNF administration (300ng i.c.v.) in ASC mice. In CBA mouse strain, BDNF moderately decreased catalepsy without any effect on TST immobility time. Significant difference between ASC and CBA mice in the effect of BDNF on 5-HT system was revealed. It was shown that central administration of BDNF led to increase of 5-HT(1A) receptor gene expression but not 5-HT(1A) functional activity in ASC mice. Increased tryptophan hydroxylase-2 (Tph-2) and 5-HT(2A) receptor genes expression accompanied by 5-HT(2A) receptor sensitization was shown in BDNF-treated ASC but not in CBA mouse strain, suggesting BDNF-induced increase of the brain 5-HT system functional activity and activation of neurogenesis in "depressive" ASC mice. There were no changes found in the 5-HT transporter mRNA level in BDNF-treated ASC and CBA mice. In conclusion, central administration of BDNF produced prolonged ameliorative effect on depressive-like behavior accompanied by increase of the Tph-2, 5-HT(1A) and 5-HT(2A) genes expression and 5-HT(2A) receptor functional activity in animal model of hereditary behavior disorders. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Serotonin 2a Receptor and serotonin 1a receptor interact within the medial prefrontal cortex during recognition memory in mice

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Juan Facundo Morici

2015-12-01

Full Text Available Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a -/- with wild type (htr2a+/+ littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex.

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour.

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Lesch, Klaus-Peter; Araragi, Naozumi; Waider, Jonas; van den Hove, Daniel; Gutknecht, Lise

2012-09-05

Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111-140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581-604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.

Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder

DEFF Research Database (Denmark)

Frokjaer, Vibe G.; Mortensen, Erik L.; Nielsen, Finn Årup

2008-01-01

Background: Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain...... regions of relevance for affective disorders. Methods: Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [F-18]altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding...... remained significant after correction for multiple comparisons (r = .35, p = .009). Conclusions: In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point...

Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

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Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

2015-12-01

Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

ROLE OF SEROTONIN IN FISH REPRODUCTION

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Parvathy ePrasad

2015-06-01

Full Text Available The neuroendocrine mechanism regulates reproduction through the hypothalamo-pituitary-gonadal (HPG axis which is evolutionarily conserved in vertebrates. The HPG axis is regulated by a variety of internal as well as external factors. Serotonin, a monoamine neurotransmitter, is involved in a wide range of reproductive functions. In mammals, serotonin regulates sexual behaviours, gonadotropin release and gonadotropin-release hormone (GnRH secretion. However, the serotonin system in teleost may play unique role in the control of reproduction as the mechanism of reproductive control in teleosts is not always the same as in the mammalian models. In fish, the serotonin system is also regulated by natural environmental factors as well as chemical substances. In particular, selective serotonin reuptake inhibitors (SSRIs are commonly detected as pharmaceutical contaminants in the natural environment. Those factors may influence fish reproductive functions via the serotonin system. This review summarizes the functional significance of serotonin in the teleosts reproduction.

Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders

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Toshchakova, Valentina A.; Bakhtiari, Yalda; Kulikov, Alexander V.; Gusev, Sergey I.; Trofimova, Marina V.; Fedorenko, Olga Yu.; Mikhalitskaya, Ekaterina V.; Popova, Nina K.; Bokhan, Nikolay A.; Hovens, Johannes E.; Loonen, Anton J.M.; Wilffert, Bob; Ivanova, Svetlana A.

2018-01-01

Background Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. Methods Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. Results No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. Conclusions The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed. PMID:29621775

Familial risk for mood disorder and the personality risk factor, neuroticism, interact in their association with frontolimbic serotonin 2A receptor binding

DEFF Research Database (Denmark)

Frøkjær, Vibe Gedsø; Vinberg, Maj; Erritzoe, David

2010-01-01

Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability...... stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission....... and is positively correlated to frontolimbic serotonin 2A (5-HT(2A)) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT(2A) receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co...

Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder.

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Sullivan, Gregory M; Oquendo, Maria A; Milak, Matthew; Miller, Jeffrey M; Burke, Ainsley; Ogden, R Todd; Parsey, Ramin V; Mann, J John

2015-02-01

Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin(1A) autoreceptor in the brainstem raphe of individuals who die by suicide. To determine the relationships between brain serotonin(1A) binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin(1A) antagonist radiotracer carbon C 11 [11C]-labeled WAY-100635. Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin(1A) binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin(1A) BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin(1A) BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin(1A )BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with

TrpC5 Mediates Acute Leptin and Serotonin Effects via Pomc Neurons

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Yong Gao

2017-01-01

Full Text Available The molecular mechanisms underlying acute leptin and serotonin 2C receptor-induced hypophagia remain unclear. Here, we show that neuronal and pro-opiomelanocortin (Pomc-specific loss of transient receptor potential cation 5 (TrpC5 subunits is sufficient to decrease energy expenditure and increase food intake resulting in elevated body weight. Deficiency of Trpc5 subunits in Pomc neurons is also sufficient to block the anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr agonists. The loss of acute anorexigenic effects of these receptors is concomitant with a blunted electrophysiological response to both leptin and Ht2Cr agonists in arcuate Pomc neurons. We also demonstrate that the Ht2Cr agonist lorcaserin-induced improvements in glucose and insulin tolerance are blocked by TrpC5 deficiency in Pomc neurons. Together, our results link TrpC5 subunits in the brain with leptin- and serotonin 2C receptor-dependent changes in neuronal activity, as well as energy balance, feeding behavior, and glucose metabolism.

The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes

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Kira V. Derkach

2015-01-01

Full Text Available In the last years the treatment of type 2 diabetes mellitus (DM2 was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS at a daily dose of 20 μg/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC activity in the hypothalamus and normalized AC stimulation by β-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications.

Iodine-123 labelled nor-β-CIT binds to the serotonin transporter in vivo as assessed by biodistribution studies in rats

International Nuclear Information System (INIS)

Booij, J.; Knol, R.J.J.; Reneman, L.; De Bruin, K.; Van Royen, E.A.; Janssen, A.G.M.

1998-01-01

Iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)nortropane (nor-β-CIT), a radioiodinated cocaine analogue, was evaluated as an agent for the in vivo labelling of serotonin transporters by biodistribution studies in rats. Intravenous injection of [ 123 I]nor-β-CIT resulted in high accumulation of radioactivity in brain areas with high densities of serotonin (hypothalamus) and dopamine transporters (striatum), although the binding was less pronounced in the hypothalamus. While binding of [ 123 I]nor-β-CIT in the hypothalamus was blocked significantly by fluvoxamine (a selective serotonin transporter blocker) but not by GBR12,909 (a selective dopamine transporter blocker), the opposite was observed in the striatum. The results of this study indicate that [ 123 I]nor-β-CIT, although not being a selective radioligand, binds specifically to serotonin transporters in the hypothalamus in vivo and thus suggest that [ 123 I]nor-β-CIT promises to be a suitable radioligand for single-photon emission tomography imaging of serotonin transporters in humans. (orig.)

Role of serotonin in pathogenesis of analgesic induced headache

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Srikiatkhachorn, A.

1999-12-16

Analgesic abuse has recently been recognized as a cause of deterioration in primary headache patients. Although the pathogenesis of this headache transformation is still obscure, and alteration of central pain control system is one possible mechanism. A number of recent studies indicated that simple analgesics exert their effect by modulating the endogenous pain control system rather than the effect at the peripheral tissue, as previously suggested. Serotonin (5-hydroxytryptamine ; 5-HT) has long been known to play a pivotal role in the pain modulatory system in the brainstem. In the present study, we investigated the changes in 5-HT system in platelets and brain tissue. A significant decrease in platelet 5-HT concentration (221.8{+-}30.7, 445.3{+-}37.4 and 467.2{+-}38.5 ng/10{sup 9} platelets, for patients with analgesic-induced headache and migraine patients, respectively, p<0.02) were evident in patients with analgesic induced headache. Chronic paracetamol administration induced a decrease in 5-HT{sub 2} serotonin receptor in cortical and brain stem tissue in experimental animals (B{sub max}=0.93{+-}0.04 and 1.79{+-}0.61 pmol/mg protein for paracetamol treated rat and controls, respectively, p<0.05). Our preliminary results suggested that chronic administration of analgesics interferes with central and peripheral 5-HT system and therefore possibly alters the 5-HT dependent antinociceptive system. (author)

Prefrontal serotonin transporter availability is positively associated with the cortisol awakening response

DEFF Research Database (Denmark)

Frokjaer, Vibe Gedsoe; Erritzoe, David; Holst, Klaus Kähler

2013-01-01

higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT...... binding in brain regions considered relevant to modify the cortisol awakening response. Methods: thirty-two healthy volunteers underwent in vivo SERT imaging with [11C]DASB-Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. Results: CAR, defined...... between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype×CAR). Conclusion: prefrontal SERT binding is positively associated with cortisol response to awakening. We speculate that in mentally healthy individuals prefrontal serotonergic neurotransmission may exert an inhibitory...

Serotonin Receptors in Hippocampus

Science.gov (United States)

Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

2012-01-01

Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

Radioprotective action of serotonin

Energy Technology Data Exchange (ETDEWEB)

Vodop' yanova, L G; Vinogradova, M F [Leningradskij Gosudarstvennyj Univ. (USSR). Biologicheskij Nauchno-Issledovatel' skij Inst.

1975-09-01

Tests in vitro were performed to study the effect of serotonin on oxidative phosphorylation in the mitochondria of rat liver. Serotonin (2.10/sup -4/ M) was shown to suppress oxidation of ..cap alpha..-ketoglutaric acid without significantly changing succinic acid consumption. A comparison of the results obtained with those from the literature allowed to assume that the radioprotective effect of serotonin was based not only on its previously known ability to cause tissue hypoxia, but also on its ability to affect oxidation processes in mitochondria.

Both stimulatory and inhibitory effects of dietary 5-hydroxytryptophan and tyrosine are found on urinary excretion of serotonin and dopamine in a large human population

Directory of Open Access Journals (Sweden)

George J Trachte

2009-04-01

Full Text Available George J Trachte1, Thomas Uncini2, Marty Hinz31Department of Physiology and Pharmacology, University of MN Medical School Duluth, Duluth, MN, USA; 2Chief Medical Examiner, St. Louis County, Hibbing, MN, USA; 3Clinical Research, NeuroResearch Clinics, Inc., Duluth, MN, USA Abstract: Amino acid precursors of dopamine and serotonin have been administered for decades to treat a variety of clinical conditions including depression, anxiety, insomnia, obesity, and a host of other illnesses. Dietary administration of these amino acids is designed to increase dopamine and serotonin levels within the body, particularly the brain. Convincing evidence exists that these precursors normally elevate dopamine and serotonin levels within critical brain tissues and other organs. However, their effects on urinary excretion of neurotransmitters are described in few studies and the results appear equivocal. The purpose of this study was to define, as precisely as possible, the influence of both 5-hydroxytryptophan (5-HTP and tyrosine on urinary excretion of serotonin and dopamine in a large human population consuming both 5-HTP and tyrosine. Curiously, only 5-HTP exhibited a marginal stimulatory influence on urinary serotonin excretion when 5-HTP doses were compared to urinary serotonin excretion; however, a robust relationship was observed when alterations in 5-HTP dose were compared to alterations in urinary serotonin excretion in individual patients. The data indicate three statistically discernible components to 5-HTP responses, including inverse, direct, and no relationships between urinary serotonin excretion and 5-HTP doses. The response to tyrosine was more consistent but primarily yielded an unexpected reduction in urinary dopamine excretion. These data indicate that the urinary excretion pattern of neurotransmitters after consumption of their precursors is far more complex than previously appreciated. These data on urinary neurotransmitter excretion might

Molecular cloning, expression and characterization of a bovine serotonin transporter

DEFF Research Database (Denmark)

Mortensen, O V; Kristensen, A S; Rudnick, G

1999-01-01

The serotonin transporter (SERT) is a member of a highly homologous family of sodium/chloride dependent neurotransmitter transporters responsible for reuptake of biogenic amines from the extracellular fluid. SERT constitutes the pharmacological target of several clinically important antidepressan......-methylenedioxymethamphetamine (MDMA) was mainly unchanged. RT-PCR amplification of RNA from different tissues demonstrated expression of SERT in placenta, brain stem, bone marrow, kidney, lung, heart, adrenal gland, liver, parathyroid gland, thyroid gland, small intestine and pancreas....

Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters.

Science.gov (United States)

Yahata, Masahiro; Chiba, Koji; Watanabe, Takao; Sugiyama, Yuichi

2017-09-01

Accurate prediction of target occupancy facilitates central nervous system drug development. In this review, we discuss the predictability of serotonin transporter (SERT) occupancy in human brain estimated from in vitro K i values for human SERT and plasma concentrations of unbound drug (C u,plasma ), as well as the impact of drug transporters in the blood-brain barrier. First, the geometric means of in vitro K i values were compared with the means of in vivo K i values (K i,u,plasma ) which were calculated as C u,plasma values at 50% occupancy of SERT obtained from previous clinical positron emission tomography/single photon emission computed tomography imaging studies for 6 selective serotonin transporter reuptake inhibitors and 3 serotonin norepinephrine reuptake inhibitors. The in vitro K i values for 7 drugs were comparable to their in vivo K i,u,plasma values within 3-fold difference. SERT occupancy was overestimated for 5 drugs (P-glycoprotein substrates) and underestimated for 2 drugs (presumably uptake transporter substrates, although no evidence exists as yet). In conclusion, prediction of human SERT occupancy from in vitro K i values and C u,plasma was successful for drugs that are not transporter substrates and will become possible in future even for transporter substrates, once the transporter activities will be accurately estimated from in vitro experiments. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

[{sup 11}C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

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Zessin, Joerg [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)]. E-mail: j.zessin@fz-rossendorf.de; Deuther-Conrad, Winnie [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Kretzschmar, Marion [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Wuest, Frank [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Pawelke, Beate [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Brust, Peter [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Steinbach, Joerg [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Bergmann, Ralf [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)

2006-01-15

N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [{sup 11}C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [{sup 11}C]S Me-Adam. The radiochemical yield was 27{+-}5%, and the specific radioactivity was 26-40 GBq/{mu}mol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59{+-}0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74{+-}0.95 at 60 min postinjection. The [{sup 11}C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38{+-}11% of the control value. Furthermore, no metabolites of [{sup 11}C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [{sup 11}C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter--a review of current understanding of its mechanism of action.

Science.gov (United States)

Zhong, Huailing; Haddjeri, Nasser; Sánchez, Connie

2012-01-01

Escitalopram is a widely used antidepressant for the treatment of patients with major depression. It is the pure S-enantiomer of racemic citalopram. Several clinical trials and meta-analyses indicate that escitalopram is quantitatively more efficacious than many other antidepressants with a faster onset of action. This paper reviews current knowledge about the mechanism of action of escitalopram. The primary target for escitalopram is the serotonin transporter (SERT), which is responsible for serotonin (or 5-hydroxytryptamine [5-HT]) reuptake at the terminals and cell bodies of serotonergic neurons. Escitalopram and selective serotonin reuptake inhibitors bind with high affinity to the 5-HT binding site (orthosteric site) on the transporter. This leads to antidepressant effects by increasing extracellular 5-HT levels which enhance 5-HT neurotransmission. SERT also has one or more allosteric sites, binding to which modulates activity at the orthosteric binding site but does not directly affect 5-HT reuptake by the transporter. In vitro studies have shown that through allosteric binding, escitalopram decreases its own dissociation rate from the orthosteric site on the SERT. R-citalopram, the nontherapeutic enantiomer in citalopram, is also an allosteric modulator of SERT but can inhibit the actions of escitalopram by interfering negatively with its binding. Both nonclinical studies and some clinical investigations have demonstrated the cellular, neurochemical, neuroadaptive, and neuroplastic changes induced by escitalopram with acute and chronic administration. The findings from binding, neurochemical, and neurophysiological studies may provide a mechanistic rationale for the clinical difference observed with escitalopram compared to other antidepressant therapies.

