Journal articles on the topic 'Serotonin reuptake transporter (SERT)'
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1
Horackova, Hana, Rona Karahoda, Lukas Cerveny, Veronika Vachalova, Ronja Ebner, Cilia Abad, and Frantisek Staud. "Effect of Selected Antidepressants on Placental Homeostasis of Serotonin: Maternal and Fetal Perspectives." Pharmaceutics 13, no. 8 (August 20, 2021): 1306. http://dx.doi.org/10.3390/pharmaceutics13081306.
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Depression is a prevalent condition affecting up to 20% of pregnant women. Hence, more than 10% are prescribed antidepressant drugs, mainly serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs). We hypothesize that antidepressants disturb serotonin homeostasis in the fetoplacental unit by inhibiting serotonin transporter (SERT) and organic cation transporter 3 (OCT3) in the maternal- and fetal-facing placental membranes, respectively. Paroxetine, citalopram, fluoxetine, fluvoxamine, sertraline, and venlafaxine were tested in situ (rat term placenta perfusion) and ex vivo (uptake studies in membrane vesicles isolated from healthy human term placenta). All tested antidepressants significantly inhibited SERT- and OCT3-mediated serotonin uptake in a dose-dependent manner. Calculated half-maximal inhibitory concentrations (IC50) were in the range of therapeutic plasma concentrations. Using in vitro and in situ models, we further showed that the placental efflux transporters did not compromise mother-to-fetus transport of antidepressants. Collectively, we suggest that antidepressants have the potential to affect serotonin levels in the placenta or fetus when administered at therapeutic doses. Interestingly, the effect of antidepressants on serotonin homeostasis in rat placenta was sex dependent. As accurate fetal programming requires optimal serotonin levels in the fetoplacental unit throughout gestation, inhibition of SERT-/OCT3-mediated serotonin uptake may help explain the poor outcomes of antidepressant use in pregnancy.
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Huot, Philippe, Susan H. Fox, and Jonathan M. Brotchie. "Monoamine Reuptake Inhibitors in Parkinson’s Disease." Parkinson's Disease 2015 (2015): 1–71. http://dx.doi.org/10.1155/2015/609428.
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The motor manifestations of Parkinson’s disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia.
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Seyer, Pascal, Franck Vandermoere, Elisabeth Cassier, Joël Bockaert, and Philippe Marin. "Physical and functional interactions between the serotonin transporter and the neutral amino acid transporter ASCT2." Biochemical Journal 473, no. 13 (June 28, 2016): 1953–65. http://dx.doi.org/10.1042/bcj20160315.
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The activity of serotonergic systems depends on the reuptake of extracellular serotonin via its plasma membrane serotonin [5-HT (5-hydroxytryptamine)] transporter (SERT), a member of the Na+/Cl−-dependent solute carrier 6 family. SERT is finely regulated by multiple molecular mechanisms including its physical interaction with intracellular proteins. The majority of previously identified SERT partners that control its functional activity are soluble proteins, which bind to its intracellular domains. SERT also interacts with transmembrane proteins, but its association with other plasma membrane transporters remains to be established. Using a proteomics strategy, we show that SERT associates with ASCT2 (alanine–serine–cysteine–threonine 2), a member of the solute carrier 1 family co-expressed with SERT in serotonergic neurons and involved in the transport of small neutral amino acids across the plasma membrane. Co-expression of ASCT2 with SERT in HEK (human embryonic kidney)-293 cells affects glycosylation and cell-surface localization of SERT with a concomitant reduction in its 5-HT uptake activity. Conversely, depletion of cellular ASCT2 by RNAi enhances 5-HT uptake in both HEK-293 cells and primary cultured mesencephalon neurons. Mimicking the effect of ASCT2 down-regulation, treatment of HEK-293 cells and neurons with the ASCT2 inhibitor D-threonine also increases 5-HT uptake. Moreover, D-threonine does not enhance further the maximal velocity of 5-HT uptake in cells depleted of ASCT2. Collectively, these findings provide evidence for a complex assembly involving SERT and a member of another solute carrier family, which strongly influences the subcellular distribution of SERT and the reuptake of 5-HT.
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Horschitz, S., R. Hummerich, and P. Schloss. "Structure, function and regulation of the 5-hydroxytryptamine (serotonin) transporter." Biochemical Society Transactions 29, no. 6 (November 1, 2001): 728–32. http://dx.doi.org/10.1042/bst0290728.
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The serotonin transporter (SERT), which terminates serotonergic neurotransmission by rapid reuptake of 5-hydroxytryptamine (5-HT) back into the nerve terminal was the subject of two studies. First, the regulatory effects of antidepressants on the expression of SERT was investigated. After chronic exposure of SERT to antidepressants, substrate transport and antidepressant binding parameters were determined. Long-term exposure of SERT to a selective 5-HT-re-uptake inhibitor, citalopram, resulted in the down-regulation of the expression level. The observed effects depend on drug concentration and exposure time and are reversible. Basal uptake levels could be regained 48 h after cessation of the treatment. Secondly, in order to gain insight into the molecular mechanism of substrate transport, potential interactions of SERT with the noradrenaline transporter (NET) have been investigated. A chimeric concatameric transporter construct consisting of rat SERT and rat NET has been cloned and characterized pharmacologically in a heterologous expression system.
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Zhang, Yuan-Wei, Benjamin E. Turk, and Gary Rudnick. "Control of serotonin transporter phosphorylation by conformational state." Proceedings of the National Academy of Sciences 113, no. 20 (May 2, 2016): E2776—E2783. http://dx.doi.org/10.1073/pnas.1603282113.
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Serotonin transporter (SERT) is responsible for reuptake and recycling of 5-hydroxytryptamine (5-HT; serotonin) after its exocytotic release during neurotransmission. Mutations in human SERT are associated with psychiatric disorders and autism. Some of these mutations affect the regulation of SERT activity by cGMP-dependent phosphorylation. Here we provide direct evidence that this phosphorylation occurs at Thr276, predicted to lie near the cytoplasmic end of transmembrane helix 5 (TM5). Using membranes from HeLa cells expressing SERT and intact rat basophilic leukemia cells, we show that agents such as Na+ and cocaine that stabilize outward-open conformations of SERT decreased phosphorylation and agents that stabilize inward-open conformations (e.g., 5-HT, ibogaine) increased phosphorylation. The opposing effects of the inhibitors cocaine and ibogaine were each reversed by an excess of the other inhibitor. Inhibition of phosphorylation by Na+ and stimulation by ibogaine occurred at concentrations that induced outward opening and inward opening, respectively, as measured by the accessibility of cysteine residues in the extracellular and cytoplasmic permeation pathways, respectively. The results are consistent with a mechanism of SERT regulation that is activated by the transport of 5-HT, which increases the level of inward-open SERT and may lead to unwinding of the TM5 helix to allow phosphorylation.
