Effects of serotonin transporter inhibition on gastrointestinal motility and colonic sensitivity in the mouse

Coates, Matthew; Johnson, Anthony C.; Meerveld, Beverley Greenwood‐Van; Mawe, Gary M.

doi:10.1111/j.1365-2982.2006.00792.x

Cited by 87 publications

(67 citation statements)

References 45 publications

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“…Also, transgenic mice lacking SERT frequently exhibit diarrhea associated with watery stools interspersed with periods of constipation (5). Additionally, SERT inhibitors decrease guinea pig colonic motility (21,36) as well as mouse intestinal transit time and fecal output (6).…”

mentioning

confidence: 99%

IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells

Foley¹,

Pantano²,

Ciolino³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Foley KF, Pantano C, Ciolino A, Mawe GM. IFN-␥ and TNF-␣ decrease serotonin transporter function and expression in Caco2 cells. Am J Physiol Gastrointest Liver Physiol 292: G779 -G784, 2007. First published December 14, 2006; doi:10.1152/ajpgi.00470.2006.-Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [3 H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE2 (10 M), IFN-␥ (500 ng/ml), TNF-␣ (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 M).[ 3 H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [ 3 H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-␣ and IFN-␥ elicited significant decreases in SERT function. Neither TNF-␣ nor IFN-␥ were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-␣ and IFN-␥ could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.SERT; tumor necrosis factor; interferon; colitis; inflammatory bowel disease; inflammation SEROTONIN (5-hydroxytryptamine; 5-HT) is the main monoamine signaling molecule in the gut, where it acts as a paracrine neurotransmitter (9, 25). Specialized enteroendocrine cells, enterochromaffin cells, release 5-HT into the lamina propria of the intestines, where it activates receptors located on processes of intrinsic and extrinsic primary afferent neurons. This leads to activation of local motor and secretory reflexes and the transduction of sensory signals to the brain stem and spinal cord. A critical aspect of paracrine and neurotransmitter signaling is the termination of transmission by degradation or removal of the signaling molecule. In the case of 5-HT, this involves rapid clearance of 5-HT from the intercellular space by the 5-HT reuptake transporter (SERT), which is expressed by mucosal epithelial cells (7,21,36).SERT is a member of the highly conserved Na ϩ /Cl Ϫ -dependent transporter gene family containing 12 transmembrane domains (2). Transporters for 5-HT and other monoamines are of particular interest because they are sites of action for most clinically efficacious antidepressants, as well as for psychoactive drugs of abuse such as amphetamines, cocaine, and MDMA (ecstasy). Furthermore, abnormal expression o...

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mentioning

confidence: 99%

IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells

Foley¹,

Pantano²,

Ciolino³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…SERT expression is reduced in the inflamed and in the healing colonic mucosa of UC patients, thereby increasing 5-HT levels [25,58]. Furthermore, deletion of SERT increases the severity of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice [59] and mice treated with the SERT inhibitor paroxetine presented alterations in GI motility and sensitivity [60]. Interestingly, the regulatory cytokine transforming growth factor-beta 1 (TGF-β1) was recently shown to stimulate SERT function suggesting a novel neuro-immune therapeutic strategy to treat GI disorders [61].…”

Section: The Intestinal Serotonergic Systemmentioning

confidence: 99%

Microbial Neuro-Immune Interactions and the Pathophysiology of IBD

Aguilera¹,

Melgar²

2016

New Insights Into Inflammatory Bowel Disease

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Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a group of debilitating disorders affecting patient's quality of life and with unknown aetiology. The collected evidence indicates that individuals can develop IBD as a result of genetic susceptibility, a dysregulated immune response and the influence of certain environmental factors. Common symptomatology includes abdominal pain, fever and bowel diarrhoea with blood and/or mucus excretion. The location and extent of disease differ between UC and CD, affecting the mucosal layer in the colon in UC patients, whereas in CD patients, a transmural inflammation is found anywhere in the gastrointestinal tract. Factors associated with IBD pathophysiology include alterations in immune responses, characterized by an atypically T helper (Th)-2 profile in UC, and a Th1/Th17 profile in CD, modifications in epithelial barrier function and alterations in the commensal microbiota composition with blooming of specific pathobionts, for example, adherent-invasive Escherichia coli (AIEC), and with diet. Recent research has uncovered that inflammation, per se, can activate the enteric nervous system inducing neurogenic inflammation and increasing visceral sensitivity, leading to pain. Similarly, alterations in the commensal microbiota composition/ligands have also led to modifications in intestinal nociceptive markers and in visceral pain. In this chapter, we aim to review the mechanisms implicated in microbial neuroimmune axis and its potential contribution to IBD pathophysiology and symptomatology. We focus on the findings identified in animal models and in IBD patients and on the prospective translation of targeting the microbial neuro-immune axis as future therapeutic treatment for intestinal inflammatory conditions.