Serotonin-1A receptor imaging in recurrent depression: replication and literature review

International Nuclear Information System (INIS)

Drevets, Wayne C.; Thase, Michael E.; Moses-Kolko, Eydie L.; Price, Julie; Frank, Ellen; Kupfer, David J.; Mathis, Chester

2007-01-01

Introduction: Serotonin-1A receptor (5-HT 1A R) function appears to be decreased in major depressive disorder (MDD) based on physiological responses to 5-HT 1A R agonists in vivo and to 5-HT 1A R binding in brain tissues postmortem or antemortem. We have previously assessed 5-HT 1A R binding potential (BP) in depression using positron emission tomography (PET) and [carbonyl- 11 C]WAY-100635, and we have demonstrated reduced 5-HT 1A R BP in the mesiotemporal cortex (MTC) and raphe in depressives with primary recurrent familial mood disorders (n=12) versus controls (n=8) [Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46(10):1375-87]. These findings were replicated by some, but not other, studies performed in depressed samples that were more generally selected using criteria for MDD. In the current study, we attempted to replicate our previous findings in an independent sample of subjects selected according to the criteria for primary recurrent depression applied in our prior study. Methods: Using PET and [carbonyl- 11 C]WAY-100635, 5-HT 1A R BP was assessed in 16 depressed subjects and 8 healthy controls. Results: Mean 5-HT 1A R BP was reduced by 26% in the MTC (P 1A R binding were similar to those found postmortem in 5-HT 1A R mRNA concentrations in the hippocampus in MDD [Lopez JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73] and in 5-HT 1A R-binding capacity in the raphe in depressed suicide victims [Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001;25(6):892-903]. There

Autoradiographic imaging of the serotonin transporter, using S-[{sup 18}F](fluoromethyl)-(+)-McN5652 ([{sup 18}F]Me-McN) in the brains of several animal species

Energy Technology Data Exchange (ETDEWEB)

Kretzschmar, M.; Zessin, J.; Brust, P.; Cumming, P. [PET Centre of Aarhus Univ. Hospitals, Aarhus C (Denmark); Bergmann, R.

2002-01-01

The [{sup 18}F]fluoromethyl analogue of (+)-McN5652 ([{sup 18}F]Me-McN) was recently proposed as a new potential PET tracer [1]. To further validate its use in PET, we studied the binding of [{sup 18}F]Me-McN in the brains of rats and pigs using autoradiography. The binding was compared with the uptake of the known 5-HT uptake inhibitor [{sup 3}H] citalopram [2] and the radioligand (+)-[{sup 11}C]McN5652. The binding of the three compounds was qualitatively identical in the autoradiograms of the individual brains. Intense labelling was observed in regions known to be serotonin uptake sites. The binding was specifically inhibited, using the 5-HT uptake inhibitors citalopram and fluoxetine. (orig.)

Comparing the Expression of Genes Related to Serotonin (5-HT in C57BL/6J Mice and Humans Based on Data Available at the Allen Mouse Brain Atlas and Allen Human Brain Atlas

Directory of Open Access Journals (Sweden)

C. A. Acevedo-Triana

2017-01-01

Full Text Available Brain atlases are tools based on comprehensive studies used to locate biological characteristics (structures, connections, proteins, and gene expression in different regions of the brain. These atlases have been disseminated to the point where tools have been created to store, manage, and share the information they contain. This study used the data published by the Allen Mouse Brain Atlas (2004 for mice (C57BL/6J and Allen Human Brain Atlas (2010 for humans (6 donors to compare the expression of serotonin-related genes. Genes of interest were searched for manually in each case (in situ hybridization for mice and microarrays for humans, normalized expression data (z-scores were extracted, and the results were graphed. Despite the differences in methodology, quantification, and subjects used in the process, a high degree of similarity was found between expression data. Here we compare expression in a way that allows the use of translational research methods to infer and validate knowledge. This type of study allows part of the relationship between structures and functions to be identified, by examining expression patterns and comparing levels of expression in different states, anatomical correlations, and phenotypes between different species. The study concludes by discussing the importance of knowing, managing, and disseminating comprehensive, open-access studies in neuroscience.

Contribution of Impulsivity and Serotonin Receptor Neuroadaptations to the Development of an MDMA ('Ecstasy') Substance Use Disorder.

Science.gov (United States)

Schenk, Susan; Aronsen, Dane

As is the case with other drugs of abuse, a proportion of ecstasy users develop symptoms consistent with a substance use disorder (SUD). In this paper, we propose that the pharmacology of MDMA, the primary psychoactive component of ecstasy tablets, changes markedly with repeated exposure and that neuroadaptations in dopamine and serotonin brain systems underlie the shift from MDMA use to MDMA misuse in susceptible subjects. Data from both the human and laboratory animal literature are synthesized to support the idea that (1) MDMA becomes a less efficacious serotonin releaser and a more efficacious dopamine releaser with the development of behaviour consistent with an SUD and (2) that upregulated serotonin receptor mechanisms contribute to the development of the MDMA SUD via dysregulated inhibitory control associated with the trait of impulsivity.

High familial risk for mood disorder is associated with low dorsolateral prefrontal cortex serotonin transporter binding

DEFF Research Database (Denmark)

Frokjaer, Vibe G; Vinberg, Maj; Erritzoe, David

2009-01-01

at risk for developing depression. The aim of this study was to explore whether abnormalities in SERT might be present in healthy individuals with familial predisposition to mood disorder. Nine individuals at high familial risk (mean age 32.2+/-4.2 years) and 11 individuals at low risk (mean age 32......Mood disorders are elicited through a combination of genetic and environmental stress factors, and treatment with selective serotonin reuptake inhibitors ameliorates depressive symptoms. Changes in the serotonin transporter (SERT) binding may therefore occur in depressive patients and in subjects.......4+/-5.0 years) for developing mood disorder were included. The subjects were healthy twins with or without a co-twin history of mood disorder identified by linking information from the Danish Twin Register and the Danish Psychiatric Central Register. Regional in vivo brain serotonin transporter binding...

Rotavirus and Serotonin Cross-Talk in Diarrhoea

Science.gov (United States)

Nordgren, Johan; Karlsson, Thommie; Sharma, Sumit; Magnusson, Karl-Eric; Svensson, Lennart

2016-01-01

Rotavirus (RV) has been shown to infect and stimulate secretion of serotonin from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice. It remains to identify which intracellularly expressed viral protein(s) is responsible for this novel property and to further establish the clinical role of serotonin in RV infection. First, we found that siRNA specifically silencing NSP4 (siRNANSP4) significantly attenuated secretion of serotonin from Rhesus rotavirus (RRV) infected EC tumor cells compared to siRNAVP4, siRNAVP6 and siRNAVP7. Second, intracellular calcium mobilization and diarrhoeal capacity from virulent and avirulent porcine viruses correlated with the capacity to release serotonin from EC tumor cells. Third, following administration of serotonin, all (10/10) infants, but no (0/8) adult mice, responded with diarrhoea. Finally, blocking of serotonin receptors using Ondansetron significantly attenuated murine RV (strain EDIM) diarrhoea in infant mice (2.9 vs 4.5 days). Ondansetron-treated mice (n = 11) had significantly (p serotonin receptor antagonist significantly (p serotonin from human EC tumor cells and that serotonin participates in RV diarrhoea, which can be attenuated by Ondansetron. PMID:27459372

Nitric oxide and the non-adrenergic non-cholinergic neurotransmission

NARCIS (Netherlands)

Boeckxstaens, G. E.; Pelckmans, P. A.

1997-01-01

In the early 1960s, the first evidence was reported demonstrating neurally mediated responses in the presence of adrenergic and cholinergic antagonists, leading to the introduction of the concept of non-adrenergic non-cholinergic neurotransmission. The inhibitory component of this part of the

Glutamate Transporters in the Blood-Brain Barrier

DEFF Research Database (Denmark)

Helms, Hans Christian Cederberg; Nielsen, Carsten Uhd; Waagepetersen, Helle S

2017-01-01

concentration of L-glutamate causes excitotoxicity. A tight control of the brain interstitial fluid L-glutamate levels is therefore imperative, in order to maintain optimal neurotransmission and to avoid such excitotoxicity. The blood-brain barrier, i.e., the endothelial lining of the brain capillaries...... cells. The mechanisms underlying transendothelial L-glutamate transport are however still not well understood. The present chapter summarizes the current knowledge on blood-brain barrier L-glutamate transporters and the suggested pathways for the brain-to-blood L-glutamate efflux......., regulates the exchange of nutrients, gases, and metabolic waste products between plasma and brain interstitial fluid. It has been suggested that brain capillary endothelial cells could play an important role in L-glutamate homeostasis by mediating brain-to-blood L-glutamate efflux. Both in vitro and in vivo...

Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies.

Science.gov (United States)

Kaye, Walter H; Frank, Guido K; Bailer, Ursula F; Henry, Shannan E; Meltzer, Carolyn C; Price, Julie C; Mathis, Chester A; Wagner, Angela

2005-05-19

Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders with relatively homogenous presentations such as age of onset and gender distribution. In addition, they share symptoms, such as extremes of food consumption, body image distortion, anxiety and obsessions, and ego-syntonic neglect, raises the possibility that these symptoms reflect disturbed brain function that contributes to the pathophysiology of this illness. Recent brain imaging studies have identified altered activity in frontal, cingulate, temporal, and parietal cortical regions in AN and BN. Importantly, such disturbances are present when subjects are ill and persist after recovery, suggesting that these may be traits that are independent of the state of the illness. Emerging data point to a dysregulation of serotonin pathways in cortical and limbic structures that may be related to anxiety, behavioral inhibition, and body image distortions. In specific, recent studies using PET with serotonin specific radioligands implicate alterations of 5-HT1A and 5-HT2A receptors and the 5-HT transporter. Alterations of these circuits may affect mood and impulse control as well as the motivating and hedonic aspects of feeding behavior. Such imaging studies may offer insights into new pharmacology and psychotherapy approaches.

Microautoradiography of [{sup 123}I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors

Energy Technology Data Exchange (ETDEWEB)

Ye, X.-X.; Chen, J.-C.; Liu, R.-S.; Wey, S.-P.; Lee, J.-S.; Chen, C.-C.; Fu, Y.-K.; Ting, Gann; Hwang, J.-J. E-mail: jjhwang@ym.edu.tw

2004-07-01

A radiopharmaceutical, {sup 123}I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([{sup 123}I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [{sup 123}I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [{sup 123}I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [{sup 123}I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [{sup 123}I]ADAM. Significant and selective accumulation of [{sup 123}I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [{sup 131}I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [{sup 123}I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine.

Increasing brain serotonin corrects CO2 chemosensitivity in methyl-CpG-binding protein 2 (Mecp2)-deficient mice

Science.gov (United States)

Toward, Marie A.; Abdala, Ana P.; Knopp, Sharon J.; Paton, Julian F. R.; Bissonnette, John M.

2013-01-01

Mice deficient in the transcription factor methyl-CpG-binding protein 2 (Mecp2), a mouse model of Rett syndrome, display reduced CO2 chemosensitivity, which may contribute to their breathing abnormalities. In addition, patients with Rett syndrome and male mice that are null for Mecp2 show reduced levels of brain serotonin (5-HT). Serotonin is known to play a role in central chemosensitivity, and we hypothesized that increasing the availability of 5-HT in this mouse model would improve their respiratory response to CO2. Here we determined the apnoeic threshold in heterozygous Mecp2-deficient female mice and examined the effects of blocking 5-HT reuptake on the CO2 response in Mecp2-null male mice. Studies were performed in B6.129P2(C)-Mecp2τm1.1Bird null males and heterozygous females. In an in situ preparation, seven of eight Mecp2-deficient heterozygous females showed arrest of phrenic nerve activity when arterial CO2 was lowered to 3%, whereas the wild-types maintained phrenic nerve amplitude at 53 ± 3% of maximal. In vivo plethysmography studies were used to determine CO2 chemosensitivity in null males. These mice were exposed sequentially to 1, 3 and 5% CO2. The percentage increase in minute ventilation in response to increased inspired CO2 was less in Mecp2−/y than in Mecp2+/y mice. Pretreatment with citalopram, a selective 5-HT reuptake inhibitor (2.5 mg kg−1 I.P.), 40 min prior to CO2 exposure, in Mecp2−/y mice resulted in an improvement in CO2 chemosensitivity to wild-type levels. These results suggest that decreased 5-HT in Mecp2-deficient mice reduces CO2 chemosensitivity, and restoring 5-HT levels can reverse this effect. PMID:23180809

PET application in psychiatry and psychopharmacology

Energy Technology Data Exchange (ETDEWEB)

Suhara, Tetsuya [National Inst. of Radiological Sciences, Chiba (Japan)

1999-07-01

In the last few decades diagnostic and research tools in the medical field have made great advances, yet psychiatry has lacked sufficiently sensitive tools to measure the aberration of brain functions. Recently however, the development of Positron emission tomography (PET) techniques has made it possible to measure changes in neurochemical components in mental disorders and the effect of psychoactive drugs in living human brain. Most of the advancement in the psychiatric field has came from the development psychoactive drugs. Brain research involving identification of neurotransmission is largely based on compounds developed in psychopharmacology. Some of these compounds have been radiolabelled and used as radioligands for quantitative examination of neuroreceptors and other aspects of neurotransmission. Using PET, radioligand binding can now be examined in the human brain in vivo. PET techniques also allow examination of an unlabelled drug by examination of its interaction with a radioligand. So one potential of PET in psychiatry is to investigate the mechanism of psychoactive drugs. Antidepressants modulate serotonin transmission by inhibiting serotonin reuptake from the synaptic cleft. High affinity [{sup 3}H]imipramine binding sites in mammalian brain have been labelled to investigate serotonin transporters in living human brain by PET. Cyanoimipramine which is described as a potent serotonin reuptake inhibitor, was labelled with {sup 11}C. In a PET experiment with 6 healthy human subjects, a high accumulation of [{sup 11}C]cyanoimipramine was found in the thalamus and striatum and lowest accumulation was observed in the cerebellum, a region relatively void of serotonin transporters. The thalamus to cerebellum ratio was about 2 at 90 min after the injection of the tracer. Recently, [{sup 11}C]McN5652-X has been introduced as a better tracer for serotonin transporter imaging. Employing [{sup 11}C]McN5652-X in a PET study of 7 healthy human subjects, a high

PET application in psychiatry and psychopharmacology

International Nuclear Information System (INIS)

Suhara, Tetsuya

1999-01-01

In the last few decades diagnostic and research tools in the medical field have made great advances, yet psychiatry has lacked sufficiently sensitive tools to measure the aberration of brain functions. Recently however, the development of Positron emission tomography (PET) techniques has made it possible to measure changes in neurochemical components in mental disorders and the effect of psychoactive drugs in living human brain. Most of the advancement in the psychiatric field has came from the development psychoactive drugs. Brain research involving identification of neurotransmission is largely based on compounds developed in psychopharmacology. Some of these compounds have been radiolabelled and used as radioligands for quantitative examination of neuroreceptors and other aspects of neurotransmission. Using PET, radioligand binding can now be examined in the human brain in vivo. PET techniques also allow examination of an unlabelled drug by examination of its interaction with a radioligand. So one potential of PET in psychiatry is to investigate the mechanism of psychoactive drugs. Antidepressants modulate serotonin transmission by inhibiting serotonin reuptake from the synaptic cleft. High affinity [ 3 H]imipramine binding sites in mammalian brain have been labelled to investigate serotonin transporters in living human brain by PET. Cyanoimipramine which is described as a potent serotonin reuptake inhibitor, was labelled with 11 C. In a PET experiment with 6 healthy human subjects, a high accumulation of [ 11 C]cyanoimipramine was found in the thalamus and striatum and lowest accumulation was observed in the cerebellum, a region relatively void of serotonin transporters. The thalamus to cerebellum ratio was about 2 at 90 min after the injection of the tracer. Recently, [ 11 C]McN5652-X has been introduced as a better tracer for serotonin transporter imaging. Employing [ 11 C]McN5652-X in a PET study of 7 healthy human subjects, a high accumulation was observed

Assessment of the Potential Role of Tryptophan as the Precursor of Serotonin and Melatonin for the Aged Sleep-wake Cycle and Immune Function: as a Model

Directory of Open Access Journals (Sweden)

Sergio D. Paredes

2009-01-01

Full Text Available In the present review we summarize the relationship between the amino acid, tryptophan, the neurotransmitter, serotonin, and the indole, melatonin, with the rhythms of sleep/wake and the immune response along with the possible connections between the alterations in these rhythms due to aging and the so-called “serotonin and melatonin deficiency state.” The decrease associated with aging of the brain and circulating levels of serotonin and melatonin seemingly contributes to the alterations of both the sleep/wake cycle and the immune response that typically accompany old age. The supplemental administration of tryptophan, e.g. the inclusion of tryptophan-enriched food in the diet, might help to remediate these age-related alterations due to its capacity of raise the serotonin and melatonin levels in the brain and blood. Herein, we also summarize a set of studies related to the potential role that tryptophan, and its derived product melatonin, may play in the restoration of the aged circadian rhythms of sleep/wake and immune response, taking the ringdove ( Streptopelia risoria as a suitable model.

Effects of diabetes on brain metabolism - is brain glycogen a significant player?

DEFF Research Database (Denmark)

Sickmann, Helle M; Waagepetersen, Helle S.