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Kohen, Ruth, Julia H. Tracy, Eric Haugen, Kevin C. Cain, Monica E. Jarrett, and Margaret M. Heitkemper. "Rare Variants of the Serotonin Transporter Are Associated With Psychiatric Comorbidity in Irritable Bowel Syndrome." Biological Research For Nursing 18, no. 4 (February 24, 2016): 394–400. http://dx.doi.org/10.1177/1099800416633296.
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Alterations in serotonin signaling are suspected in the pathophysiology of irritable bowel syndrome (IBS). By modulating the extracellular reuptake of serotonin, the serotonin transporter (SERT) acts as a key regulator of the bioavailability of serotonin. This study is the first to investigate the impact of rare SERT variants (i.e., those with a minor allele frequency of < 1%) on the risk for IBS, gastrointestinal (GI) symptom level, response to cognitive–behavioral treatment, and psychiatric comorbidity. We sequenced a 0.19 megabase chromosomal stretch containing the SERT gene and surrounding regions in a community sample of 304 IBS patients and 83 controls. We found no significant associations between rare variants in and around the SERT gene and IBS risk, GI symptom profile, or response to treatment. We found preliminary evidence, however, that IBS subjects with a history of either depression or anxiety were significantly more likely to carry multiple rare likely functional variant alleles than IBS patients without psychiatric comorbidity.
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Bowman, Melodi A., Melissa Vitela, Kyra M. Clarke, Wouter Koek, and Lynette C. Daws. "Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice." International Journal of Molecular Sciences 21, no. 20 (October 14, 2020): 7581. http://dx.doi.org/10.3390/ijms21207581.
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Major depressive disorder is typically treated with selective serotonin reuptake inhibitors (SSRIs), however, SSRIs take approximately six weeks to produce therapeutic effects, if any. Not surprisingly, there has been great interest in findings that low doses of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce rapid and long-lasting antidepressant effects. Preclinical studies show that the antidepressant-like effects of ketamine are dependent upon availability of serotonin, and that ketamine increases extracellular serotonin, yet the mechanism by which this occurs is unknown. Here we examined the role of the high-affinity, low-capacity serotonin transporter (SERT), and the plasma membrane monoamine transporter (PMAT), a low-affinity, high-capacity transporter for serotonin, as mechanisms contributing to ketamine’s ability to increase extracellular serotonin and produce antidepressant-like effects. Using high-speed chronoamperometry to measure real-time clearance of serotonin from CA3 region of hippocampus in vivo, we found ketamine robustly inhibited serotonin clearance in wild-type mice, an effect that was lost in mice constitutively lacking SERT or PMAT. As expected, in wild-type mice, ketamine produced antidepressant-like effects in the forced swim test. Mapping onto our neurochemical findings, the antidepressant-like effects of ketamine were lost in mice lacking SERT or PMAT. Future research is needed to understand how constitutive loss of either SERT or PMAT, and compensation that occurs in other systems, is sufficient to void ketamine of its ability to inhibit serotonin clearance and produce antidepressant-like effects. Taken together with existing literature, a critical role for serotonin, and its inhibition of uptake via SERT and PMAT, cannot be ruled out as important contributing factors to ketamine’s antidepressant mechanism of action. Combined with what is already known about ketamine’s action at NMDA receptors, these studies help lead the way to the development of drugs that lack ketamine’s abuse potential but have superior efficacy in treating depression.
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Bischoff, Stephan C., Reiner Mailer, Oliver Pabst, Gisela Weier, Wanda Sedlik, Zhishan Li, Jason J. Chen, Dennis L. Murphy, and Michael D. Gershon. "Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 3 (March 2009): G685—G695. http://dx.doi.org/10.1152/ajpgi.90685.2008.
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Serotonin (5-HT) regulates peristaltic and secretory reflexes in the gut. The serotonin reuptake transporter (SERT; SLC6A4), which inactivates 5-HT, is expressed in the intestinal mucosa and the enteric nervous system. Stool water content is increased and colonic motility is irregular in mice with a targeted deletion of SERT. We tested the hypotheses that 5-HT plays a role in regulating intestinal inflammation and that the potentiation of serotonergic signaling that results from SERT deletion is proinflammatory. Rectal installation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce an immune-mediated colitis, which was compared in SERT knockout mice and littermate controls. Intestinal myeloperoxidase and histamine levels were significantly increased, whereas the survival rate and state of health were significantly decreased in TNBS-treated mice that lacked SERT. Deletion of SERT thus increases the severity of TNBS colitis. These data suggest that 5-HT and its SERT-mediated termination play roles in intestinal immune/inflammatory responses in mice.
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Gershon, Michael D., Sam Li, Jason X. Chen, and Dennis L. Murphy. "Abnormal intestinal function in mice lacking the serotonin reuptake transporter (SERT)." Gastroenterology 118, no. 4 (April 2000): A402. http://dx.doi.org/10.1016/s0016-5085(00)83717-8.
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Gershon, Michael D., Sam Li, Jason X. Chen, Christine Weihems, and Dennis L. Murphy. "Abnormal intestinal function in mice lacking the serotonin reuptake transporter (SERT)." Gastroenterology 118, no. 4 (April 2000): A1173. http://dx.doi.org/10.1016/s0016-5085(00)80515-6.
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Li, Mu, Qingyang Chen, and Yuan-Wei Zhang. "Determining Ligand and Ion-Induced Conformational Changes in Serotonin Transporter with Its Fluorescent Substrates." International Journal of Molecular Sciences 23, no. 18 (September 18, 2022): 10919. http://dx.doi.org/10.3390/ijms231810919.
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Conformational changes are fundamental events in the transport mechanism. The serotonin transporter (SERT) catalyzes reuptake of the neurotransmitter serotonin after its release by serotonergic neurons and is the molecular target for antidepressant drugs and psychostimulants. Despite significant progress in characterizing the structure–function relationship of SERT, its conformational mechanism has not been fully understood. We present here a cell-based method for determining conformational changes in SERT with its fluorescent substrates by fluorescence imaging analysis. This method fluorometrically measures accessibility of strategically positioned cysteine residues in the substrate permeation pathway to calculate the rate constants of reactivity with MTS reagents in live or permeabilized cells. We validated this method by investigating ligand and ion-induced conformational changes in both the extracellular and cytoplasmic pathways of SERT. Furthermore, we applied this method for examining the influence of Cl− binding and vilazodone inhibition on SERT conformation. Our results showed that Cl− ion, in the presence of Na+, facilitates the conformational conversion from outward to inward open states, and that vilazodone binding stabilizes SERT in an outward open and inward-closed conformation. The present work provided insights into the conformational mechanism of SERT and also indicated that the cell-based fluorometric method is robust, straightforward to perform, and potentially applicable to any monoamine transporters in exploring the transport mechanism and mechanism of action of therapeutic agents for the treatment of several psychiatric disorders.