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“…Desse percentual, aproximadamente 90% é sintetizado em células enteroendócrinas, um subtipo de células enterocromafins, e 10% nos neurônios entéricos. Essa 5-HT, presente no trato gastrintestinal age como um neurotransmissor das funções sensório-motoras gastrintestinais (KIM; CAMILLERI, 2000;COATES et al, 2006;GERSHON;TACK, 2007).…”

Section: Desenvolvimento Serotoninaunclassified

O Eixo Intestino-Cérebro E O Papel Da Serotonina

Vedovato¹,

Trevizan²,

Zucoloto³

et al. 2015

Arq. Ciênc. Saúde Unipar

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VEDOVATO, K.; TREVIZAN, A. R.; ZUCOLOTO, C. N.; BERNARDI, M. D. L.; ZANONI, J. N.; MARTINS, J. V. C. P. O eixo intestinocérebro e o papel da serotonina. Arq. Ciênc. Saúde Unipar, Umuarama, v. 18 n. 1, p. 33-42, jan./abr. 2014 RESUMO: Este trabalho teve por finalidade buscar informações na literatura que descrevam a interação entre o sistema nervoso central (SNC) e sistema nervoso entérico (SNE), e que demonstrem de que forma a serotonina pode atuar no "eixo intestino-cérebro". A serotonina (5-hidroxitriptamina, 5-HT) originalmente descoberta em 1937 por Vittorio Erspamer é uma indolamina, encontrada em células do trato gastrointestinal, plaquetas e no sistema nervoso central de mamíferos, sendo que cerca de 95% da 5-HT corpórea é produzida no intestino. De acordo com a literatura o trato gastrointestinal é inervado por cinco diferentes classes de neurônios: neurônios entéricos, aferentes vagal, aferentes da coluna vertebral, eferentes parassimpáticos e eferentes simpáticos. Os alvos primários da 5-HT que é secretado pelas células enteroendócrinas são as projeções intrínsecas constituída por neurônios aferentes primários da mucosa e plexo mientérico, e projeções extrínsecas, constituída por nervos que transmitem sensações gerais além de náuseas e desconforto para o sistema nervoso central. Após os dados compilados da literatura fica claro que o SNE desempenha papel singular, podendo agir de maneira independente, mas também mantém sinapses com o SNC, por meio do nervo vago. Dessa forma, ambos os sistemas podem influenciar a atividade um do outro mediante o "eixo intestino-cérebro". Adicionalmente a 5-HT apresenta-se como um importante neurotransmissor envolvido na interação entre o SNE o SNC, importante na regulação da sensação de motilidade e secreção intestinal e também atua na ativação e condução da informação ao SNC. PALAVRAS-CHAVE: Sistema nervoso entérico; Sistema nervoso central; Intestino; Serotonina. THE BRAIN-INTESTINE AXIS AND THE ROLE OF SEROTONINABSTRACT: This paper aims to seek literature information describing the interaction between the central and enteric nervous system, and to demonstrate how serotonin may be acting on the "brain-intestine axis." Serotonin, originally discovered in 1937 by Vittorio Erspamer, is an indoleamine found in cells in the gastrointestinal tract, platelets and in the central nervous system of mammals, with approximately 95% of body 5-HT produced in the intestine. According to literature, the gastrointestinal tract is innervated by five different neuron classes: enteric neurons, vagal afferent, spinal afferent, parasympathetic efferent, and sympathetic efferent. The primary targets of serotonin secreted by entero-endocrine cells are the intrinsic projections composed by primary afferent neurons of the mucosa and myenteric plexus, and extrinsic projections, consisting of nerves that send general sensations as well as nausea and general discomfort to the central nervous system. After the data were compiled from the literature, it is clear that the enteric nervous system p...

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Effects of serotonin transporter inhibition on gastrointestinal motility and colonic sensitivity in the mouse

Cited by 87 publications

References 45 publications

IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells

IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells

Microbial Neuro-Immune Interactions and the Pathophysiology of IBD

O Eixo Intestino-Cérebro E O Papel Da Serotonina

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