2015-01-01

Brain glycogen, being an intracellular glucose reservoir, contributes to maintain energy and neurotransmitter homeostasis under physiological as well as pathological conditions. Under conditions with a disturbance in systemic glucose metabolism such as in diabetes, the supply of glucose to the br......Brain glycogen, being an intracellular glucose reservoir, contributes to maintain energy and neurotransmitter homeostasis under physiological as well as pathological conditions. Under conditions with a disturbance in systemic glucose metabolism such as in diabetes, the supply of glucose...... to the brain may be affected and have important impacts on brain metabolism and neurotransmission. This also implies that brain glycogen may serve an essential role in the diabetic state to sustain appropriate brain function. There are two main types of diabetes; type 1 and type 2 diabetes and both types may...... understanding of how brain energy and neurotransmitter metabolism is affected in diabetes. There will be a particular focus on the role of brain glycogen to support glycolytic and TCA cycle activity as well as glutamate-glutamine cycle in type 1 and type 2 diabetes....

Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders

Energy Technology Data Exchange (ETDEWEB)

Kugaya, Akira; Fujita, Masahiro; Innis, R.B. [Yale Univ., New Haven, CT (United States). School of Medicine

2000-02-01

Single photon emission computed tomography (SPECT) tracers selective for pre- and post-synaptic targets have allowed measurements of several aspects of dopaminergic (DA) neurotransmission. In this article, we will first review our DA transporter imaging in Parkinson's disease. We have developed the in vivo dopamine transporter (DAT) imaging with [{sup 123}I]{beta}-CIT ((1R)-2{beta}-Carbomethoxy-3{beta}-(4-iodophenyl)tropane). This method showed that patients with Parkinson's disease have markedly reduced DAT levels in striatum, which correlated with disease severity and disease progression. Second, we applied DA imaging techniques in patients with schizophrenia. Using amphetamine as a releaser of DA, we observed the enhanced DA release, which was measured by imaging D2 receptors with [{sup 123}I]IBZM (iodobenzamide), in schizophrenics. Further we developed the measurement of basal synaptic DA levels by AMPT (alpha-methyl-paratyrosine)-induced unmasking of D2 receptors. Finally, we expanded our techniques to the measurement of extrastriatal DA receptors using [{sup 123}I]epidepride. The findings suggest that SPECT is a useful technique to measure DA transmission in human brain and may further our understanding of the pathophysiology of neuropsychiatric disorders. (author)

Iodine-123 labelled nor-{beta}-CIT binds to the serotonin transporter in vivo as assessed by biodistribution studies in rats

Energy Technology Data Exchange (ETDEWEB)

Booij, J.; Knol, R.J.J.; Reneman, L.; De Bruin, K.; Van Royen, E.A. [Dept. of Nuclear Medicine, Univ. of Amsterdam (Netherlands); Janssen, A.G.M. [Amersham Cygne and Eindhoven University of Technology (Netherlands)

1998-12-01

Iodine-123 labelled 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)nortropane (nor-{beta}-CIT), a radioiodinated cocaine analogue, was evaluated as an agent for the in vivo labelling of serotonin transporters by biodistribution studies in rats. Intravenous injection of [{sup 123}I]nor-{beta}-CIT resulted in high accumulation of radioactivity in brain areas with high densities of serotonin (hypothalamus) and dopamine transporters (striatum), although the binding was less pronounced in the hypothalamus. While binding of [{sup 123}I]nor-{beta}-CIT in the hypothalamus was blocked significantly by fluvoxamine (a selective serotonin transporter blocker) but not by GBR12,909 (a selective dopamine transporter blocker), the opposite was observed in the striatum. The results of this study indicate that [{sup 123}I]nor-{beta}-CIT, although not being a selective radioligand, binds specifically to serotonin transporters in the hypothalamus in vivo and thus suggest that [{sup 123}I]nor-{beta}-CIT promises to be a suitable radioligand for single-photon emission tomography imaging of serotonin transporters in humans. (orig.) With 1 fig., 2 tabs., 15 refs.

Breaking Away: The Role of Homeostatic Drive in Perpetuating Depression.

Science.gov (United States)

Tory Toole, J; Rice, Mark A; Craddock, Travis J A; Nierenberg, Barry; Klimas, Nancy G; Fletcher, Mary Ann; Zysman, Joel; Morris, Mariana; Broderick, Gordon

2018-01-01

We propose that the complexity of regulatory interactions modulating brain neurochemistry and behavior is such that multiple stable responses may be supported, and that some of these alternate regulatory programs may play a role in perpetuating persistent psychological dysfunction. To explore this, we constructed a model network representing major neurotransmission and behavioral mechanisms reported in literature as discrete logic circuits. Connectivity and information flow through this biobehavioral circuitry supported two distinct and stable regulatory programs. One such program perpetuated a depressive state with a characteristic neurochemical signature including low serotonin. Further analysis suggested that small irregularities in glutamate levels may render this pathology more directly accessible. Computer simulations mimicking selective serotonin reuptake inhibitor (SSRI) therapy in the presence of everyday stressors predicted recidivism rates similar to those reported clinically and highlighted the potentially significant benefit of concurrent behavioral stress management therapy.

Treatment with selective serotonin reuptake inhibitors and mirtapazine results in differential brain activation by visual erotic stimuli in patients with major depressive disorder.

Science.gov (United States)

Kim, Won; Jin, Bo-Ra; Yang, Wan-Seok; Lee, Kyuong-Uk; Juh, Ra-Hyung; Ahn, Kook-Jin; Chung, Yong-An; Chae, Jeong-Ho

2009-06-01

The objective of this study was to identify patterns of brain activation elicited by erotic visual stimuli in patients treated with either Selective Serotonin Reuptake Inhibitors (SSRIs) or mirtazipine. Nine middle-aged men with major depressive disorder treated with an SSRI and ten middle-aged men with major depressive disorder treated with mirtazapine completed the trial. Ten subjects with no psychiatric illness were included as a control group. We conducted functional brain magnetic resonance imaging (fMRI) while a film alternatively played erotic and non-erotic contents for 14 minutes and 9 seconds. The control group showed activation in the occipitotemporal area, anterior cingulate gyrus, insula, orbitofrontal cortex, and caudate nucleus. For subjects treated with SSRIs, the intensity of activity in these regions was much lower compared to the control group. Intensity of activation in the group treated with mirtazapine was less than the control group but grea-ter than those treated with SSRIs. Using subtraction analysis, the SSRI group showed significantly lower activation than the mirtazapine group in the anterior cingulate gyrus and the caudate nucleus. Our study suggests that the different rates of sexual side effects between the patients in the SSRI-treated group and the mirtazapine-treated group may be due to different effects on brain activation.

Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA

OpenAIRE

Gantz, Stephanie C.; Levitt, Erica S.; Llamosas Muñozguren, Nerea; Neve, Kim A.; Williams, John T.

2015-01-01

Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson's disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigr...

Lactate Receptor Sites Link Neurotransmission, Neurovascular Coupling, and Brain Energy Metabolism

DEFF Research Database (Denmark)

Lauritzen, Knut H; Morland, Cecilie; Puchades, Maja

2013-01-01

The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiolog......The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated...

An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor- or Serotonin-Norepinephrine Reuptake Inhibitor-Resistant Depression in Adult Women.

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Kious, Brent M; Sabic, Hana; Sung, Young-Hoon; Kondo, Douglas G; Renshaw, Perry

2017-10-01

Many women with major depressive disorder (MDD) respond inadequately to standard treatments. Augmentation of conventional antidepressants with creatine monohydrate and 5-hydroxytryptophan (5-HTP) could correct deficits in serotonin production and brain bioenergetics associated with depression in women, yielding synergistic benefit. We describe an open-label study of 5-HTP and creatine augmentation in women with MDD who had failed selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) monotherapy. Fifteen women who were adequately adherent to an SSRI or SNRI and currently experiencing MDD, with a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher, were treated with 5 g of creatine monohydrate daily and 100 mg of 5-HTP twice daily for 8 weeks, with 4 weeks of posttreatment follow-up. The primary outcome was change in mean HAM-D scores. Mean HAM-D scores declined from 18.9 (SD, 2.5) at pretreatment visits to 7.5 (SD, 4.4) (P creatine and 5-HTP may represent an effective augmentation strategy for women with SSRI- or SNRI-resistant depression. Given the limitations of this small, open-label trial, future study in randomized, placebo-controlled trials is warranted.

DARPP-32: from neurotransmission to cancer

Science.gov (United States)

Belkhiri, Abbes; Zhu, Shoumin; El-Rifai, Wael

2016-01-01

Dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32), also known as phosphoprotein phosphatase-1 regulatory subunit 1B (PPP1R1B), was initially discovered as a substrate of dopamine-activated protein kinase A (PKA) in the neostriatum in the brain. While phosphorylation at Thr-34 by PKA converts DARPP-32 into a potent inhibitor of protein phosphatase 1 (PP1), phosphorylation at Thr-75 transforms DARPP-32 into an inhibitor of PKA. Through regulation of DARPP-32 phosphorylation and modulation of protein phosphatase and kinase activities, DARPP-32 plays a critical role in mediating the biochemical, electrophysiological, and behavioral effects controlled by dopamine and other neurotransmitters in response to drugs of abuse and psychostimulants. Altered expression of DARPP-32 and its truncated isoform (t-DARPP), specifically in the prefrontal cortex, has been associated with schizophrenia and bipolar disorder. Moreover, cleavage of DARPP-32 by calpain has been implicated in Alzheimer's disease. Amplification of the genomic locus of DARPP-32 at 17q12 has been described in several cancers. DARPP-32 and t-DARPP are frequently overexpressed at the mRNA and protein levels in adenocarcinomas of the breast, prostate, colon, and stomach. Several studies demonstrated the pro-survival, pro-invasion, and pro-angiogenic functions of DARPP-32 in cancer. Overexpression of DARPP-32 and t-DARPP also promotes chemotherapeutic drug resistance and cell proliferation in gastric and breast cancers through regulation of pro-oncogenic signal transduction pathways. The expansion of DARPP-32 research from neurotransmission to cancer underscores the broad scope and implication of this protein in disparate human diseases. PMID:26872373

Altered dopamine and serotonin metabolism in motorically asymptomatic R6/2 mice.

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Fanny Mochel

Full Text Available The pattern of cerebral dopamine (DA abnormalities in Huntington disease (HD is complex, as reflected by the variable clinical benefit of both DA antagonists and agonists in treating HD symptoms. In addition, little is known about serotonin metabolism despite the early occurrence of anxiety and depression in HD. Post-mortem enzymatic changes are likely to interfere with the in vivo profile of biogenic amines. Hence, in order to reliably characterize the regional and chronological profile of brain neurotransmitters in a HD mouse model, we used a microwave fixation system that preserves in vivo concentrations of dopaminergic and serotoninergic amines. DA was decreased in the striatum of R6/2 mice at 8 and 12 weeks of age while DA metabolites, 3-methoxytyramine and homovanillic acid, were already significantly reduced in 4-week-old motorically asymptomatic R6/2 mice. In the striatum, hippocampus and frontal cortex of 4, 8 and 12-week-old R6/2 mice, serotonin and its metabolite 5-hydroxyindoleacetic acid were significantly decreased in association with a decreased turnover of serotonin. In addition, automated high-resolution behavioural analyses displayed stress-like behaviours such as jumping and grooming and altered spatial learning in R6/2 mice at age 4 and 6 weeks respectively. Therefore, we describe the earliest alterations of DA and serotonin metabolism in a HD murine model. Our findings likely underpin the neuropsychological symptoms at time of disease onset in HD.

Minireview of Stereoselective Brain Imaging

DEFF Research Database (Denmark)

Smith, Donald F.; Jakobsen, Steen

2014-01-01

Stereoselectivity is a fundamental principle in living systems. Stereoselectivity reflects the dependence of molecular processes on the spatial orientation of constituent atoms. Stereoselective processes govern many aspects of brain function and direct the course of many psychotropic drugs. Today......, modern imaging techniques such as SPECT and PET provide a means for studying stereoselective processes in the living brain. Chemists have prepared numerous radiolabelled stereoisomers for use in SPECT and PET in order to explore various molecular processes in the living brain of anesthetized laboratory...... animals and awake humans. The studies have demonstrated how many aspects of neurotransmission consist of crucial stereoselective events that can affect brain function in health and disease. Here, we present a brief account of those findings in hope of stimulating further interest in the vital topic....

Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding

NARCIS (Netherlands)

Versteeg, Ruth I.; Schrantee, Anouk; Adriaanse, Sofie M.; Unmehopa, Unga A.; Booij, Jan; Reneman, Liesbeth; Fliers, Eric; la Fleur, Susanne E.; Serlie, Mireille J.

2017-01-01

Recent studies have shown that meal timing throughout the day contributes to maintaining or regaining weight after hypocaloric diets. Although brain serotonin and dopamine are well known to be involved in regulating feeding, it is unknown whether meal timing during energy restriction affects these

Transgenic overexpression of adenosine kinase in brain leads to multiple learning impairments and altered sensitivity to psychomimetic drugs.

Science.gov (United States)

Yee, Benjamin K; Singer, Philipp; Chen, Jiang-Fan; Feldon, Joram; Boison, Detlev

2007-12-01

The neuromodulator adenosine fulfills a unique role in the brain affecting glutamatergic neurotransmission and dopaminergic signaling via activation of adenosine A1 and A2A receptors, respectively. The adenosine system is thus ideally positioned to integrate glutamatergic and dopaminergic neurotransmission, which in turn could affect behavior and cognition. In the adult brain, adenosine levels are largely regulated by its key metabolic enzyme adenosine kinase (ADK), which may assume the role of an 'upstream regulator' of these two neurotransmitter pathways. To test this hypothesis, transgenic mice with an overexpression of ADK in brain (Adk-tg), and therefore reduced brain adenosine levels, were evaluated in a panel of behavioral and psychopharmacological assays to assess possible glutamatergic and dopaminergic dysfunction. In comparison to non-transgenic control mice, Adk-tg mice are characterized by severe learning deficits in the Morris water maze task and in Pavlovian conditioning. The Adk-tg mice also exhibited reduced locomotor reaction to systemic amphetamine, whereas their reaction to the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 was enhanced. Our results confirmed that ADK overexpression could lead to functional concomitant alterations in dopaminergic and glutamatergic functions, which is in keeping with the hypothesized role of ADK in the balance and integration between glutamatergic and dopaminergic neurotransmission. The present findings are of relevance to current pathophysiological hypotheses of schizophrenia and its pharmacotherapy.

Serotonin regulates the phase of the rat suprachiasmatic circadian pacemaker in vitro only during the subjective day.

Science.gov (United States)

Medanic, M; Gillette, M U

1992-05-01

1. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker for circadian rhythms in mammals. The 24 h pacemaker is endogenous to the SCN and persists for multiple cycles in the suprachiasmatic brain slice. 2. While serotonin is not endogenous to the SCN, a major midbrain hypothalamic afferent pathway is serotonergic. Within this tract the dorsal raphe nucleus sends direct projections to the ventrolateral portions of the SCN. We investigated a possible regulatory role for serotonin in the mammalian circadian system by examining its effect, when applied at projection sites, on the circadian rhythm of neuronal activity in rat SCN in vitro. 3. Eight-week-old male rats from our inbred colony, housed on a 12 h light: 12 h dark schedule, were used. Hypothalamic brain slices containing the paired SCN were prepared in the day and maintained in glucose and bicarbonate-supplemented balanced salt solution for up to 53 h. 4. A 10(-11) ml drop of 10(-6) M-serotonin (5-hydroxytryptamine (5-HT) creatinine sulphate complex) in medium was applied to the ventrolateral portion of one of the SCN for 5 min on the first day in vitro. The effect of the treatment at each of seven time points across the circadian cycle was examined. The rhythm of spontaneous neuronal activity was recorded extracellularly on the second and third days in vitro. Phase shifts were determined by comparing the time-of-peak of neuronal activity in serotonin- vs. media-treated slices. 5. Application of serotonin during the subjective day induced significant advances in the phase of the electrical activity rhythm (n = 11). The most sensitive time of treatment was CT 7 (circadian time 7 is 7 h after 'lights on' in the animal colony), when a 7.0 +/- 0.1 h phase advance was observed (n = 3). This phase advance was perpetuated on day 3 in vitro without decrement. Serotonin treatment during the subjective night had no effect on the timing of the electrical activity rhythm (n = 9). 6. The

Preparation and evaluation of serotonin labelled with 125I

International Nuclear Information System (INIS)

Sivaprasad, N.; Geetha, R.; Ghodke, A.S.; Karmalkar, C.P.; Pilkhwal, N.S.; Sarnaik, J.S.; Borkute, S.D.; Nadkarni, G.D.