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González Delgado, Samantha, Idalia Garza-Veloz, Fabiola Trejo-Vazquez, and Margarita L. Martinez-Fierro. "Interplay between Serotonin, Immune Response, and Intestinal Dysbiosis in Inflammatory Bowel Disease." International Journal of Molecular Sciences 23, no. 24 (December 9, 2022): 15632. http://dx.doi.org/10.3390/ijms232415632.
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Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal disorder characterized by periods of activity and remission. IBD includes Crohn’s disease (CD) and ulcerative colitis (UC), and even though IBD has not been considered as a heritable disease, there are genetic variants associated with increased risk for the disease. 5-Hydroxytriptamine (5-HT), or serotonin, exerts a wide range of gastrointestinal effects under both normal and pathological conditions. Furthermore, Serotonin Transporter (SERT) coded by Solute Carrier Family 6 Member 4 (SLC6A4) gene (located in the 17q11.1-q12 chromosome), possesses genetic variants, such as Serotonin Transporter Gene Variable Number Tandem Repeat in Intron 2 (STin2-VNTR) and Serotonin-Transporter-linked promoter region (5-HTTLPR), which have an influence over the functionality of SERT in the re-uptake and bioavailability of serotonin. The intestinal microbiota is a crucial actor in normal human gut physiology, exerting effects on serotonin, SERT function, and inflammatory processes. As a consequence of abnormal serotonin signaling and SERT function under these inflammatory processes, the use of selective serotonin re-uptake inhibitors (SSRIs) has been seen to improve disease activity and extraintestinal manifestations, such as depression and anxiety. The aim of this study is to integrate scientific data linking the intestinal microbiota as a regulator of gut serotonin signaling and re-uptake, as well as its role in the pathogenesis of IBD. We performed a narrative review, including a literature search in the PubMed database of both review and original articles (no date restriction), as well as information about the SLC6A4 gene and its genetic variants obtained from the Ensembl website. Scientific evidence from in vitro, in vivo, and clinical trials regarding the use of selective serotonin reuptake inhibitors as an adjuvant therapy in patients with IBD is also discussed. A total of 194 articles were used between reviews, in vivo, in vitro studies, and clinical trials.
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Damsbo, Andreas Gammelgaard, Kristian Lundsgaard Kraglund, Henriette Nørmølle Buttenschøn, Søren Paaske Johnsen, Grethe Andersen, and Janne Kaergaard Mortensen. "Serotonergic Regulation and Cognition after Stroke: The Role of Antidepressant Treatment and Genetic Variation." Cerebrovascular Diseases 47, no. 1-2 (2019): 72–79. http://dx.doi.org/10.1159/000498911.
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Introduction: Serotonin affects several brain functions including cognition. The serotonin transporter (SERT) regulates brain serotonin levels through reuptake into neurons. The gene encoding this transporter, the SERT gene, has several functional polymorphisms affecting the number of transporters and thereby the serotonin levels. SERT gene expression may be important for cognition and selective serotonin reuptake inhibitors (SSRI) may improve cognition post stroke. We therefore examined the association between SERT genotypes, cognitive function and early treatment with the SSRI citalopram among non-depressed Caucasian stroke patients. Patients and Methods: SERT gene polymorphisms in 270 non-depressed first-ever acute ischemic stroke patients randomized to citalopram, n = 130, or placebo, n = 140, were investigated. Patients were genotyped for a length polymorphism (L = long and S = short allele) and a single nucleotide polymorphism (A/G substitution) dividing the L-allele into LA and LG. According to these genotypes, patients were further grouped according to low (S/S, LG/S and LG/LG), medium (S/LA and LG/LA), or high functional gene expression (LALA). Cognition was measured by the Symbol Digit Modalities Test (SDMT) at 1 and 6 months. Mean SDMT scores according to genotype and randomization groups were compared using multiple logistic regression adjusting for age, stroke severity, premorbid functional status, and vascular risk factors including smoking, hypertension, and diabetes. Results: Stratified by genotype groups, there were no statistically significant differences in SDMT scores between randomization groups. Placebo-treated patients with low SERT expression genotypes, however, tended to have lower mean SDMT scores (at 1 month: 30.2, SD 10.8) compared to citalopram-treated patients (33.6, SD 13.7). Within the placebo group, the low genotype expression patients had significantly lower adjusted mean SDMT scores at 1 month compared to the high genotype expression patients (adjusted mean difference of –6 points, CI –12.0 to –0.05). We found similar results at 6 months, although not statistically significant. The genotype expression was not associated with SDMT scores among citalopram-treated patients. Conclusion: There was no difference in cognition between citalopram and placebo-treated patients according to the genotype group. Our results indicate, however, that low expression SERT genotype may contribute to reduced cognitive function post stroke as placebo-treated patients with low SERT expression tended to score lower on the SDMT. The significant difference in SDMT scores between low and high expression patients was present only in the placebo-treated group, thereby warranting further exploration of the potential effect of early citalopram treatment on cognitive functioning. Our results are preliminary and need replication in larger-scale studies.
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Aldosary, Fahad, Sandhaya Norris, Philippe Tremblay, Jonathan S. James, James C. Ritchie, and Pierre Blier. "Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder." International Journal of Neuropsychopharmacology 25, no. 4 (December 27, 2021): 283–92. http://dx.doi.org/10.1093/ijnp/pyab086.
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Abstract Background Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). Methods This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. Results All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. Conclusion These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.
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Linden, David R., Jing-Xian Chen, Michael D. Gershon, Keith A. Sharkey, and Gary M. Mawe. "Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 285, no. 1 (July 2003): G207—G216. http://dx.doi.org/10.1152/ajpgi.00488.2002.