1999-01-01

Radiolabelled serotonin is an important tool for studying serotonin receptors and estimating serotonin levels in plants and animals. In this paper we report the synthesis of serotonin - 125 I. Tyrosine Methyl Ester (TME) was first labelled with 125 I using chloramine-T method. 125 I-TME was then conjugated with serotonin using carbodimide. The labelled conjugate was purified using gel filtration. Yield and radiochemical purity were estimated using electrophoresis and ITLC in different solvent systems. The binding of the purified tracer to serotonin receptors and serotonin antibodies was studied. (author)

Assessment of the Potential Role of Tryptophan as the Precursor of Serotonin and Melatonin for the Aged Sleep-wake Cycle and Immune Function: Streptopelia Risoria as a Model

Directory of Open Access Journals (Sweden)

Sergio D. Paredes

2009-01-01

Full Text Available In the present review we summarize the relationship between the amino acid, tryptophan, the neurotransmitter, serotonin, and the indole, melatonin, with the rhythms of sleep/wake and the immune response along with the possible connections between the alterations in these rhythms due to aging and the so-called “serotonin and melatonin deficiency state.” The decrease associated with aging of the brain and circulating levels of serotonin and melatonin seemingly contributes to the alterations of both the sleep/wake cycle and the immune response that typically accompany old age. The supplemental administration of tryptophan, e.g. the inclusion of tryptophan-enriched food in the diet, might help to remediate these age- related alterations due to its capacity of raise the serotonin and melatonin levels in the brain and blood. Herein, we also summarize a set of studies related to the potential role that tryptophan, and its derived product melatonin, may play in the restoration of the aged circadian rhythms of sleep/wake and immune response, taking the ringdove (Streptopelia risoria as a suitable model.

Decreased exploratory activity in a mouse model of 15q duplication syndrome; implications for disturbance of serotonin signaling.

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Kota Tamada

Full Text Available Autism spectrum disorders (ASDs have garnered significant attention as an important grouping of developmental brain disorders. Recent genomic studies have revealed that inherited or de novo copy number variations (CNVs are significantly involved in the pathophysiology of ASDs. In a previous report from our laboratory, we generated mice with CNVs as a model of ASDs, with a duplicated mouse chromosome 7C that is orthologous to human chromosome 15q11-13. Behavioral analyses revealed paternally duplicated (patDp/+ mice displayed abnormal behaviors resembling the symptoms of ASDs. In the present study, we extended these findings by performing various behavioral tests with C57BL/6J patDp/+ mice, and comprehensively measuring brain monoamine levels with ex vivo high performance liquid chromatography. Compared with wild-type controls, patDp/+ mice exhibited decreased locomotor and exploratory activities in the open field test, Y-maze test, and fear-conditioning test. Furthermore, their decreased activity levels overcame increased appetite induced by 24 hours of food deprivation in the novelty suppressed feeding test. Serotonin levels in several brain regions of adult patDp/+ mice were lower than those of wild-type control, with no concurrent changes in brain levels of dopamine or norepinephrine. Moreover, analysis of monoamines in postnatal developmental stages demonstrated reduced brain levels of serotonin in young patDp/+ mice. These findings suggest that a disrupted brain serotonergic system, especially during postnatal development, may generate the phenotypes of patDp/+ mice.

Microbiome-Gut-Brain Axis: A Pathway for Improving Brainstem Serotonin Homeostasis and Successful Autoresuscitation in SIDS-A Novel Hypothesis.

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Praveen, Vijayakumar; Praveen, Shama

2016-01-01

Sudden infant death syndrome (SIDS) continues to be a major public health issue. Following its major decline since the "Back to Sleep" campaign, the incidence of SIDS has plateaued, with an annual incidence of about 1,500 SIDS-related deaths in the United States and thousands more throughout the world. The etiology of SIDS, the major cause of postneonatal mortality in the western world, is still poorly understood. Although sleeping in prone position is a major risk factor, SIDS continues to occur even in the supine sleeping position. The triple-risk model of Filiano and Kinney emphasizes the interaction between a susceptible infant during a critical developmental period and stressor/s in the pathogenesis of SIDS. Recent evidence ranges from dysregulated autonomic control to findings of altered neurochemistry, especially the serotonergic system that plays an important role in brainstem cardiorespiratory/thermoregulatory centers. Brainstem serotonin (5-HT) and tryptophan hydroxylase-2 (TPH-2) levels have been shown to be lower in SIDS, supporting the evidence that defects in the medullary serotonergic system play a significant role in SIDS. Pathogenic bacteria and their enterotoxins have been associated with SIDS, although no direct evidence has been established. We present a new hypothesis that the infant's gut microbiome, and/or its metabolites, by its direct effects on the gut enterochromaffin cells, stimulates the afferent gut vagal endings by releasing serotonin (paracrine effect), optimizing autoresuscitation by modulating brainstem 5-HT levels through the microbiome-gut-brain axis, thus playing a significant role in SIDS during the critical period of gut flora development and vulnerability to SIDS. The shared similarities between various risk factors for SIDS and their relationship with the infant gut microbiome support our hypothesis. Comprehensive gut-microbiome studies are required to test our hypothesis.

Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.

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Takeaki Saijo

Full Text Available A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A receptor, called Wf-516 (structural formula: (2S-1-[4-(3,4-dichlorophenylpiperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-ylbenzo[b]furan-4-yloxy]propan-2-ol monohydrochloride, has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A receptors. In addition, [(35S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.

Science.gov (United States)

Saijo, Takeaki; Maeda, Jun; Okauchi, Takashi; Maeda, Jun-ichi; Morio, Yasunori; Kuwahara, Yasuhiro; Suzuki, Masayuki; Goto, Nobuharu; Fukumura, Toshimitsu; Suhara, Tetsuya; Higuchi, Makoto

2012-01-01

A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A)) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A) receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A) receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A) receptors. In addition, [(35)S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A) receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A) receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

Interactions between lysergic acid diethylamide and dopamine-sensitive adenylate cyclase systems in rat brain.

Science.gov (United States)

Hungen, K V; Roberts, S; Hill, D F

1975-08-22

Investigations were carried out on the interactions of the hallucinogenic drug, D-lysergic acid diethylamide (D-LSD), and other serotonin antagonists with catecholamine-sensitive adenylate cyclase systems in cell-free preparations from different regions of rat brain. In equimolar concentration, D-LSD, 2-brono-D-lysergic acid diethylamide (BOL), or methysergide (UML) strongly blocked maximal stimulation of adenylate cyclase activity by either norepinephrine or dopamine in particulate preparations from cerebral cortices of young adult rats. D-LSD also eliminated the stimulation of adenylate cyclase activity of equimolar concentrations of norepinephrine or dopamine in particulate preparations from rat hippocampus. The effects of this hallucinogenic agent on adenylate cyclase activity were most striking in particulate preparations from corpus striatum. Thus, in 10 muM concentration, D-LSD not only completely eradicated the response to 10 muM dopamine in these preparations but also consistently stimulated adenylate cyclase activity. L-LSD (80 muM) was without effect. Significant activation of striatal adenylate cyclase was produced by 0.1 muM D-LSD. Activation of striatal adenylate cyclase of either D-LSD or dopamine was strongly blocked by the dopamine-blocking agents trifluoperazine, thioridazine, chlorpromazine, and haloperidol. The stimulatory effects of D-LSD and dopamine were also inhibited by the serotonin-blocking agents, BOL, 1-methyl-D-lysergic acid diethylamide (MLD), and cyproheptadine, but not by the beta-adrenergic-blocking agent, propranolol. However, these serotonin antagonists by themselves were incapable of stimulating adenylate cyclase activity in the striatal preparations. Several other hallucinogens, which were structurally related to serotonin, were also inactive in this regard, e.g., mescaline, N,N-dimethyltryptamine, psilocin and bufotenine. Serotonin itself produced a small stimulation of adenylate cyclase activity in striatal preparations and

Inorganic phosphate inhibits sympathetic neurotransmission in canine saphenous veins

International Nuclear Information System (INIS)

Edoute, Y.; Vanhoutte, P.M.; Shepherd, J.T.

1987-01-01

Inorganic phosphate has been proposed as the initiator of metabolic vasodilatation in active skeletal muscle. The present study was primarily designed to determine if this substance has an inhibitory effect on adrenergic neurotransmission. Rings of canine saphenous veins were suspended for isometric tension recording in organ chambers. A comparison was made of the ability of inorganic phosphate (3 to 14 mM) to relax rings contracted to the same degree by electrical stimulation, exogenous norepinephrine, and prostaglandin F/sub 2α/. The relaxation during electrical stimulation was significantly greater at all concentrations of phosphate. In strips of saphenous veins previously incubated with [ 3 H]norepinephrine, the depression of the contractile response caused by phosphate during electrical stimulated was accompanied by a significant reduction in the overflow of labeled neurotransmitter. Thus inorganic phosphate inhibits sympathetic neurotransmission and hence may have a key role in the sympatholysis in the active skeletal muscles during exercise. By contrast, in this preparation, it has a modest direct relaxing action on the vascular smooth muscle

Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

Science.gov (United States)

Dobry, Yuriy; Rice, Timothy; Sher, Leo

2013-01-01

At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

Pathological glutamatergic neurotransmission in Gilles de la Tourette syndrome.

Science.gov (United States)

Kanaan, Ahmad Seif; Gerasch, Sarah; García-García, Isabel; Lampe, Leonie; Pampel, André; Anwander, Alfred; Near, Jamie; Möller, Harald E; Müller-Vahl, Kirsten

2017-01-01

measurements. Multiple regression analysis revealed a significant negative correlation between (i) striatal Gln and actual tic severity; and (ii) thalamic Glu and premonitory urges. Our results indicate that patients with Gilles de la Tourette syndrome exhibit an abnormality in the flux of metabolites in the GABA-Glu-Gln cycle, thus implying perturbations in astrocytic-neuronal coupling systems that maintain the subtle balance between excitatory and inhibitory neurotransmission within subcortical nuclei. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Evolving knowledge of sex differences in brain structure, function, and chemistry.

Science.gov (United States)

Cosgrove, Kelly P; Mazure, Carolyn M; Staley, Julie K

2007-10-15

Clinical and epidemiologic evidence demonstrates sex differences in the prevalence and course of various psychiatric disorders. Understanding sex-specific brain differences in healthy individuals is a critical first step toward understanding sex-specific expression of psychiatric disorders. Here, we evaluate evidence on sex differences in brain structure, chemistry, and function using imaging methodologies, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), and structural magnetic resonance imaging (MRI) in mentally healthy individuals. MEDLINE searches of English-language literature (1980-November 2006) using the terms sex, gender, PET, SPECT, MRI, fMRI, morphometry, neurochemistry, and neurotransmission were performed to extract relevant sources. The literature suggests that while there are many similarities in brain structure, function, and neurotransmission in healthy men and women, there are important differences that distinguish the male from the female brain. Overall, brain volume is greater in men than women; yet, when controlling for total volume, women have a higher percentage of gray matter and men a higher percentage of white matter. Regional volume differences are less consistent. Global cerebral blood flow is higher in women than in men. Sex-specific differences in dopaminergic, serotonergic, and gamma-aminobutyric acid (GABA)ergic markers indicate that male and female brains are neurochemically distinct. Insight into the etiology of sex differences in the normal living human brain provides an important foundation to delineate the pathophysiological mechanisms underlying sex differences in neuropsychiatric disorders and to guide the development of sex-specific treatments for these devastating brain disorders.

Modulation of defensive reflex conditioning in snails by serotonin

Science.gov (United States)

Andrianov, Vyatcheslav V.; Bogodvid, Tatiana K.; Deryabina, Irina B.; Golovchenko, Aleksandra N.; Muranova, Lyudmila N.; Tagirova, Roza R.; Vinarskaya, Aliya K.; Gainutdinov, Khalil L.

2015-01-01

Highlights Daily injection of serotonin before a training session accelerated defensive reflex conditioning in snails.Daily injection of 5-hydroxytryptophan before a training session in snails with a deficiency of serotonin induced by the “neurotoxic” analog of serotonin 5,7-dihydroxytryptamine, restored the ability of snails to learn.After injection of the “neurotoxic” analogs of serotonin 5,6- and 5,7-dihydroxytryptamine as well as serotonin, depolarization of the membrane and decrease of the threshold potential of premotor interneurons was observed. We studied the role of serotonin in the mechanisms of learning in terrestrial snails. To produce a serotonin deficit, the “neurotoxic” analogs of serotonin, 5,6- or 5,7-dihydroxytryptamine (5,6/5,7-DHT) were used. Injection of 5,6/5,7-DHT was found to disrupt defensive reflex conditioning. Within 2 weeks of neurotoxin application, the ability to learn had recovered. Daily injection of serotonin before a training session accelerated defensive reflex conditioning and daily injections of 5-HTP in snails with a deficiency of serotonin induced by 5,7-DHT restored the snail's ability to learn. We discovered that injections of the neurotoxins 5,6/5,7-DHT as well as serotonin, caused a decrease in the resting and threshold potentials of the premotor interneurons LPa3 and RPa3. PMID:26557063

Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents.

Science.gov (United States)

Croarkin, Paul E; Nakonezny, Paul A; Wall, Christopher A; Murphy, Lauren L; Sampson, Shirlene M; Frye, Mark A; Port, John D

2016-01-30

Abnormalities in glutamate neurotransmission may have a role in the pathophysiology of adolescent depression. The present pilot study examined changes in cortical glutamine/glutamate ratios in depressed adolescents receiving high-frequency repetitive transcranial magnetic stimulation. Ten adolescents with treatment-refractory major depressive disorder received up to 30 sessions of 10-Hz repetitive transcranial magnetic stimulation at 120% motor threshold with 3000 pulses per session applied to the left dorsolateral prefrontal cortex. Baseline, posttreatment, and 6-month follow-up proton magnetic resonance spectroscopy scans of the anterior cingulate cortex and left dorsolateral prefrontal cortex were collected at 3T with 8-cm(3) voxels. Glutamate metabolites were quantified with 2 distinct proton magnetic resonance spectroscopy sequences in each brain region. After repetitive transcranial magnetic stimulation and at 6 months of follow-up, glutamine/glutamate ratios increased in the anterior cingulate cortex and left dorsolateral prefrontal cortex with both measurements. The increase in the glutamine/glutamate ratio reached statistical significance with the TE-optimized PRESS sequence in the anterior cingulate cortex. Glutamine/glutamate ratios increased in conjunction with depressive symptom improvement. This reached statistical significance with the TE-optimized PRESS sequence in the left dorsolateral prefrontal cortex. High-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex may modulate glutamate neurochemistry in depressed adolescents. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Cerebral serotonin release correlates with [¹¹C]AZ10419369 PET measures of 5-HT_1B receptor binding in the pig brain

DEFF Research Database (Denmark)

Jørgensen, Louise M; Weikop, Pia; Svarer, Claus

2018-01-01

of extracellular serotonin levels with microdialysis after various acute interventions (saline, escitalopram, fenfluramine). The interventions increased the cerebral extracellular serotonin levels to two to six times baseline, with fenfluramine being the most potent pharmacological enhancer of serotonin release...

Adenoviral vectors for highly selective gene expression in central serotonergic neurons reveal quantal characteristics of serotonin release in the rat brain

Directory of Open Access Journals (Sweden)

Teschemacher Anja G

2009-03-01

Full Text Available Abstract Background 5-hydroxytryptamine (5 HT, serotonin is one of the key neuromodulators in mammalian brain, but many fundamental properties of serotonergic neurones and 5 HT release remain unknown. The objective of this study was to generate an adenoviral vector system for selective targeting of serotonergic neurones and apply it to study quantal characteristics of 5 HT release in the rat brain. Results We have generated adenoviral vectors which incorporate a 3.6 kb fragment of the rat tryptophan hydroxylase-2 (TPH-2 gene which selectively (97% co-localisation with TPH-2 target raphe serotonergic neurones. In order to enhance the level of expression a two-step transcriptional amplification strategy was employed. This allowed direct visualization of serotonergic neurones by EGFP fluorescence. Using these vectors we have performed initial characterization of EGFP-expressing serotonergic neurones in rat organotypic brain slice cultures. Fluorescent serotonergic neurones were identified and studied using patch clamp and confocal Ca2+ imaging and had features consistent with those previously reported using post-hoc identification approaches. Fine processes of serotonergic neurones could also be visualized in un-fixed tissue and morphometric analysis suggested two putative types of axonal varicosities. We used micro-amperometry to analyse the quantal characteristics of 5 HT release and found that central 5 HT exocytosis occurs predominantly in quanta of ~28000 molecules from varicosities and ~34000 molecules from cell bodies. In addition, in somata, we observed a minority of large release events discharging on average ~800000 molecules. Conclusion For the first time quantal release of 5 HT from somato-dendritic compartments and axonal varicosities in mammalian brain has been demonstrated directly and characterised. Release from somato-dendritic and axonal compartments might have different physiological functions. Novel vectors generated in this

Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain.