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5-HT released from enterochromaffin cells acts on enteric nerves to initiate motor reflexes. 5-HT's actions are terminated by a serotonin reuptake transporter (SERT). In this study, we tested the hypothesis that inflammation leads to altered mucosal 5-HT signaling. Colitis was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS), and experiments were conducted on day 6. 5-HT content, number of 5-HT-immunoreactive cells, and the proportion of epithelial cells that were 5-HT-immunoreactive increased twofold in colitis. The amount of 5-HT released under basal and stimulated conditions was significantly increased in colitis. SERT inhibition increased the 5-HT concentration in media bathing-stimulated control tissue to a level comparable to that of the stimulated colitis tissue. mRNA encoding SERT and SERT immunoreactivity were reduced during inflammation. Slower propulsion and reduced sensitivity to 5-HT-receptor antagonism were observed in colitis. These data suggest that colitis alters 5-HT signaling by increasing 5-HT availability while decreasing 5-HT reuptake. Altered 5-HT availability may contribute to the dysmotility of inflammatory bowel disease, possibly due to desensitization of 5-HT receptors.
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O’Reilly, Kally C., Simon Trent, Sarah J. Bailey, and Michelle A. Lane. "13-cis-Retinoic Acid Alters Intracellular Serotonin, Increases 5-HT1A Receptor, and Serotonin Reuptake Transporter Levels In Vitro." Experimental Biology and Medicine 232, no. 9 (October 2007): 1195–203. http://dx.doi.org/10.3181/0703-rm-83.
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In addition to their established role in nervous system development, vitamin A and related retinoids are emerging as regulators of adult brain function. Accutane (13- cis-retinoic acid, isotretinoin) treatment has been reported to increase depression in humans. Recently, we showed that chronic administration of 13- cis-retinoic acid (13- cis-RA) to adolescent male mice increased depression-related behaviors. Here, we have examined whether 13- cis-RA regulates components involved in serotonergic neurotransmission in vitro. We used the RN46A-B14 cell line, derived from rat embryonic raphe nuclei. This cell line synthesizes serotonin (5-hydroxytryptamine, 5-HT) and expresses the 5-HT1A receptor and the serotonin reuptake transporter (SERT). Cells were treated with 0, 2.5, or 10 μ M 13- cis-RA for 48 or 96 hrs, and the levels of 5-HT; its metabolite, 5-hydroxyindoleacetic acid (5HIAA); 5-HT1A receptor; and SERT were determined. Treatment with 13- cis-RA for 96 hrs increased the intracellular levels of 5-HT and tended to increase intra-cellular 5HIAA levels. Furthermore, 48 hrs of treatment with 2.5 and 10 μ M 13- cis-RA significantly increased 5-HT1A protein to 168.5 ± 20.0% and 148.7 ± 2.2% of control respectively. SERT protein levels were significantly increased to 142.5 ± 11.1% and 119.2 ± 3.6% of control by 48 hrs of treatment with 2.5 and 10 μ M of 13- cis-RA respectively. Increases in both 5-HT1A receptor and SERT proteins may lead to decreased serotonin availability at synapses. Such an effect of 13- cis-RA could contribute to the increased depression-related behaviors we have shown in mice.
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Haub, Synia, Giridhar Kanuri, Valentina Volynets, Thomas Brune, Stephan C. Bischoff, and Ina Bergheim. "Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no. 3 (March 2010): G335—G344. http://dx.doi.org/10.1152/ajpgi.00088.2009.
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Elevated dietary fructose intake, altered intestinal motility, and barrier function may be involved in the development of nonalcoholic fatty liver disease (NAFLD). Because intestinal motility and permeability are also regulated through the bioavailability of serotonin (5-HT), we assessed markers of hepatic injury in serotonin reuptake transporter knockout (SERT−/−) and wild-type mice chronically exposed to different monosaccharide solutions (30% glucose or fructose solution) or water for 8 wk. The significant increase in hepatic triglyceride, TNF-α, and 4-hydroxynonenal adduct as well as portal endotoxin levels found in fructose-fed mice was associated with a significant decrease of SERT and the tight-junction occludin in the duodenum. Similar effects were not found in mice fed glucose. In contrast, in SERT−/− mice fed glucose, portal endotoxin levels, concentration of occludin, and indices of hepatic damage were similar to those found in wild-type and SERT−/− mice fed fructose. In fructose-fed mice treated with a 5-HT3 receptor antagonist, hepatic steatosis was significantly attenuated. Our data suggest that a loss of intestinal SERT is a critical factor in fructose-induced impairment of intestinal barrier function and subsequently the development of steatosis.
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Mlinar, Boris, Alberto Montalbano, Gilda Baccini, Francesca Tatini, Rolando Berlinguer Palmini, and Renato Corradetti. "Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity." Journal of General Physiology 145, no. 3 (February 23, 2015): 225–51. http://dx.doi.org/10.1085/jgp.201411330.
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The firing activity of serotonergic neurons in raphe nuclei is regulated by negative feedback exerted by extracellular serotonin (5-HT)o acting through somatodendritic 5-HT1A autoreceptors. The steady-state [5-HT]o, sensed by 5-HT1A autoreceptors, is determined by the balance between the rates of 5-HT release and reuptake. Although it is well established that reuptake of 5-HTo is mediated by 5-HT transporters (SERT), the release mechanism has remained unclear. It is also unclear how selective 5-HT reuptake inhibitor (SSRI) antidepressants increase the [5-HT]o in raphe nuclei and suppress serotonergic neuron activity, thereby potentially diminishing their own therapeutic effect. Using an electrophysiological approach in a slice preparation, we show that, in the dorsal raphe nucleus (DRN), continuous nonexocytotic 5-HT release is responsible for suppression of phenylephrine-facilitated serotonergic neuron firing under basal conditions as well as for autoinhibition induced by SSRI application. By using 5-HT1A autoreceptor-activated G protein–gated inwardly rectifying potassium channels of patched serotonergic neurons as 5-HTo sensors, we show substantial nonexocytotic 5-HT release under conditions of abolished firing activity, Ca2+ influx, vesicular monoamine transporter 2–mediated vesicular accumulation of 5-HT, and SERT-mediated 5-HT transport. Our results reveal a cytosolic origin of 5-HTo in the DRN and suggest that 5-HTo may be supplied by simple diffusion across the plasma membrane, primarily from the dense network of neurites of serotonergic neurons surrounding the cell bodies. These findings indicate that the serotonergic system does not function as a sum of independently acting neurons but as a highly interdependent neuronal network, characterized by a shared neurotransmitter pool and the regulation of firing activity by an interneuronal, yet activity-independent, nonexocytotic mechanism.
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Zoons, Evelien, Marina A. J. Tijssen, Yasmine E. M. Dreissen, Marenka Smit, and Jan Booij. "The Effect of Escitalopram on Central Serotonergic and Dopaminergic Systems in Patients with Cervical Dystonia, and Its Relationship with Clinical Treatment Effects: A Double-Blind Placebo-Controlled Trial." Biomolecules 10, no. 6 (June 8, 2020): 880. http://dx.doi.org/10.3390/biom10060880.