Science.gov (United States)

Buckholtz, N S; Zhou, D F; Freedman, D X; Potter, W Z

1990-04-01

A dosage regimen of lysergic acid diethylamide (LSD) that reliably produces behavioral tolerance in rats was evaluated for effects on neurotransmitter receptor binding in rat brain using a variety of radioligands selective for amine receptor subtypes. Daily administration of LSD [130 micrograms/kg (0.27 mumol/kg) intraperitoneally (IP)] for 5 days produced a decrease in serotonin2 (5-hydroxytryptamine2, 5-HT2) binding in cortex (measured 24 hours after the last drug administration) but did not affect binding to other receptor systems (5-HT1A, 5-HT1B, beta-adrenergic, alpha 1- or alpha 2-adrenergic, D2-dopaminergic) or to a recognition site for 5-HT uptake. The decrease was evident within 3 days of LSD administration but was not demonstrable after the first LSD dose. Following 5 days of LSD administration the decrease was still present 48 hours, but not 96 hours, after the last administration. The indole hallucinogen psilocybin [1.0 mg/kg (3.5 mumol/kg) for 8 days] also produced a significant decrease in 5HT2 binding, but neither the nonhallucinogenic analog bromo-LSD [1.3 mg/kg (2.4 mumol/kg) for 5 days] nor mescaline [10 mg/kg (40.3 mumol/kg) for 5 or 10 days] affected 5-HT2 binding. These observations suggest that LSD and other indole hallucinogens may act as 5-HT2 agonists at postsynaptic 5-HT2 receptors. Decreased 5-HT2 binding strikingly parallels the development and loss of behavioral tolerance seen with repeated LSD administration, but the decreased binding per se cannot explain the gamut of behavioral tolerance and cross-tolerance phenomena among the indole and phenylethylamine hallucinogens.

FlipADAM: a potential new SPECT imaging agent for the serotonin transporter

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Wang, Julie L.; Deutsch, Eric C. [Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Oya, Shunichi [Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Kung, Hank F., E-mail: kunghf@gmail.co [Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States)

2010-07-15

Introduction: Single photon emission computed tomography (SPECT) imaging of the serotonin transporter (SERT) in the brain is a useful tool for examining normal physiological functions and disease states involving the serotonergic system. The goal of this study was to develop an improved SPECT radiotracer with faster kinetics than the current leading SPECT tracer, [{sup 123}I]ADAM, for selective SERT imaging. Methods: The in vitro binding affinities of (2-(2'-((dimethylamino)methyl)-4'-iodophenylthio)benzenamine) (FlipADAM) (1c), were determined using Hampshire pig kidney cells stably overexpressing the serotonin, norepinephrine (NET) or dopamine transporter (DAT). Localization of [{sup 125}I]FlipADAM (1c) was evaluated through biodistribution and autoradiography in male Sprague Dawley rats, and the specificity of binding was assessed by injecting selective SERT or NET inhibitors prior to [{sup 125}I]FlipADAM (1c). Results: FlipADAM (1c) displayed a high binding affinity for SERT (K{sub i}=1.0 nM) and good selectivity over NET and DAT binding (43-fold and 257-fold, respectively). [{sup 125}I]FlipADAM (1c) successfully penetrated the blood brain barrier, as evidenced by the brain uptake at 2 min (1.75% dose/g). [{sup 125}I]FlipADAM(1c) also had a good target to non-target (hypothalamus/cerebellum) ratio of 3.35 at 60 min post-injection. In autoradiography studies, [{sup 125}I]FlipADAM (1c) showed selective localization in SERT-rich brain regions such as the thalamic nuclei, amygdala, dorsal raphe nuclei and other areas. Conclusion: [{sup 125}I]FlipADAM (1c) exhibited faster clearance from the brain and time to binding equilibrium when compared to [{sup 125}I]2-(2'-((dimethylamino)methyl)-phenylthio)-5-iodophenylamine [{sup 125}I]ADAM (1b) and a higher target to non-target ratio when compared to [{sup 125}I]5-iodo-2-(2'-((dimethylamino)methyl)-phenylthio)benzyl alcohol [{sup 125}I]IDAM (1a). Therefore, [{sup 123}I]FlipADAM (1c) may be an improved

The effect of partial agonist of serotonin-1A receptor on cognitive functions in animal model of schizophrenia

OpenAIRE

Antošová, Eliška

2011-01-01

Serotoin is a neurotransmitter participating in regulation of many physiologic fuctions. Main serotogenous neurons can be found in nukleus raphe of the brain stem. Nucleus raphe inervates many areas of the brain including the cerebal cortex and hipocampus. These structures are important for controling of higher cognitive functions. 5HT1A receptor is one of many subtypes of serotonin receptors and its activation inhibits iniciating of the action potencials. 5HT1A receptor is expressed presynap...

Influence of gallamine, pancuronium, d-tubocurarine and succinylcholine on adrenergic neurotransmission

NARCIS (Netherlands)

Vercruysse, P.; Bossuyt, P.; Verbeuren, T. J.; Vanhoutte, P. M.; Hanegreefs, G.

1979-01-01

The influence of gallamine, pancuronium, d-tubocurarine and succinylcholine on adrenergic neurotransmission was studied in the isolated saphenous vein of the dog. Pancuronium increased the response of vascular smooth muscle to adrenergic nerve stimulation and to exogenous norepinephrine; gallamine,

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

Science.gov (United States)

Serotonin and norepinephrine reuptake inhibitors (SNRIs) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, ... effects they may cause. By Mayo Clinic Staff Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class ...

Aging and depression vulnerability interaction results in decreased serotonin innervation associated with reduced BDNF levels in hippocampus of rats bred for learned helplessness

DEFF Research Database (Denmark)

Aznar, Susana; Klein, Anders B; Santini, Martin A

2010-01-01

. These observations indicate that aging should be taken into account when studying the neurobiological factors behind the vulnerability for depression and that understanding the effect of aging on genetically predisposed individuals may contribute to a better understanding of the pathophysiology behind depression....... Brains from young (5 months old) and old (13 months old) congenital Learned Helplessness rats (cLH), and congenital Non Learned Helplessness rats (cNLH) were immunohistochemically stained for the serotonin transporter and subsequently stereologically quantified for estimating hippocampal serotonin fiber...

Stimulation of aortic smooth muscle cell mitogenesis by serotonin

International Nuclear Information System (INIS)

Nemecek, G.M.; Coughlin, S.R.; Handley, D.A.; Moskowitz, M.A.

1986-01-01

Bovine aortic smooth muscle cells in vitro responded to 1 nM to 10 μM serotonin with increased incorporation of [ 3 H]thymidine into DNA. The mitogenic effect of serotonin was half-maximal at 80 nM and maximal above 1 μM. At a concentration of 1 μM, serotonin stimulated smooth muscle cell mitogenesis to the same extent as human platelet-derived growth factor (PDGF) at 12 ng/ml. Tryptamine was ≅ 1/10th as potent as serotonin as a mitogen for smooth muscle cells. Other indoles that are structurally related to serotonin (D- and L-tryptophan, 5-hydroxy-L-tryptophan, N-acetyl-5-hydroxytryptamine, melatonin, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophol) and quipazine were inactive. The stimulatory effect of serotonin on smooth muscle cell DNA synthesis required prolonged (20-24 hr) exposure to the agonist and was attenuated in the presence of serotonin D receptor antagonists. When smooth muscle cells were incubated with submaximal concentrations of serotonin and PDGF, synergistic rather than additive mitogenic responses were observed. These data indicate that serotonin has a significant mitogenic effect on smooth muscle cells in vitro, which appears to be mediated by specific plasma membrane receptors

Subsecond Sensory Modulation of Serotonin Levels in a Primary Sensory Area and Its Relation to Ongoing Communication Behavior in a Weakly Electric Fish.

Science.gov (United States)

Fotowat, Haleh; Harvey-Girard, Erik; Cheer, Joseph F; Krahe, Rüdiger; Maler, Leonard

2016-01-01

Serotonergic neurons of the raphe nuclei of vertebrates project to most regions of the brain and are known to significantly affect sensory processing. The subsecond dynamics of sensory modulation of serotonin levels and its relation to behavior, however, remain unknown. We used fast-scan cyclic voltammetry to measure serotonin release in the electrosensory system of weakly electric fish, Apteronotus leptorhynchus . These fish use an electric organ to generate a quasi-sinusoidal electric field for communicating with conspecifics. In response to conspecific signals, they frequently produce signal modulations called chirps. We measured changes in serotonin concentration in the hindbrain electrosensory lobe (ELL) with a resolution of 0.1 s concurrently with chirping behavior evoked by mimics of conspecific electric signals. We show that serotonin release can occur phase locked to stimulus onset as well as spontaneously in the ELL region responsible for processing these signals. Intense auditory stimuli, on the other hand, do not modulate serotonin levels in this region, suggesting modality specificity. We found no significant correlation between serotonin release and chirp production on a trial-by-trial basis. However, on average, in the trials where the fish chirped, there was a reduction in serotonin release in response to stimuli mimicking similar-sized same-sex conspecifics. We hypothesize that the serotonergic system is part of an intricate sensory-motor loop: serotonin release in a sensory area is triggered by sensory input, giving rise to motor output, which can in turn affect serotonin release at the timescale of the ongoing sensory experience and in a context-dependent manner.

Changes in aminoacidergic and monoaminergic neurotransmission in the hippocampus and amygdala of rats after ayahuasca ingestion

Institute of Scientific and Technical Information of China (English)

Eduardo; Ferreira; de; Castro-Neto; Rafael; Henrique; da; Cunha; Dartiu; Xavier; da; Silveira; Mauricio; Yonamine; Telma; Luciana; Furtado; Gouveia; Esper; Abro; Cavalheiro; Débora; Amado; Maria; da; Graa; Naffah-Mazzacoratti

2013-01-01

AIM: To evaluate changes in neurotransmission induced by a psychoactive beverage ayahuasca in the hippocampus and amygdala of naive rats. METHODS: The level of monoamines, their main metabolites and amino acid neurotransmitters concentrations were quantified using high performance liquid chromatography(HPLC). Four groups of rats were employed: saline-treated and rats receiving 250, 500 and 800 mg/kg of ayahuasca infusion(gavage). Animals were killed 40 min after drug ingestion and the structures stored at-80 ℃ until HPLC assay. The data from all groups were compared using Analysis of variance and Scheffé as post test and P < 0.05 was accepted as significant. RESULTS: The results showed decreased concentrations of glycine(GLY)(0.13 ± 0.03 vs 0.29 ± 0.07, P < 0.001) and γ-aminobutyric acid(GABA)(1.07 ± 0.14 vs 1.73 ± 0.25, P < 0.001) in the amygdala of rats that received 500 of ayahuasca. Animals that ingested 800 mg/kg of ayahuasca also showed a reduction of GLY level(0.11 ± 0.01 vs 0.29 ± 0.07, P < 0.001) and GABA(0.98 ± 0.06 vs 1.73 ± 0.25, P < 0.001). In the hippocampus, increased GABA levels were found in rats that received all ayahuasca doses: 250 mg/kg(1.29 ± 0.19 vs 0.84 ± 0.21, P < 0.05); 500 mg/kg(2.23 ± 038 vs 084 ± 0.21, P < 0.05) and 800 mg/kg(1.98 ± 0.92 vs 0.84 ± 0.21, P < 0.05). In addition, an increased utilization rate of all monoamines was found in the amygdala after ayahuasca administration in doses: 250 mg/kg(noradrenaline: 0.16 ± 0.02 vs 0.36 ± 0.06, P < 0.01; dopamine: 0.39 ± 0.012 vs 2.39 ± 0.84, P < 0.001; serotonin: 1.02 ± 0.22 vs 4.04 ± 0.91, P < 0.001), 500 mg/kg(noradrenaline: 0.08 ± 0.02 vs 0.36 ± 0.06, P < 0.001; dopamine: 0.33 ± 0.19 vs 2.39 ± 0.84, P < 0.001; serotonin: 0.59 ± 0.08 vs 4.04 ± 0.91, P < 0.001) and 800 mg/kg(noradrenaline: 0.16 ± 0.04 vs 0.36 ± 0.06, P < 0.001; dopamine: 0.84 ± 0.65 vs2.39 ± 0.84, P < 0.05; serotonin: 0.36 ± 0.02 vs 4.04 ± 0.91, P < 0.001). CONCLUSION: Our data suggest

Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans.

NARCIS (Netherlands)

Molteni, R.; Cattaneo, A.; Calabrese, F.; Macchi, F.; Olivier, J.D.A.; Racagni, G.; Ellenbroek, A.A.; Gennarelli, M.; Riva, M.A.

2010-01-01

In order to identify the molecular mechanisms that may contribute to the enhanced susceptibility to depression under serotonin transporter (SERT) dysfunction, we analyzed the expression of brain-derived neurotrophic factor (BDNF), a key player in neuronal plasticity, which is implicated in the

Serotonin Neuron Abnormalities in the BTBR Mouse Model of Autism

Science.gov (United States)

Guo, Yue-Ping; Commons, Kathryn G.

2017-01-01

The inbred mouse strain BTBR T+ Itpr3tf/J (BTBR) i studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. PMID:27478061

Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia.

Science.gov (United States)

Lewis, David A; Hashimoto, Takanori; Morris, Harvey M

2008-10-01

Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission. Specifically, using a combination of methods, we found that subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding presynaptic regulators of GABA neurotransmission, neuropeptide markers of specific subpopulations of GABA neurons, and certain subunits of the GABA(A) receptor. In particular, alterations in the expression of the neuropeptide somatostatin suggested that GABA neurotransmission is impaired in the Martinotti subset of GABA neurons that target the dendrites of pyramidal cells. In contrast, none of the GABA-related transcripts assessed to date were altered in the DLPFC of monkeys chronically exposed to antipsychotic medications, suggesting that the effects observed in the human studies reflect the disease process and not its treatment. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia may be attributable to altered GABA neurotransmission in specific DLPFC microcircuits.

The effect of prolonged simvastatin application on serotonin uptake, membrane microviscosity and behavioral changes in the animal model

Czech Academy of Sciences Publication Activity Database

Vevera, J.; Valeš, Karel; Fišar, Z.; Hroudová, J.; Singh, N.; Stuchlík, Aleš; Kačer, P.; Nekovářová, Tereza

2016-01-01

Roč. 158, May 1 (2016), s. 112-120 ISSN 0031-9384 R&D Projects: GA MZd(CZ) NT13403; GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GAP303/12/1464 Grant - others:Rada Programu interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111204 Institutional support: RVO:67985823 Keywords : statins * rats * cholesterol * brain * serotonergic neurotransmission * behavior Subject RIV: FH - Neurology Impact factor: 2.341, year: 2016

Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

Directory of Open Access Journals (Sweden)

Albert Paul R

2011-05-01

Full Text Available Abstract The serotonin-1A (5-HT1A receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019G (rs6295 polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

Serotonin Test

Science.gov (United States)

... microscope. (For more, see the article on Anatomic Pathology .) See More Common Questions See Less Common Questions ... tumor. Accessed December 2010. Vorvick, L. (Updated 2009 March 14). Serum serotonin level. MedlinePlus Medical Encyclopedia [On- ...

The molecular mechanism for overcoming the rate-limiting step in monoamine neurotransmitter transport

DEFF Research Database (Denmark)

Sinning, Steffen; Said, Saida; Malinauskaite, Lina

The monoamine transporter family consists of dopamine (DAT), norepinephrine (NET) and serotonin transporters (SERT) that mediate the reuptake of the monoamine neurotransmitters after their release during neurotransmission. These transporters play prominent roles in psychiatric disorders and are t......The monoamine transporter family consists of dopamine (DAT), norepinephrine (NET) and serotonin transporters (SERT) that mediate the reuptake of the monoamine neurotransmitters after their release during neurotransmission. These transporters play prominent roles in psychiatric disorders...... membrane. The rate-limiting step in monoamine reuptake is the return of the empty transporter from an inward-facing to an outward-facing conformation without neurotransmitter and sodium bound. The molecular mechanism underlying this important conformational transition has not been described. Crystal...

The role of serotonin and norepinephrine in sleep-waking activity.

Science.gov (United States)

Morgane, P J; Stern, W C

1975-11-01

A critical review of the evidences relating the biogenic amines serotonin and norepinephrine to the states of slow-wave and rapid eye movement (REM) sleep is presented. Various alternative explanations for specific chemical regulation of the individual sleep states, including the phasic events of REM sleep, are evaluated within the overall framework of the monoamine theory of sleep. Several critical neuropsychopharmacological studies relating to metabolsim of the amines in relation to sleep-waking behavior are presented. Models of the chemical neuronal circuitry involved in sleep-waking activity are derived and interactions between several brainstem nuclei, particularly the raphé complex and locus coeruleus, are discussed. Activity in these aminergic systems in relation to oscillations in the sleep-waking cycles is evaluated. In particular, the assessment of single cell activity in specific chemical systems in relations to chemical models of sleep is reviewed. Overall, it appears that the biogenic amines, especially serotonin and norepinephrine, play key roles in the generation and maintenance of the sleep states. These neurotransmitters participate in some manner in the "triggering" processes necessary for actuating each sleep phase and in regulating the transitions from sleep to waking activity. The biogenic amines are, however, probably not "sleep factors" or direct inducers of the sleep states. Rather, they appear to be components of a multiplicity of interacting chemical circuitry in the brain whose activity maintains various chemical balances in different brain regions. Shifts in these balances appear to be involved in the triggering and maintenance of the various states comprising the vigilance continuum.

Serotonin-1A receptor imaging in recurrent depression: replication and literature review

Energy Technology Data Exchange (ETDEWEB)

Drevets, Wayne C. [Mood and Anxiety Disorders Program, MINH Molecular Imaging Branch, Bethesda, MD 20892 (United States); Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Department of Radiology, University of Pittsburgh, Pittsburgh, PA 19213 (United States)], E-mail: drevetsw@mail.nih.gov; Thase, Michael E. [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Department of Psychiatry, University of Pennsylvania, School of Medicine and Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104 (United States); Moses-Kolko, Eydie L. [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Price, Julie [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Department of Radiology, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Frank, Ellen; Kupfer, David J. [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Mathis, Chester [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Department of Radiology, University of Pittsburgh, Pittsburgh, PA 19213 (United States)

2007-10-15

Introduction: Serotonin-1A receptor (5-HT{sub 1A}R) function appears to be decreased in major depressive disorder (MDD) based on physiological responses to 5-HT{sub 1A}R agonists in vivo and to 5-HT{sub 1A}R binding in brain tissues postmortem or antemortem. We have previously assessed 5-HT{sub 1A}R binding potential (BP) in depression using positron emission tomography (PET) and [carbonyl-{sup 11}C]WAY-100635, and we have demonstrated reduced 5-HT{sub 1A}R BP in the mesiotemporal cortex (MTC) and raphe in depressives with primary recurrent familial mood disorders (n=12) versus controls (n=8) [Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46(10):1375-87]. These findings were replicated by some, but not other, studies performed in depressed samples that were more generally selected using criteria for MDD. In the current study, we attempted to replicate our previous findings in an independent sample of subjects selected according to the criteria for primary recurrent depression applied in our prior study. Methods: Using PET and [carbonyl-{sup 11}C]WAY-100635, 5-HT{sub 1A}R BP was assessed in 16 depressed subjects and 8 healthy controls. Results: Mean 5-HT{sub 1A}R BP was reduced by 26% in the MTC (P < .005) and by 43% in the raphe (P < .001) in depressives versus controls. Conclusions: These data replicate our original findings, which showed that BP was reduced by 27% in the MTC (P < .025) and by 42% in the raphe (P < .02) in depression. The magnitudes of these reductions in 5-HT{sub 1A}R binding were similar to those found postmortem in 5-HT{sub 1A}R mRNA concentrations in the hippocampus in MDD [Lopez JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73] and in 5-HT{sub 1A

Molecular imaging of serotonin degeneration in mild cognitive impairment.

Science.gov (United States)

Smith, Gwenn S; Barrett, Frederick S; Joo, Jin Hui; Nassery, Najlla; Savonenko, Alena; Sodums, Devin J; Marano, Christopher M; Munro, Cynthia A; Brandt, Jason; Kraut, Michael A; Zhou, Yun; Wong, Dean F; Workman, Clifford I

2017-09-01

Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer's disease. The evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions and is found in high concentrations in the serotonergic cell bodies of origin of these projections (raphe nuclei). Twenty-eight participants with mild cognitive impairment (age 66.6±6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2±7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to evaluate, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, the serotonin transporter would be lower to a greater extent and observed in a more widespread pattern than lower grey matter volumes or lower regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic

Possible role of selective serotonin reuptake inhibitor sertraline on oxidative stress responses.

Science.gov (United States)

Battal, D; Yalin, S; Eker, E D; Aktas, A; Sahin, N O; Cebo, M; Berköz, M

2014-01-01

The naphthylamine derivative sertraline is a potent and selective inhibitor of serotonin reuptake into presynaptic terminals and the most widely used that has been shown to have both antidepressant and antianxiety effects. In the present study the possible role of sertraline (acute and chronically doses) was evaluated on lipid peroxidation levels and antioxidant enzyme activities in plasma and brain tissues of (10, 40, 80 mg/kg) sertraline treated Wistar albino rats (n=48). Lipid peroxidation levels (MDA) of plasma and brain tissue increased in all acute and chronic sertraline treated rats (p Catalase (CAT) levels of plasma and brain tissue and paraoxonase (PON) levels of plasma decreased (p < 0.05) as compared with vehicle group. Based on the data, it can be concluded that high dose sertraline administration enhances oxidative stress. Therefore, dose adjustment in depression patients seems significant as it may help prevention of further prognosis of the diseases.

Serotonin binding in vitro by releasable proteins from human blood platelets

International Nuclear Information System (INIS)

Heemstra, V.L.

1983-11-01

Among the substances released from human blood platelets are serotonin and various proteins. It was hypothesized that one of these proteins binds serotonin and that serotonin might be important to the protein's function or that the protein might be important to serotonin's function. Two platelet-specific proteins, platelet factor 4 (PF4) and β-thromboglobulin (βTG) were found to bind serotonin in vitro. Endogenous PF4 was isolated by serotonin-affinity chromatography and was identified by radioimmunoassay. Purified [ 125 I] -PF4 and native PF4 bound to and eluted from a serotonin-affinity column similarly. Ultrafiltration of the homologous protein, βTG, with [ 14 C]-serotonin demonstrated binding of about 8 moles serotonin per mole tetrameric βTG with a dissociation constant of about 4 X 10(sup-8) M. Equilibrium dialysis of PF4 with radiolabelled serotonin was attempted, but no binding constant values were obtained because serotonin apparently bound to the dialysis membrane. Since EDTA was one of the two agents that eluted PF4 from the serotonin-affinity gel, calcium binding by PF4 was investigated by equilibrium dialysis. Evidence was obtained for positively cooperative binding of calcium ions by PF4. It is concluded that PF4 and βTG bind serotonin in vitro, that they may also bind in vivo when platelets undergo release, and that the functions of serotonin, PF4 and βTG may be mediated in part by serotonin-protein associations

Advances in ammonia metabolism and hepatic encephalopathy

International Nuclear Information System (INIS)

Soeters, P.B.; Wilson, J.H.P.; Meijer, A.J.; Holm, E.

1988-01-01

There are four main 'parts' within the book: the first is devoted to peripheral and hepatic ammonia metabolism, the urea cycle, acid base status and its regulation; part two addresses animal models in liver failure, GABA-ergic neurotransmission and its relevance in hepatic failure; a third part concerns neurochemistry including brain ammonia metabolism, serotonin metabolism and energy status, in vivo evaluated with modern techniques like infusion of compounds labeled with stable or radioactive isotopes and with NMR, while the last section provides a description of the determination of ammonia and the treatment of encephalopathy with established but also with experimental techniques. refs.; figs.; tabs

Pesticides Drive Stochastic Changes in the Chemoreception and Neurotransmission System of Marine Ectoparasites

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Gustavo Núñez-Acuña

2016-05-01

Full Text Available Scientific efforts to elucidate the mechanisms of chemical communication between organisms in marine environments are increasing. This study applied novel molecular technology to outline the effects of two xenobiotic drugs, deltamethrin (DM and azamethiphos (AZA, on the neurotransmission system of the copepod ectoparasite Caligus rogercresseyi. Transcriptome sequencing and bioinformatics analyses were conducted to evaluate treatment effects on the glutamatergic synaptic pathway of the parasite, which is closely related to chemoreception and neurotransmission. After drug treatment with DM or AZA, stochastic mRNA expression patterns of glutamatergic synapse pathway components were observed. Both DM and AZA promoted a down-regulation of the glutamate-ammonia ligase, and DM activated a metabotropic glutamate receptor that is a suggested inhibitor of neurotransmission. Furthermore, the delousing drugs drove complex rearrangements in the distribution of mapped reads for specific metabotropic glutamate receptor domains. This study introduces a novel methodological approach that produces high-quality results from transcriptomic data. Using this approach, DM and AZA were found to alter the expression of numerous mRNAs tightly linked to the glutamatergic signaling pathway. These data suggest possible new targets for xenobiotic drugs that play key roles in the delousing effects of antiparasitics in sea lice.

Elevated midbrain serotonin transporter availability in mixed mania: a case report

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Kuikka Jyrki

2004-09-01

Full Text Available Abstract Background Results obtained from brain imaging studies indicate that serotonin transporter (SERT and dopamine transporter (DAT densities are altered in major depression. However, no such studies have been published on current mania or hypomania. Case presentation In this single photon emission computed tomography (SPECT study with [123I]nor-β-CIT we present a case with simultaneous symptoms of major depression and hypomania. She had an elevated serotonin transporter availability (SERT in the midbrain and elevated dopamine transporter availability (DAT in the striatum, which normalised in a one-year follow-up period during which she received eight months of psychodynamic psychotherapy. Conclusions To our knowledge, this is the first report on SERT and DAT associated with mania. In our case the availability of both SERT in the midbrain and DAT in the striatum were elevated at baseline and declined during psychotherapy, while the SERT and DAT of the depressed controls increased during psychotherapy. Symptoms of hypomania in the case were alleviated during psychotherapy. Clinical recovery was also reflected in the Hamilton Depression Rating Scale (HDRS scores.

Early-life stress induces persistent alterationsin 5-HT1Areceptor and serotonin transporter mRNA expression in the adultrat brain.

Directory of Open Access Journals (Sweden)

Javier A. Bravo

2014-04-01

Full Text Available Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT1A receptor and serotonin transporter (SERT mRNA expression in brain areas involved in the control of emotions, memory and fear as well as in regions controlling the central serotonergic tone.To test this, Sprague-Dawley rats were subjected to MS for 3h daily during post-natal days 2-12. As control, age matched rats were not separated (NS from their dams. When animals reached adulthood (11-13 weeks brain was extracted and mRNA expression of 5-HT1A receptor in amygdala, hippocampus and dorsal raphé nucleus (DRN and SERT in the DRN was analyzed through in-situ hybridisation.Densitometric analysis revealed that MS increased 5-HT1A receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats.These results suggest that early-life stress induces persistent changes in 5-HT1A receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood.

Regulation of serotonin release from enterochromaffin cells of rat cecum mucosa

International Nuclear Information System (INIS)

Simon, C.; Ternaux, J.P.

1990-01-01

The release of endogenous serotonin or previously taken up tritiated serotonin from isolated strips of rat cecum mucosa containing enterochromaffin cells was studied in vitro. Release of tritiated serotonin was increased by potassium depolarization and was decreased by tetrodotoxin, veratridine and the absence of calcium. Endogenous serotonin was released at a lower rate than tritiated serotonin; endogenous serotonin release was stimulated by potassium depolarization but was unaffected by tetrodotoxin, veratridine or the absence of calcium. Carbachol, norepinephrine, clonidine and isoproterenol decreased release of tritiated serotonin but had less or reverse effect on release of endogenous serotonin. The results suggest two different serotoninergic pools within the enterochromaffin cell population

Triple Reuptake Inhibitors: The Next Generation of Antidepressants

OpenAIRE

Marks, David M; Pae, Chi-Un; Patkar, Ashwin A

2008-01-01

Depression has been associated with impaired neurotransmission of serotonergic, norepinephrinergic, and dopaminergic pathways, although most pharmacologic treatment strategies for depression enhance only serotonin and norepinephrine neurotransmission. Current drug development efforts are aimed at a new class of antidepressants which inhibit the reuptake of all three neurotransmitters in the hope of creating medications with broader efficacy and/or quicker onset of action. The current review e...

Effect of serotonin on small intestinal contractility in healthy volunteers

DEFF Research Database (Denmark)

Hansen, M.B.; Arif, F.; Gregersen, H.

2008-01-01

The physiological significance of serotonin released into the intestinal lumen for the regulation of motility is unknown in humans. The aim of this study was to evaluate the effect of serotonin infused into the lumen of the gastric antrum, duodenum or the jejunum, on antro-duodeno-jejunal contrac......The physiological significance of serotonin released into the intestinal lumen for the regulation of motility is unknown in humans. The aim of this study was to evaluate the effect of serotonin infused into the lumen of the gastric antrum, duodenum or the jejunum, on antro......-duodeno-jejunal contractility in healthy human volunteers. Manometric recordings were obtained and the effects of either a standard meal, continuous intravenous infusion of serotonin (20 nmol/kg/min) or intraluminal bolus infusions of graded doses of serotonin (2.5, 25 or 250 nmol) were compared. In addition, platelet......-depleted plasma levels of serotonin, blood pressure, heart rate and electrocardiogram were evaluated. All subjects showed similar results. Intravenous serotonin increased migrating motor complex phase In frequency 3-fold and migrating velocity 2-fold. Intraluminal infusion of serotonin did not change contractile...

Developmental changes in GABAergic neurotransmission to presympathetic and cardiac parasympathetic neurons in the brainstem.

Science.gov (United States)

Dergacheva, Olga; Boychuk, Carie R; Mendelowitz, David

2013-08-01

Cardiovascular function is regulated by a dynamic balance composed of sympathetic and parasympathetic activity. Sympathoexcitatory presympathetic neurons (PSNs) in the rostral ventrolateral medulla project directly to cardiac and vasomotor sympathetic preganglionic neurons in the spinal cord. In proximity to the PSNs in the medulla, there are preganglionic cardiac vagal neurons (CVNs) within the nucleus ambiguus, which are critical for parasympathetic control of heart rate. Both CVNs and PSNs receive GABAergic synaptic inputs that change with challenges such as hypoxia and hypercapnia (H/H). Autonomic control of cardiovascular function undergoes significant changes during early postnatal development; however, little is known regarding postnatal maturation of GABAergic neurotransmission to these neurons. In this study, we compared changes in GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs and PSNs under control conditions and during H/H in postnatal day 2-5 (P5), 16-20 (P20), and 27-30 (P30) rats using an in vitro brainstem slice preparation. There was a significant enhancement in GABAergic neurotransmission to both CVNs and PSNs at age P20 compared with P5 and P30, with a more pronounced increase in PSNs. H/H did not significantly alter this enhanced GABAergic neurotransmission to PSNs in P20 animals. However, the frequency of GABAergic IPSCs in PSNs was reduced by H/H in P5 and P30 animals. In CVNs, H/H elicited an inhibition of GABAergic neurotransmission in all ages studied, with the most pronounced inhibition occurring at P20. In conclusion, there are critical development periods at which significant rearrangement occurs in the central regulation of cardiovascular function.

Positron emission tomography - a new approach to brain chemistry

International Nuclear Information System (INIS)

Jacobson, H.G.

1988-01-01

Positron emission tomography permits examination of the chemistry of the brain in living beings. Until recently, positron emission tomography had been considered a research tool, but it is rapidly moving into clinical practice. This report describes the uses and applications of positron emission tomography in examinations of patients with strokes, epilepsy, malignancies, dementias, and schizophrenia and in basic studies of synaptic neurotransmission

Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression.

Directory of Open Access Journals (Sweden)

Dongsha Wang

Full Text Available The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET measures of brain serotonin (5-HT synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC. Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25 who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20 where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"): preliminary findings

NARCIS (Netherlands)

Reneman, L.; Lavalaye, J.; Schmand, B.; de Wolff, F. A.; van den Brink, W.; den Heeten, G. J.; Booij, J.

2001-01-01

BACKGROUND: Although the popular drug 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") has been shown to damage brain serotonin (5-HT) neurons in animals, the fate and functional consequences of 5-HT neurons after MDMA injury are not known in humans. We investigated the long-term effects of

Protective effect of serotonin on phospholipids and lipid peroxides contents in brain and liver of gamma irradiated rats

International Nuclear Information System (INIS)

Mohamed, M.A.; Saada, H.A.