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Purpose: The pathophysiology of cervical dystonia (CD) is thought to be related to changes in dopamine and serotonin levels in the brain. We performed a double-blind trial with escitalopram (selective serotonin reuptake inhibitor; SSRI) in patients with CD. Here, we report on changes in dopamine D2/3 receptor (D2/3R), dopamine transporter (DAT) and serotonin transporter (SERT) binding potential (BPND) after a six-week treatment course with escitalopram or placebo. Methods: CD patients had [123I]FP-CIT SPECT (I-123 fluoropropyl carbomethoxy-3 beta-(4-iodophenyltropane) single-photon emission computed tomography) scans, to quantify extrastriatal SERT and striatal DAT, and [123I]IBZM SPECT (I-123 iodobenzamide SPECT) scans to quantify striatal D2/3R BPND before and after six weeks of treatment with either escitalopram or placebo. Treatment effect was evaluated with the Clinical Global Impression scale for dystonia, jerks and psychiatric symptoms, both by physicians and patients. Results: In both patients treated with escitalopram and placebo there were no significant differences after treatment in SERT, DAT or D2/3R BPND. Comparing scans after treatment with escitalopram (n = 8) to placebo (n = 8) showed a trend (p = 0.13) towards lower extrastriatal SERT BPND in the SSRI group (median SERT occupancy of 64.6%). After treatment with escitalopram, patients who reported a positive effect on dystonia or psychiatric symptoms had significantly higher SERT occupancy compared to patients who did not experience an effect. Conclusion: Higher extrastriatal SERT occupancy after treatment with escitalopram is associated with a trend towards a positive subjective effect on dystonia and psychiatric symptoms in CD patients.
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Yang, Hyun, Hye Jin Kim, Eui-Ju Hong, Bo-Jeong Pyun, Byung-Seob Ko, and Hye Won Lee. "Antidepressant Effect ofTetragonia tetragonoides (Pall.) KuntzeExtract on Serotonin Turnover." Evidence-Based Complementary and Alternative Medicine 2019 (February 3, 2019): 1–7. http://dx.doi.org/10.1155/2019/7312842.
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Tetragonia tetragonoides (Pall.) Kuntze(TTK) is a groundcover found along coastal areas of the Korean peninsula. TTK is traditionally used to improve women’s health and treat gastrointestinal diseases. Use of herbal medicines in the treatment of mood disorders has recently been suggested as an alternative therapeutic strategy. In the present study, we determined that consumption of TTK extract ameliorated progression of depressive-like symptoms in ovariectomized (OVX) rats and further examined the mechanisms involved, i.e., synthesis, release, and reuptake(s) of serotonin (also known as 5-HT). We assessed the mRNA expression levels of tryptophan hydroxylases (TPH-1 and TPH-2) and serotonin transporter (SERT) as well as the reuptake activity of serotonin in RBL-2H3 cells. We also determined whether or not TTK extract regulates the serum level of serotonin and improves depressive-like symptoms in 0.5, 1, and 2% TTK-fed OVX female rats in a forced swimming test. Our results show that the mRNA levels of TPH-1 and SERT were significantly reduced, whereas the mRNA level of TPH-2 was dose-dependently elevated by TTK (50 and 100μg/mL) in RBL-2H3 cells. TTK significantly inhibited LPS- (lipopolysaccharide-) induced serotonin uptake in RBL-2H3 cells in a dose-dependent manner. The serum level(s) of serotonin was elevated by 1% and 2% TTK treatment in OVX female rats. Moreover, immobility time in the forced swimming test was reduced by 1% and 2% TTK treatment but not altered by 0.5% TTK treatment in OVX female rats. Taken together, these results indicate that TTK may significantly inhibit depressive-like symptoms due to upregulation of serotonin level(s) and regulation of serotonin reuptake activity. Thus, TTK may exert beneficial effects on depression during pre- or/and postmenopausal periodsviamodulation of serotonin synthesis and metabolism.
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Lazarevic, Vesna, Ioannis Mantas, Ivana Flais, and Per Svenningsson. "Fluoxetine Suppresses Glutamate- and GABA-Mediated Neurotransmission by Altering SNARE Complex." International Journal of Molecular Sciences 20, no. 17 (August 30, 2019): 4247. http://dx.doi.org/10.3390/ijms20174247.
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Major depressive disorder is one of the most common neuropsychiatric disorders worldwide. The treatment of choice that shows good efficacy in mood stabilization is based on selective serotonin reuptake inhibitors (SSRIs). Their primary mechanism of action is considered to be the increased synaptic concentration of serotonin through blockade of the serotonin transporter (SERT). In this study, we described an alternative mode of action of fluoxetine (FLX), which is a representative member of the SSRI class of antidepressants. We observed that FLX robustly decreases both glutamatergic and gamma-Aminobutyric acid (GABA)-ergic synaptic release in a SERT-independent manner. Moreover, we showed that this effect may stem from the ability of FLX to change the levels of main components of the SNARE (solubile N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Our data suggest that this downregulation of SNARE fusion machinery involves diminished activity of protein kinase C (PKC) due to FLX-induced blockade of P/Q type of voltage-gated calcium channels (VGCCs). Taken together, by virtue of its inhibition at SERT, fluoxetine increases extracellular serotonin levels; however, at the same time, by reducing SNARE complex function, this antidepressant reduces glutamate and GABA release.
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Herrera-Pérez, José Jaime, Alonso Fernández-Guasti, and Lucía Martínez-Mota. "Brain SERT Expression of Male Rats Is Reduced by Aging and Increased by Testosterone Restitution." Neuroscience Journal 2013 (December 18, 2013): 1–8. http://dx.doi.org/10.1155/2013/201909.
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In preclinical and clinical studies aging has been associated with a deteriorated response to antidepressant treatment. We hypothesize that such impairment is explained by an age-related decrease in brain serotonin transporter (SERT) expression associated with low testosterone (T) levels. The objectives of this study were to establish (1) if brain SERT expression is reduced by aging and (2) if the SERT expression in middle-aged rats is increased by T-restitution. Intact young rats (3–5 months) and gonad-intact middle-aged rats with or without T-restitution were used. The identification of the brain SERT expression was done by immunofluorescence in prefrontal cortex, lateral septum, hippocampus, and raphe nuclei. An age-dependent reduction of SERT expression was observed in all brain regions examined, while T-restitution recovered the SERT expression only in the dorsal raphe of middle-aged rats. This last action seems relevant since dorsal raphe plays an important role in the antidepressant action of selective serotonin reuptake inhibitors. All data suggest that this mechanism accounts for the T-replacement usefulness to improve the response to antidepressants in the aged population.
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Hinz, Rainer, Sudhakar Selvaraj, N. Venkatesha Murthy, Zubin Bhagwagar, Matthew Taylor, Philip J. Cowen, and Paul M. Grasby. "Effects of Citalopram Infusion on the Serotonin Transporter Binding of [11C]DASB in Healthy Controls." Journal of Cerebral Blood Flow & Metabolism 28, no. 8 (May 14, 2008): 1478–90. http://dx.doi.org/10.1038/jcbfm.2008.41.
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The positron emission tomography (PET) ligand [11C]DASB is currently the most widely used imaging agent for quantitative studies of the serotonin transporter (SERT) in human brain. The aim of this work was to assess the effects of an intravenous infusion of 10 mg citalopram, a selective serotonin reuptake inhibitor (SSRI), before the PET scan on the kinetics of [11C]DASB in arterial plasma and in selected brain regions. Four healthy male volunteers underwent two PET scans with a mean of 523 MBq injected activity after either placebo or Citalopram infusion in a randomised design. The Citalopram infusion led to a substantial increase of the area under the curve of the metabolite-corrected arterial plasma input function. Total volumes of distribution VT were estimated applying the Logan plot to regional time—activity curves or by generating parametric maps with spectral analysis. A mean reduction of the cerebellar VT of 19% with Logan analysis and of 24% with spectral analysis was observed after Citalopram infusion, which confirms previous findings of displaceable SERT ligand binding in cerebellar grey matter. The SERT occupancy for six target regions with moderate to high binding was 60% derived from BPND and 69% derived from BPP.
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Purnawati, Susy, Luh Putu Wrasiati, Cokorda Bagus Jaya Lesmana, Sandra Megantara, and Ronny Lesmana. "A study of molecular docking of l-tryptophan ligand as a compound in pineapples and bananas binding with the human serotonin transporter (SERT)." Bali Medical Journal 11, no. 3 (September 23, 2022): 1243–49. http://dx.doi.org/10.15562/bmj.v11i3.3526.
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Introduction: Low mood condition is related to a low level of brain serotonin. An early sign of depression with low mood symptoms is generally treated with psychotropic drugs that work as selective serotonin reuptake and monoamine oxidase (MAO) inhibitors (one of which is sertraline), to increase serotonin levels in the brain. There are some concerns regarding side effects available medication like serotonin syndrome, suicidality and aggressive behavior. Thus, development of alternative herbal products made from a combination of pineapple and banana extract with less side effect and its potential affinity with serotonin regulation is important. Aim of the study: To determine potential herbal rich (banana and pineapple) of L-tryptophan and potential active compounds interaction with the human serotonin transporter. Method: In the present study, using in silico molecular docking techniques, the active compound of banana and pineapple and its potential interaction with human serotonin transporter were assed. Docking study explored the bioactive compounds interactions with specific target like catechin, dopamine, epigallocatechin, gallic acid, L-tryptophan, malvidin, norepinephrine, pelargonidin, peonidin, and serotonin. Molecular docking simulations were performed using AutoDock 4.2 software. The docking method was validated first by re-docking sertraline (nature ligand) in a complex with PDB ID: 6AWO against the target receptor (SERT). Result: The molecular docking results had showed that L-tryptophan, peonidin, and catechin could bind to esential amino acid residues in the binding pocket, with binding affinity -5.69, -8.63, -8.24 kcal/mol respectively. Conclusion: L-tryptophan, peonidin, and catechin are the most promising compounds that have good potency as anti-depressant agents through SERT inhibitory activity. This compounds in bananas and pineapples have the potential to affect serotonin transporter receptors that play a role in mood and behavior.
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Gross, Kara J., Nima Karamooz, Zhishan Li, and Michael D. Gershon. "W1698 Loss of the Serotonin Reuptake Transporter (SERT) Worsens the Severity of Colonic Inflammation." Gastroenterology 136, no. 5 (May 2009): A—719—A—720. http://dx.doi.org/10.1016/s0016-5085(09)63321-7.
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Kim, E., O. D. Howes, J. W. Park, S. N. Kim, S. A. Shin, B. H. Kim, F. E. Turkheimer, Y. S. Lee, and J. S. Kwon. "Altered serotonin transporter binding potential in patients with obsessive-compulsive disorder under escitalopram treatment: [11C]DASB PET study." Psychological Medicine 46, no. 2 (October 1, 2015): 357–66. http://dx.doi.org/10.1017/s0033291715001865.
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BackgroundObsessive-compulsive disorder (OCD) is a chronic, relapsing mental illness. Selective serotonin reuptake inhibitors block serotonin transporters (SERTs) and are the mainstay of treatment for OCD. SERT abnormalities are reported in drug-free patients with OCD, but it is not known what happens to SERT levels during treatment. This is important as alterations in SERT levels in patients under treatment could underlie poor response, or relapse during or after treatment. The aim of the present study was first to validate a novel approach to measuring SERT levels in people taking treatment and then to investigate SERT binding potential (BP) using [11C]DASB PET in patients with OCD currently treated with escitalopram in comparison with healthy controls.MethodTwelve patients and age- and sex-matched healthy controls were enrolled. The patients and healthy controls underwent serial PET scans after administration of escitalopram and blood samples for drug concentrations were collected simultaneously with the scans. Drug-free BPs were obtained by using an inhibitory Emax model we developed previously.ResultsThe inhibitory Emax model was able to accurately predict drug-free SERT BP in people taking drug treatment. The drug-free BP in patients with OCD currently treated with escitalopram was significantly different from those in healthy volunteers [Cohen's d = 0.03 (caudate), 1.16 (putamen), 1.46 (thalamus), −5.67 (dorsal raphe nucleus)].ConclusionsThis result extends previous findings showing SERT abnormalities in drug-free patients with OCD by indicating that altered SERT availability is seen in OCD despite treatment. This could account for poor response and the high risk of relapse in OCD.
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Szöllősi, Dániel, and Thomas Stockner. "Sodium Binding Stabilizes the Outward-Open State of SERT by Limiting Bundle Domain Motions." Cells 11, no. 2 (January 12, 2022): 255. http://dx.doi.org/10.3390/cells11020255.