1999-01-01

Treatment of normal rats with serotonin (2 mg/100 g body weight) produced no significant change in levels of phospholipids and lipid peroxides of the cerebral hemispheres and liver 1,3 and days after treatment. The content of lipid peroxides was measured as malondialdehyde (MDA). Whole body gamma-irradiation of rats at 8 Gy resulted in significant decrease in the level of phospholipids and significant increase in MDA level in cerebral hemispheres and lever. Changes were more pronounced in liver. Treatment with serotonin, 15 minutes before irradiation, had a pronounced protective effect against the radiation induced changes in the levels of phospholipids and MDA only in the liver through all the experimental period

Decreased uptake of 3H-serotonin and endogenous content of serotonin in blood platelets in hypertensive patients

International Nuclear Information System (INIS)

Kamal, L.A.; Le Quan-Bui, K.H.; Meyer, P.

1984-01-01

The uptake and content of serotonin in blood platelets were studied in patients with essential hypertension and in five families in which at least one member was hypertensive. Blood was obtained from male and female normotensive volunteers and hypertensive patients who were free of medication. Lineweaver-Burk plots of 3H-serotonin uptake from both control subjects and hypertensive patients were linear, which suggested simple Michaelis-Menten uptake kinetics. The maximal uptake velocity (Vmax) in hypertensive patients was significantly lower than in control subjects (control . 41.7 +/- 3.3 pmol/min/10(8) platelets, n . 17; hypertensive . 26.6 +/- 3.0 pmol/min/10(8) platelets, n . 16; p less than 0.005). The affinity constant (Km) was slightly but significantly lower in hypertensive patients (control . 0.70 +/- 0.08 microM; hypertensive . 0.46 +/- 0.08 microM; p less than 0.05). The serotonin content in blood platelets determined by high pressure liquid chromatography with electrochemical detection was significantly lower in hypertensive patients (control . 165.0 +/- 12.9 nmol/10(11) platelets, n . 29; hypertensive . 105.9 +/- 10.4 nmol/10(11) platelets, n . 27; p less than 0.001). In the five families investigated, the lowered serotonin content was observed in some normotensive members. The reduced number of carriers of serotonin uptake and the slight decrease in the affinity constant observed in platelets of patients with essential hypertension suggest that serotonin metabolism is altered in essential hypertension and that blood platelets may be a useful model in studying the serotonergic modifications at the molecular level

INFLUENCE OF A SEROTONIN-RICH AND DOPAMINE-RICH DIET ON PLATELET SEROTONIN CONTENT AND URINARY-EXCRETION OF BIOGENIC-AMINES AND THEIR METABOLITES

NARCIS (Netherlands)

KEMA, IP; SCHELLINGS, AMJ; MEIBORG, G; HOPPENBROUWERS, CJM; MUSKIET, FAJ

Using high-performance liquid chromatography and gas chromatography, we reevaluated the 24-h influence of a serotonin- and dopamine-rich diet on platelet serotonin and serotonin, 5-hydroxyindoleacetic acid (5-HIAA), and major catecholamine metabolites in the urine of 15 healthy adults. Although

[Metabolism of serotonin in autism in children].

Science.gov (United States)

Bursztejn, C; Ferrari, P; Dreux, C; Braconnier, A; Lancrenon, S

1988-01-01

In this controlled study of 22 autistic children and 22 normal controls matched for age and sex, the frequency of hyperserotonemia in infantile autism was confirmed. Platelet serotonin was elevated in patients. Comparative to controls, serotonin was also high in urine of autistic patients, while, on the contrary there was no difference for the urinary excretion of 5-HIAA. No difference was observed either for serotonin uptake and efflux or for MAO activity, in isolated platelets. The elevation of plasma free tryptophan - significant only with the Kolmogorov Smirnov test - suggests that 5-HT biosynthesis might be enhanced. In the group of patient reported in this study, disorders of serotonin metabolism are associated with disturbances of platelet catecholamines, and also with elevated immunoglobulins and enhanced cellular immunity reactions.

Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors.

Science.gov (United States)

Degnan, Andrew P; Tora, George O; Han, Ying; Rajamani, Ramkumar; Bertekap, Robert; Krause, Rudolph; Davis, Carl D; Hu, Joanna; Morgan, Daniel; Taylor, Sarah J; Krause, Kelly; Li, Yu-Wen; Mattson, Gail; Cunningham, Melissa A; Taber, Matthew T; Lodge, Nicholas J; Bronson, Joanne J; Gillman, Kevin W; Macor, John E

2015-08-01

Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Brain, nutrition and metabolism : Studies in lean, obese and insulin resistant humans

NARCIS (Netherlands)

Versteeg, R.I.

2017-01-01

This thesis describes studies on the effects of obesity, weight loss and meal timing on the human brain and glucose metabolism. We investigated effects of meal timing during a hypocaloric diet and weight loss on brain serotonin transporters (SERT) and dopamine transporters (DAT), neuronal activity

Automated mass spectrometric analysis of urinary and plasma serotonin

NARCIS (Netherlands)

de Jong, Wilhelmina H. A.; Wilkens, Marianne H. L. I.; de Vries, Elisabeth G. E.; Kema, Ido P.

Serotonin emerges as crucial neurotransmitter and hormone in a growing number of different physiologic processes. Besides extensive serotonin production previously noted in patients with metastatic carcinoid tumors, serotonin now is implicated in liver cell regeneration and bone formation. The aim

Pharmacokinetics and brain distribution in non human primate of R(-)[123I]DOI, A 5HT2A/2C serotonin agonist

International Nuclear Information System (INIS)

Zea-Ponce, Yolanda; Kegeles, Lawrence S.; Guo, Ningning; Raskin, Leonid; Bakthavachalam, Venkatesalu; Laruelle, Marc

2002-01-01

Our goal was to synthesize with high specific activity R(-)-1-(2,5-Dimethoxy-4-[ 123 I]iodophenyl)-2-aminopropane [R(-)[ 123 I]DOI], an in vitro potent and selective 5-HT 2A/2C serotonin agonist, and study in vivo its plasma pharmacokinetics and brain distribution in baboon by SPECT. The purpose was to evaluate this radiotracer as a potential tool in discerning the role of the agonist high affinity state of 5-HT 2 receptors in depression and other neurological disorders. The radiotracer was prepared by electrophilic radioiodination of the N-trifluoroacetyl precursor of R(-)-1-(2,5-Dimethoxyphenyl)-2-aminopropane [R(-)DMA-TFA] with high-purity sodium [ 123 I]iodide in the presence of chloramine-T, followed by amino deprotection with KOH in isopropanol (labeling yield: 73%, radiochemical yield: 62%, radiochemical purity: 99%). In vivo studies in baboon showed high accumulation of radioactivity in thalamus, the frontoparietal cortex, temporal, occipital and the striatum regions, with slightly lower accumulation in the midbrain and cerebellum. Ketanserin did not displaced the radioactivity in any of these brain regions. Plasma metabolite analysis was performed using methanol protein precipitation, the methanol fractions contained from 68% to 92% of the mixture of a labeled metabolite and parent compound. The recovery coefficient of unmetabolized R(-)[ 123 I]DOI was 68%. The percent parent compound present in the extracted fraction, measured by HPLC, decreased gradually with time from 99.8% to 0.3% still present after 4.7 hours post injection whereas the percentage of the only one detected metabolite increased conversely. Free fraction determination (f 1 ), was 31±0.9% (n=3). For comparison purposes, ex-vivo brain distribution, displacement and metabolite analysis was also carried out in rodents. Although R(-)[ 123 I]DOI displayed good brain uptake and localized in serotonergic areas of the brain, its target to non target ratio and its insensitivity to ketanserin

Feeding motivation as a personality trait in Nile tilapia (Oreochromis niloticus): role of serotonergic neurotransmission

DEFF Research Database (Denmark)

Silva, P.I.M.; Martins, C.I.M.; Höglund, Erik

2014-01-01

Consistent individual variation in behaviour and physiology (i.e. animal personality or coping style) has emerged as a central topic in many biological disciplines. Yet, underlying mechanisms of crucial personality traits like feeding behaviour in novel environments remain unclear. Comparative...... to determine to what degree brain 5-hydroxytryptamine (5-HT, serotonin) activity pertains to this aspect of animal personality, as a correlate to feed anticipatory behaviour and recovery of feed intake after transfer to a novel environment. Crucial to the definition of animal personality, a strong degree...... of individual consistency in different measures of feeding behaviour (feeding latency and feeding score), was demonstrated. Furthermore, low serotonergic activity in the hypothalamus was highly correlated with a personality characterized by high feeding motivation, with feeding motivation represented...

Reversibility of ecstasy-induced reduction in serotonin transporter availability in polydrug ecstasy users

International Nuclear Information System (INIS)

Buchert, Ralph; Wilke, Florian; Nebeling, Bruno; Clausen, Malte; Thomasius, Rainer; Petersen, Kay; Obrocki, Jost; Wartberg, Lutz; Zapletalova, Pavlina

2006-01-01

Animal data suggest that the synthetic drug ecstasy may damage brain serotonin neurons. Previously we reported protracted reductions in the availability of the serotonin transporter (SERT), an index of integrity of the axon terminals of brain serotonergic neurons, in SERT-rich brain regions in current human ecstasy users. Comparison of current ecstasy users and former ecstasy users yielded some evidence that this reduction might be reversible. However, participant selection effects could not be ruled out. Therefore, follow-up examinations were performed in these subjects to test the following a priori hypothesis in a prospective longitudinal design that eliminates participant selection effects to a large extent: availability of the SERT increases towards normal levels when ecstasy use is stopped, and remains unchanged or is further decreased if use is continued. Two follow-up positron emission tomography measurements using the SERT ligand [ 11 C](+)McN5652 were completed by 15 current and nine former ecstasy users. All subjects used illicit drugs other than ecstasy, too. The time interval between repeated measurements was about 1 year. The time course of the availability of the SERT was analysed in the following SERT-rich regions: mesencephalon, putamen, caudate and thalamus. Current ecstasy users showed a consistent increase in the availability of the SERT in the mesencephalon during the study (Friedman test: p=0.010), which most likely was caused by a decrease in the intensity of ecstasy consumption (Spearman correlation coefficient -0.725, p=0.002). Former ecstasy users showed a consistent increase in SERT availability in the thalamus (Friedman test: p=0.006). Ecstasy-induced protracted alterations in the availability of the SERT might be reversible. (orig.)

Reversibility of ecstasy-induced reduction in serotonin transporter availability in polydrug ecstasy users

Energy Technology Data Exchange (ETDEWEB)

Buchert, Ralph; Wilke, Florian; Nebeling, Bruno; Clausen, Malte [University Medical Center Hamburg-Eppendorf, Department of Nuclear Medicine, Hamburg (Germany); Thomasius, Rainer; Petersen, Kay; Obrocki, Jost; Wartberg, Lutz; Zapletalova, Pavlina [University Medical Center Hamburg-Eppendorf, Departments of Psychiatry and Psychotherapy, Hamburg (Germany)

2006-02-01

Animal data suggest that the synthetic drug ecstasy may damage brain serotonin neurons. Previously we reported protracted reductions in the availability of the serotonin transporter (SERT), an index of integrity of the axon terminals of brain serotonergic neurons, in SERT-rich brain regions in current human ecstasy users. Comparison of current ecstasy users and former ecstasy users yielded some evidence that this reduction might be reversible. However, participant selection effects could not be ruled out. Therefore, follow-up examinations were performed in these subjects to test the following a priori hypothesis in a prospective longitudinal design that eliminates participant selection effects to a large extent: availability of the SERT increases towards normal levels when ecstasy use is stopped, and remains unchanged or is further decreased if use is continued. Two follow-up positron emission tomography measurements using the SERT ligand [{sup 11}C](+)McN5652 were completed by 15 current and nine former ecstasy users. All subjects used illicit drugs other than ecstasy, too. The time interval between repeated measurements was about 1 year. The time course of the availability of the SERT was analysed in the following SERT-rich regions: mesencephalon, putamen, caudate and thalamus. Current ecstasy users showed a consistent increase in the availability of the SERT in the mesencephalon during the study (Friedman test: p=0.010), which most likely was caused by a decrease in the intensity of ecstasy consumption (Spearman correlation coefficient -0.725, p=0.002). Former ecstasy users showed a consistent increase in SERT availability in the thalamus (Friedman test: p=0.006). Ecstasy-induced protracted alterations in the availability of the SERT might be reversible. (orig.)

Non-conventional features of peripheral serotonin signalling - the gut and beyond.

Science.gov (United States)

Spohn, Stephanie N; Mawe, Gary M

2017-07-01

Serotonin was first discovered in the gut, and its conventional actions as an intercellular signalling molecule in the intrinsic and extrinsic enteric reflexes are well recognized, as are a number of serotonin signalling pharmacotherapeutic targets for treatment of nausea, diarrhoea or constipation. The latest discoveries have greatly broadened our understanding of non-conventional actions of peripheral serotonin within the gastrointestinal tract and in a number of other tissues. For example, it is now clear that bacteria within the lumen of the bowel influence serotonin synthesis and release by enterochromaffin cells. Also, serotonin can act both as a pro-inflammatory and anti-inflammatory signalling molecule in the intestinal mucosa via activation of serotonin receptors (5-HT 7 or 5-HT 4 receptors, respectively). For decades, serotonin receptors have been known to exist in a variety of tissues other than the gut, but studies have now provided strong evidence for physiological roles of serotonin in several important processes, including haematopoiesis, metabolic homeostasis and bone metabolism. Furthermore, evidence for serotonin synthesis in peripheral tissues outside of the gut is emerging. In this Review, we expand the discussion beyond gastrointestinal functions to highlight the roles of peripheral serotonin in colitis, haematopoiesis, energy and bone metabolism, and how serotonin is influenced by the gut microbiota.

No evidence for a role of the serotonin 4 receptor in five-factor personality traits

DEFF Research Database (Denmark)

Stenbæk, Dea Siggaard; Dam, Vibeke Høyrup; Fisher, Patrick Mac Donald

2017-01-01

Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo...... in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated...... using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits...

Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

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Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei

2015-07-01

Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

Increased hypothalamic serotonin turnover in inflammation-induced anorexia.

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Dwarkasing, J T; Witkamp, R F; Boekschoten, M V; Ter Laak, M C; Heins, M S; van Norren, K

2016-05-20

Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6. In vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice. Overall, our results underline that peripheral inflammation reaches the hypothalamus where it affects hypothalamic serotoninergic metabolism. These hypothalamic changes in serotonin pathways are associated with decreased food intake, providing evidence for a role of serotonin in inflammation-induced anorexia.

Serotonin induces peripheral antinociception via the opioidergic system.

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Diniz, Danielle Aguiar; Petrocchi, Júlia Alvarenga; Navarro, Larissa Caldeira; Souza, Tâmara Cristina; Castor, Marina Gomes Miranda E; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima

2018-01-01

Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE 2 (2 μg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model. The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 μg), naltrindole (60 μg) and nor-binaltorfimina (200 μg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 μg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng). These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Molecular fingerprint of neuropeptide S-producing neurons in the mouse brain

DEFF Research Database (Denmark)

Liu, Xiaobin; Zeng, Joanne; Zhou, Anni

2011-01-01

Neuropeptide S (NPS) has been associated with a number of complex brain functions, including anxiety-like behaviors, arousal, sleep-wakefulness regulation, drug-seeking behaviors, and learning and memory. In order to better understand how NPS influences these functions in a neuronal network context...... of incoming neurotransmission, controlling neuronal activity of NPS-producing neurons. Stress-induced functional activation of NPS-producing neurons was detected by staining for the immediate-early gene c-fos, thus supporting earlier findings that NPS might be part of the brain stress response network....

In vivo imaging of cerebral serotonin transporter and serotonin(2A) receptor binding in 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and hallucinogen users

DEFF Research Database (Denmark)

Erritzoe, David; Frøkjær, Vibe; Holst, Klaus K

2011-01-01

Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin.......Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin....

Influence of acute treatment with sibutramine on the sympathetic neurotransmission of the young rat vas deferens.

Science.gov (United States)

de Souza, Bruno Palmieri; da Silva, Edilson Dantas; Jurkiewicz, Aron; Jurkiewicz, Neide Hyppolito

2014-09-05

The effects of acute treatment with sibutramine on the peripheral sympathetic neurotransmission in vas deferens of young rats were still not evaluated. Therefore, we carried out this study in order to verify the effects of acute sibutramine treatment on the neuronal- and exogenous agonist-induced contractions of the young rat vas deferens. Young 45-day-old male Wistar rats were pretreated with sibutramine 6 mg/kg and after 4h the vas deferens was used for experiment. The acute treatment with sibutramine was able to increase the potency (pD2) of noradrenaline and phenylephrine. Moreover, the efficacy (Emax) of noradrenaline was increased while the efficacy of serotonin and nicotine were decreased. The maximum effect induced by a single concentration of tyramine was diminished in the vas deferens from treated group. Moreover, the leftward shift of the noradrenaline curves promoted by uptake blockers (cocaine and corticosterone) and β-adrenoceptor antagonist (propranolol) was reduced in the vas deferens of treated group. The initial phasic and secondary tonic components of the neuronal-evoked contractions of vas deferens from treated group at the frequencies of 2 Hz were decreased. Moreover, only the initial phasic component at 5 Hz was diminished by the acute treatment with sibutramine. In conclusion, we showed that the acute treatment with sibutramine in young rats was able to affect the peripheral sympathetic nervous system by inhibition of noradrenaline uptake and reduction of the neuronal content of this neurotransmitter, leading to an enhancement of vas deferens sensitivity to noradrenaline. Copyright © 2014 Elsevier B.V. All rights reserved.