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The human serotonin transporter (hSERT) removes the neurotransmitter serotonin from the synaptic cleft by reuptake into the presynaptic nerve terminal. A number of neurologic diseases are associated with dysfunction of the hSERT, and several medications for their treatment are hSERT blockers, including citalopram, fluoxetine, and paroxetine. The substrate transport is energized by the high concentration of external NaCl. We showed through molecular dynamics simulations that the binding of NaCl stabilized the hSERT in the substrate-binding competent conformation, which was characterized by an open access path to the substrate-binding site through the outer vestibule. Importantly, the binding of NaCl reduced the dynamics of the hSERT by decreasing the internal fluctuations of the bundle domain as well as the movement of the bundle domain relative to the scaffold domain. In contrast, the presence of only the bound chloride ion did not reduce the high domain mobility of the apo state.
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Lu, N. Z., A. J. Eshleman, A. Janowsky, and C. L. Bethea. "Ovarian steroid regulation of serotonin reuptake transporter (SERT) binding, distribution, and function in female macaques." Molecular Psychiatry 8, no. 3 (March 2003): 353–60. http://dx.doi.org/10.1038/sj.mp.4001243.
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Houwing, Danielle J., Diana C. Esquivel-Franco, Anouschka S. Ramsteijn, Kirsten Schuttel, Eline L. Struik, Chantal Arling, Sietse F. de Boer, and Jocelien D. A. Olivier. "Perinatal fluoxetine treatment and dams’ early life stress history have opposite effects on aggressive behavior while having little impact on sexual behavior of male rat offspring." Psychopharmacology 237, no. 9 (July 17, 2020): 2589–600. http://dx.doi.org/10.1007/s00213-020-05535-7.
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Abstract Rationale Many depressed women continue antidepressant treatment during pregnancy. Selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy increases the risk for abnormal social development of the child, including increased aggressive or defiant behavior, with unknown effects on sexual behavior. Objectives Our aim was to investigate the effects of perinatal SSRI treatment and maternal depression, both separately and combined, on aggressive and sexual behavior in male rat offspring. Methods Heterozygous serotonin transporter (SERT± ) knockout dams exposed to early life stress (ELSD) were used as an animal model of maternal depression. Early life stress consisted of separating litters from their mother for 6 h a day on postnatal day (PND)2–15, resulting in a depressive-like phenotype in adulthood. Depressive-like dams were treated with fluoxetine (FLX, 10 mg/kg) or vehicle throughout pregnancy and lactation (gestational day 1 until PND 21). Male offspring were tested for aggressive and sexual behavior in adulthood. As lifelong reductions in SERT expression are known to alter behavioral outcome, offspring with normal (SERT+/+) and reduced (SERT± ) SERT expression were assessed. Results Perinatal FLX treatment reduced offensive behavior and the number of animals attacking and increased the latency to attack, especially in SERT+/+ offspring. Perinatal FLX treatment reduced the mounting frequency in SERT+/+ offspring. ELSD increased offensive behavior, without affecting sexual behavior in SERT± offspring. Conclusions Overall, our research demonstrates that perinatal FLX treatment and ELSD have opposite effects on aggressive behavior, with little impact on sexual behavior of male offspring.
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Sun, Wenjing, Yan Guo, Shirong Zhang, Zhihui Chen, Kangqi Wu, Qin Liu, Kaijun Liu, et al. "Fecal Microbiota Transplantation Can Alleviate Gastrointestinal Transit in Rats with High-Fat Diet-Induced Obesity via Regulation of Serotonin Biosynthesis." BioMed Research International 2018 (October 2, 2018): 1–9. http://dx.doi.org/10.1155/2018/8308671.
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Aim. We tested the hypothesis that fecal microbiota transplantation (FMT) could regulate the biotransformation of bile acids, such as deoxycholic acid (DCA) and cholic acid (CA), which in turn regulate the biosynthesis of serotonin in the gut and relieve gastrointestinal dysmotility in high-fat diet- (HFD-) induced obesity in rats. Methods. Male Sprague-Dawley rats were randomly divided into the control diet group, HFD group, and HFD-fed with receiving FMT. HFD was fed for 12 weeks. At the end of two-week HFD, FMT was carried out for two weeks. The gastrointestinal transit, serotonin concentration, the expression of tryptophan hydroxylase 1 (TPH1) and serotonin reuptake transporter (SERT), and the levels of bile acids in intestinal contents were examined. Results. Compared with the control group, the gastrointestinal transit and small intestinal serotonin concentration of HFD-fed rats were increased. In HFD-fed rats, TPH1 protein expression was increased significantly, while SERT protein expression was decreased, but not significant. The levels of CA and DCA in intestinal contents were also significantly increased in HFD-fed rats compared with the control group. After HFD-fed rats receiving FMT treatment, the gastrointestinal transit, small intestinal serotonin concentration, and TPH1 expression were decreased, while SERT expression was not affected. Moreover, the levels of CA and DCA in intestinal contents were also decreased. Conclusions. FMT could alleviate small intestinal transit in the HFD-fed rats by regulating the serotonin biosynthesis. In this process, CA and DCA may be related to the regulation of synthesis of serotonin.
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Lee, Eun-Jae, Mi-Sun Oh, Jong S. Kim, Dae-Il Chang, Jong-Ho Park, Jae-Kwan Cha, Ji Hoe Heo, et al. "Serotonin transporter gene polymorphisms may be associated with poststroke neurological recovery after escitalopram use." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 3 (October 13, 2017): 271–76. http://dx.doi.org/10.1136/jnnp-2017-316882.
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ObjectiveSelective serotonin reuptake inhibitors (SSRIs) putatively improve neurological recovery after stroke. We aimed to investigate whether serotonin transporter (SERT) gene polymorphisms are related to the responsiveness to SSRIs in the poststroke neurological recovery.MethodsThis was a post hoc analysis of the EMOTION study (ClinicalTrials.gov NCT01278498), a randomised, placebo-controlled, double-blind trial examining the efficacy of escitalopram on emotional and neurological disturbances after acute stroke. Patients with no/minimal disability initially (modified Rankin Scale (mRS) 0–1) were excluded. Of the participants, 301 underwent genetic studies of the STin2 (a variable number tandem repeat (VNTR) in intron 2) (STin2 12/10 and STin2 12/12 genotypes) and 5-HTTLPR (a variable-length repeat in the promoter region) polymorphisms of SERT. We explored whether neurological function (National Institutes of Health Stroke Scale (NIHSS) score and mRS) at 3 months would differ according to SERT polymorphisms within each treatment arm (escitalopram and placebo).ResultsAmong the escitalopram users (n=159), neurological function in subjects with STin2 12/10 (n=29) improved significantly more than that in STin2 12/12 carriers (n=130) at 3 months. After adjusting for age, initial NIHSS and depression, STin2 12/10 independently predicted a good clinical outcome (mRS 0–1) (OR 2.99, 95% CI 1.04 to 8.58) at 3 months. However, differences between STin2 polymorphisms were not shown in the placebo group (n=142). 5-HTTLPR polymorphisms were not associated with neurological recovery in any treatment group.ConclusionSTin2 VNTR polymorphisms may be associated with poststroke neurological recovery after SSRI therapy. Further studies are needed to identify the role of serotonin in neurological recovery after stroke.