Serotonin synthesis, release and reuptake in terminals: a mathematical model

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Best Janet

2010-08-01

Full Text Available Abstract Background Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. Methods We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. Results We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to

Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans.

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Worbe, Yulia; Savulich, George; de Wit, Sanne; Fernandez-Egea, Emilio; Robbins, Trevor W

2015-02-05

Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood. We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results. Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control. The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Depression, osteoporosis, serotonin and cell membrane viscosity between biology and philosophical anthropology

Directory of Open Access Journals (Sweden)

Gabrielli Fabio

2011-03-01

Full Text Available Abstract Due to the relationship between biology and culture, we believe that depression, understood as a cultural and existential phenomenon, has clear markers in molecular biology. We begin from an existential analysis of depression constituting the human condition and then shift to analysis of biological data confirming, according to our judgment, its original (ontological structure. In this way philosophy is involved at the anthropological level, in as much as it detects the underlying meanings of depression in the original biological-cultural horizon of human life. Considering the integration of knowledge it is the task of molecular biology to identify the aforementioned markers, to which the existential aspects of depression are linked to. In particular, recent works show the existence of a link between serotonin and osteoporosis as a result of a modified expression of the low-density lipoprotein receptor-related protein 5 gene. Moreover, it is believed that the hereditary or acquired involvement of tryptophan hydroxylase 2 (Tph2 or 5-hydroxytryptamine transporter (5-HTT is responsible for the reduced concentration of serotonin in the central nervous system, causing depression and affective disorders. This work studies the depression-osteoporosis relationship, with the aim of focusing on depressive disorders that concern the quantitative dynamic of platelet membrane viscosity and interactome cytoskeleton modifications (in particular Tubulin and Gsα protein as a possible condition of the involvement of the serotonin axis (gut, brain and platelet, not only in depression but also in connection with osteoporosis.

Brain Serotonin Transporter Occupancy by Oral Sibutramine Dosed to Steady State: A PET Study Using 11C-DASB in Healthy Humans

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Talbot, Peter S; Bradley, Stefan; Clarke, Cyril P; Babalola, Kola O; Philipp, Andrew W; Brown, Gavin; McMahon, Adam W; Matthews, Julian C

2010-01-01

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. 11C-DASB PET scans were performed on the HRRT camera. Binding potentials (BPND) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30±10%), was similar across brain regions, but varied widely across subjects (15–46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET. PMID:19890256

Modulation of Midbrain Dopamine Neurotransmission by Serotonin, a Versatile Interaction Between Neurotransmitters and Significance for Antipsychotic Drug Action

NARCIS (Netherlands)

Olijslagers, J.E.; Werkman, T.R.; McCreary, A.C.; Kruse, C.G.; Wadman, W.J.

2006-01-01

Schizophrenia has been associated with a dysfunction of brain dopamine (DA). This, so called, DA hypothesis has been refined as new insights into the pathophysiology of schizophrenia have emerged. Currently, dysfunction of prefrontocortical glutamatergic and GABAergic projections and dysfunction of

Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus.

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Chen, Z L; Huang, R Q

2014-06-20

Changes in extracellular pH have a modulatory effect on GABAA receptor function. It has been reported that pH sensitivity of the GABA receptor is dependent on subunit composition and GABA concentration. Most of previous investigations focused on GABA-evoked currents, which only reflect the postsynaptic receptors. The physiological relevance of pH modulation of GABAergic neurotransmission is not fully elucidated. In the present studies, we examined the influence of extracellular pH on the GABAA receptor-mediated inhibitory neurotransmission in rat hypothalamic neurons. The inhibitory postsynaptic currents (IPSCs), tonic currents, and the GABA-evoked currents were recorded with whole-cell patch techniques on the hypothalamic slices from Sprague-Dawley rats at 15-26 postnatal days. The amplitude and frequency of spontaneous GABA IPSCs were significantly increased while the external pH was changed from 7.3 to 8.4. In the acidic pH (6.4), the spontaneous GABA IPSCs were reduced in amplitude and frequency. The pH induced changes in miniature GABA IPSCs (mIPSCs) similar to that in spontaneous IPSCs. The pH effect on the postsynaptic GABA receptors was assessed with exogenously applied varying concentrations of GABA. The tonic currents and the currents evoked by sub-saturating concentration of GABA ([GABA]) (10 μM) were inhibited by acidic pH and potentiated by alkaline pH. In contrast, the currents evoked by saturating [GABA] (1mM) were not affected by pH changes. We also investigated the influence of pH buffers and buffering capacity on pH sensitivity of GABAA receptors on human recombinant α1β2γ2 GABAA receptors stably expressed in HEK 293 cells. The pH influence on GABAA receptors was similar in HEPES- and MES-buffered media, and not dependent on protonated buffers, suggesting that the observed pH effect on GABA response is a specific consequence of changes in extracellular protons. Our data suggest that the hydrogen ions suppress the GABAergic neurotransmission

In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin(2A) Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and Hallucinogen Users

DEFF Research Database (Denmark)

Erritzoe, David; Frokjaer, Vibe G.; Holst, Klaus K.

2011-01-01

Context: Both hallucinogens and 3,4-methylenedioxy-methamphetamine( MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin.Objective: ......Context: Both hallucinogens and 3,4-methylenedioxy-methamphetamine( MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin...

The serotonin transporter in psychiatric disorders

DEFF Research Database (Denmark)

Spies, Marie; Knudsen, Karen Birgitte Moos; Lanzenberger, Rupert

2015-01-01

Over the past 20 years, psychotropics affecting the serotonergic system have been used extensively in the treatment of psychiatric disorders. Molecular imaging, in particular PET, has allowed for elucidation of the essential contribution of the serotonin transporter to the pathophysiology...... of various psychiatric disorders and their treatment. We review studies that use PET to measure cerebral serotonin transporter activity in psychiatric disorders, focusing on major depressive disorder and antidepressant treatment. We also discuss opportunities and limitations in the application...... of this neuroimaging method in clinical practice. Although results from individual studies diverge, meta-analysis indicates a trend towards reduced serotonin transporter availability in patients with major depressive disorder. Inconsistencies in results might suggest symptom heterogeneity in major depressive disorder...

Chronic intermittent hypoxia-hypercapnia blunts heart rate responses and alters neurotransmission to cardiac vagal neurons.

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Dyavanapalli, Jhansi; Jameson, Heather; Dergacheva, Olga; Jain, Vivek; Alhusayyen, Mona; Mendelowitz, David

2014-07-01

Patients with obstructive sleep apnoea experience chronic intermittent hypoxia-hypercapnia (CIHH) during sleep that elicit sympathetic overactivity and diminished parasympathetic activity to the heart, leading to hypertension and depressed baroreflex sensitivity. The parasympathetic control of heart rate arises from pre-motor cardiac vagal neurons (CVNs) located in nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX). The mechanisms underlying diminished vagal control of heart rate were investigated by studying the changes in blood pressure, heart rate, and neurotransmission to CVNs evoked by acute hypoxia-hypercapnia (H-H) and CIHH. In vivo telemetry recordings of blood pressure and heart rate were obtained in adult rats during 4 weeks of CIHH exposure. Retrogradely labelled CVNs were identified in an in vitro brainstem slice preparation obtained from adult rats exposed either to air or CIHH for 4 weeks. Postsynaptic inhibitory or excitatory currents were recorded using whole cell voltage clamp techniques. Rats exposed to CIHH had increases in blood pressure, leading to hypertension, and blunted heart rate responses to acute H-H. CIHH induced an increase in GABAergic and glycinergic neurotransmission to CVNs in NA and DMNX, respectively; and a reduction in glutamatergic neurotransmission to CVNs in both nuclei. CIHH blunted the bradycardia evoked by acute H-H and abolished the acute H-H evoked inhibition of GABAergic transmission while enhancing glycinergic neurotransmission to CVNs in NA. These changes with CIHH inhibit CVNs and vagal outflow to the heart, both in acute and chronic exposures to H-H, resulting in diminished levels of cardioprotective parasympathetic activity to the heart as seen in OSA patients. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Oméga 3 et neurotransmission cérébrale

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Vancassel Sylvie

2004-01-01

Full Text Available Les acides gras polyinsaturés (AGPI sont des constituants structuraux fondamentaux du système nerveux central (SNC dont la teneur conditionne le fonctionnement des cellules neuronales. Ils sont des acteurs de la communication intercellulaire, notamment à travers les processus de neurotransmission. De nombreuses études ont montré chez l’animal que le déficit des membranes cérébrales en oméga 3, et plus particulièrement en acide docosahexaénoïque (22 : 6ω-3 ou DHA induit par une carence alimentaire spécifique en cette famille d’AGPI, s’accompagne de troubles de l’apprentissage. Un support neurochimique a été avancé, impliquant les processus de libération de neurotransmetteurs, notamment les monoamines et l’acétylcholine. Cette relation entre AGPI ω3 et neurotransmission est d’autant plus intéressante qu’elle pourrait être également impliquée chez l’Homme dans l’apparition et\\\\ou la sévérité de certains troubles neuropsychiatriques dans lesquels des dysfonctionnements de la neurotransmission sont constatés (schizophrénie, dépression, hyperactivité chez l’enfant. En effet, de nombreuses études révèlent un déficit du statut corporel en AGPI oméga 3 (20 : 5 et 22 : 6 mais aussi en oméga 6, qui peut être corrigé par voie nutritionnelle, permettant alors de réduire significativement certains des symptômes pathologiques. Dans ce contexte, nous développons au laboratoire des recherches visant à comprendre les mécanismes d’action des oméga 3, et en particulier du DHA, dans les membranes nerveuses et l’incidence sur le fonctionnement de ces cellules.

Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system

International Nuclear Information System (INIS)

Passchier, J.; Waarde, A. van

2001-01-01

The 5-HT 1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT 1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl- 11 C] WAY-100635 (WAY), [carbonyl- 11 C]desmethyl-WAY-100635 (DWAY), p-[ 18 F]MPPF and [ 11 C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT 1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET. (orig.)

Serotonin storage pools in basophil leukemia and mast cells: characterization of two types of serotonin binding protein and radioautographic analysis of the intracellular distribution of [3H]serotonin

International Nuclear Information System (INIS)

Tamir, H.; Theoharides, T.C.; Gershon, M.D.; Askenase, P.W.

1982-01-01

The binding of serotonin to protein(s) derived from rat basophil leukemia (RBL) cells and mast cells was studied. Two types of serotonin binding protein in RBL cells was found. These proteins differed from one another in molecular weight and eluted in separate peaks from sephadex G-200 columns. Peak I protein (KD = 1.9 x 10 -6 M) was a glycoprotein that bound to concanavalin A (Con A); Peak II protein (KD 1 = 4.5 x 10 - 8 M; KD 2 = 3.9 x 10 -6 M) did not bind to Con A. Moreover, binding of [ 3 H]serotonin to protein of Peak I was sensitive to inhibition by reserpine, while binding of [ 3 H]serotonin to protein of Peak II resisted inhibition by that drug. Other differences between the two types of binding protein were found, the most significant of which was the far more vigorous conditions of homogenization required to extract Peak I than Peak II protein. Electron microscope radioautographic analysis of the intracellular distribution of [ 3 H] serotonin taken up in vitro by RBL cells or in vivo by murine mast cells indicated that essentially all of the labeled amine was located in cytoplasmic granules.No evidence for a pool in the cytosol was found and all granules were capable of becoming labeled. The presence of two types of intracellular serotonin binding proteins in these cells may indicate that there are two intracellular storage compartments for the amine. Both may be intragranular, but Peak I protein may be associated with the granular membrane while Peak II protein may be more free within the granular core. Different storage proteins may help to explain the differential release of amines from mast cell granules

The influence of a subanaesthetic dose of ketamine on circulating pro-inflammatory cytokines and serotonin in brain reply

Czech Academy of Sciences Publication Activity Database

Horáček, J.; Tejkalová, H.; Novák, T.; Bubeníková-Valešová, V.; Páleníček, T.; Rambousek, L.; Růžičková, Šárka; Vaculín, Š.; Hoeschl, C.

2011-01-01

Roč. 41, č. 8 (2011), s. 1787-1789 ISSN 0033-2917 Institutional research plan: CEZ:AV0Z50520701 Keywords : serotonin * proinflammatory * cytokines Subject RIV: AN - Psychology Impact factor: 6.159, year: 2011

Infrared Thermography in Serotonin-Induced Itch Model in Rats

DEFF Research Database (Denmark)

Jasemian, Yousef; Gazerani, Parisa; Dagnæs-Hansen, Frederik

2012-01-01

The study validated the application of infrared thermography in a serotonin-induced itch model in rats since the only available method in animal models of itch is the count of scratching bouts. Twenty four adult Sprague-Dawley male rats were used in 3 experiments: 1) local vasomotor response...... with no scratching reflex was investigated. Serotonin elicited significant scratching and lowered the local temperature at the site of injection. A negative dose-temperature relationship of serotonin was found by thermography. Vasoregulation at the site of serotonin injection took place in the absence of scratching...

Opposing functions of two sub-domains of the SNARE-complex in neurotransmission

DEFF Research Database (Denmark)

Weber, Jens P; Reim, Kerstin; Sørensen, Jakob B

2010-01-01

The SNARE-complex consisting of synaptobrevin-2/VAMP-2, SNAP-25 and syntaxin-1 is essential for evoked neurotransmission and also involved in spontaneous release. Here, we used cultured autaptic hippocampal neurons from Snap-25 null mice rescued with mutants challenging the C-terminal, N-terminal...

Endogenous cholinergic neurotransmission contributes to behavioral sensitization to morphine.

Directory of Open Access Journals (Sweden)

Dusica Bajic

Full Text Available Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg, a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg.

Neurochemical Effects of Chronic Administration of Calcitriol in Rats

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Pei Jiang

2014-12-01

Full Text Available Despite accumulating data showing the various neurological actions of vitamin D (VD, its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25-dihydroxyvitamin D administration (50 ng/kg/day or 100 ng/kg/day. Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated γ-aminobutyric acid (GABA status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH and tryptophan hydroxylase 2 (TPH2 expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAOA expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function.

Effects on selective serotonin antagonism on central neurotransmission

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Aggression and cannibalism in laying hens can differ in intensity and degree due to many factors, including genetics. Behavioral analysis of DeKalb XL (DXL) and high group productivity and survivability (HGPS) strains revealed high and low aggressiveness, respectively. However, the exact genetic me...

Effects of selective serotonin antagonism on central neurotransmission

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Serotonergic and dopaminergic mediation of aggression has been evidenced in numerous studies. However, these studies have met with varying and sometimes conflicting results. Here we test the hypothesis that hens with genetic propensity for high and low aggressiveness exhibit distinctly different agg...

D-Serine and Glycine Differentially Control Neurotransmission during Visual Cortex Critical Period.

Directory of Open Access Journals (Sweden)

Claire N J Meunier

Full Text Available N-methyl-D-aspartate receptors (NMDARs play a central role in synaptic plasticity. Their activation requires the binding of both glutamate and d-serine or glycine as co-agonist. The prevalence of either co-agonist on NMDA-receptor function differs between brain regions and remains undetermined in the visual cortex (VC at the critical period of postnatal development. Here, we therefore investigated the regulatory role that d-serine and/or glycine may exert on NMDARs function and on synaptic plasticity in the rat VC layer 5 pyramidal neurons of young rats. Using selective enzymatic depletion of d-serine or glycine, we demonstrate that d-serine and not glycine is the endogenous co-agonist of synaptic NMDARs required for the induction and expression of Long Term Potentiation (LTP at both excitatory and inhibitory synapses. Glycine on the other hand is not involved in synaptic efficacy per se but regulates excitatory and inhibitory neurotransmission by activating strychnine-sensitive glycine receptors, then producing a shunting inhibition that controls neuronal gain and results in a depression of synaptic inputs at the somatic level after dendritic integration. In conclusion, we describe for the first time that in the VC both D-serine and glycine differentially regulate somatic depolarization through the activation of distinct synaptic and extrasynaptic receptors.

Behavioral and neurochemical responses to 8-OH-DPAT in restrained and unrestrained animals treated with lithium carbonate in drinking water

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