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Zhao, Jun, Huiling Tian, Hongtao Song, Xu Wang, Tong Luo, Liya Ai, Yumin Fang, Jianghao Zhao, Saiyin Chao-ke-tu, and Zhigang Li. "Effect of Electroacupuncture on Reuptake of Serotonin via miRNA-16 Expression in a Rat Model of Depression." Evidence-Based Complementary and Alternative Medicine 2019 (December 24, 2019): 1–16. http://dx.doi.org/10.1155/2019/7124318.
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The current study aimed to investigate the effects and mechanisms of electroacupuncture (EA) treatment applied to Bai hui (GV20) and Yin tang (GV29) acupoints (1 mA, 2 Hz, continuous wave, 20 minutes) for 28 days in a rat model of chronic unpredictable mild stress (CUMS) on reuptake of serotonin (5-hydroxytryptamine (5-HT)) and miRNA-16 levels in the hippocampus and serum. Rats were housed in individual cages, and CUMS was used to establish a rat model of depression. After EA treatment for 4 weeks, behavioral changes and indices including 5-HT transporter (SERT), 5-HT, and miRNA-16 levels in the hippocampus and serum were examined. The EA treatment significantly improved base levels of sucrose preference and exploratory behavior and significantly decreased SERT protein and mRNA expression in the hippocampus of depressed rats. Significantly increased 5-HT levels were observed, and miRNA-16 levels were significantly decreased in the hippocampus and serum of depressed rats. In conclusion, the antidepressant effects of EA treatment may be affected via inhibition of 5-HT reuptake, upregulation of 5-HT levels, and inhibition of miRNA-16 expression in the hippocampus and serum.
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Tsai, Chi-Jung, Chuang-Hsin Chiu, Yu-Yeh Kuo, Wen-Sheng Huang, Tsung-Hsun Yu, Leo Garcia Flores, Skye Hsin-Hsien Yeh, and Kuo-Hsing Ma. "3,4-Methylenedioxymethamphetamine (MDMA) Model: In Vivo 4-[18F]-ADAM PET Imaging." International Journal of Molecular Sciences 23, no. 13 (June 24, 2022): 7035. http://dx.doi.org/10.3390/ijms23137035.
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Numerous studies have confirmed that 3,4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the density of the serotonin reuptake transporter (SERT). Amitriptyline (AMI) has been shown to exert neuroprotective properties in neuropathologic injury. Here, we used a SERT-specific radionuclide, 4-[18F]-ADAM, to assess the longitudinal alterations in SERT binding and evaluate the synergistic neuroprotective effect of AMI in a rat MDMA model. In response to MDMA treatment regimens, SERT binding was significantly reduced in rat brains. Region-specific recovery rate (normalized to baseline) in the MDMA group at day 14 was 71.29% ± 3.21%, and progressively increased to 90.90% ± 7.63% at day 35. AMI dramatically increased SERT binding in all brain regions, enhancing average ~18% recovery rate at day 14 when compared with the MDMA group. The immunochemical staining revealed that AMI markedly increased the serotonergic fiber density in the cingulate and thalamus after MDMA-induction, and confirmed the PET findings. Using in vivo longitudinal PET imaging, we demonstrated that SERT recovery was positively correlated with the duration of MDMA abstinence, implying that lower SERT densities in MDMA-induced rats reflected neurotoxic effects and were (varied) region-specific and reversible. AMI globally accelerated the recovery rate of SERT binding and increased SERT fiber density with possible neuroprotective effects.
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Pushkina, A. V., A. B. Avalueva, I. G. Bakulin, A. A. Topanova, A. A. Murzina, S. I. Sitkin, I. V. Lapinsky, and E. V. Skazyvaeva. "Functional polymorphism of the serotonin reuptake transporter SLC6A4 gene in various clinical variants of irritable bowel syndrome." Almanac of Clinical Medicine 47, no. 6 (December 22, 2019): 496–504. http://dx.doi.org/10.18786/2072-0505-2019-47-072.
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Rationale: Irritable bowel syndrome (IBS) is a multifactorial disease, the genetic aspect of which is being actively studied.Aim: To investigate functional polymorphism of the serotonin reuptake transporter (SERT) SLC6A4 gene of various clinical variants of IBS.Materials and methods: We performed a cross-sectional single center study in 79 Caucasian patients with IBS (according to the Rome criteria IV). The patients were divided into two groups: group 1, IBS with diarrhea (IBS-D, n = 45) and group 2, IBS with constipation (IBS-C, n = 34). The control group included 59 Caucasian patients with gastrointestinal disorders without IBS. Polymorphism 5-HTTLPR of the SLC6A4 gene was assessed in all subjects. In group 1 patients, blood serotonin levels were measured and psychological tests were performed, including Spielberger's State / Trait Anxiety Inventory, quality of life by SF36 and GSRS, Asthenia scale, VAS scores for pain intensity.Results: Thirty-five of 45 (77.8%) patients with IBS-D carried the mutant S allele, which was significantly more frequent than in the IBS-C group (p = 0.002) and in the control group (p = 0.005). There were no statistically significant differences (p = 0.54) in the frequency of detection of the homozygous LL genotype (normal allele) and the heteroand homozygous mutant alleles (SL and SS) genotype between the IBS-C and control patients. In the IBS-D group, a gender difference for the mutant SS allele of 5-HTTLPR was found, with significantly higher frequency in female patients (p = 0.0147). No significant gender differences in the genotype distribution between the patients with IBS-C and the control group were found. There were also no differences in blood serotonin levels in the IBS patients with various 5-HTTLPR types (p = 0.086); they were all in the reference range. However, there was a trend towards lower serotonin levels in the LL genotype carriers compared to those with the SS/SL polymorphisms. The Gastroenterological inventory GSRS demonstrated significantly higher total score for the constipation syndrome in the patients with homozygous LL 5-HTTLPR polymorphism, compared to that in the patients with the SS/SL genotype (p = 0.013).Conclusion: The results may be related to lower expression of the SLC6A4 gene in the carriers of the mutant allele in the 5-HTTLPR promoter and subsequent decreased rate of serotonin uptake, with resulting stimulation of the gastrointestinal tract. The SERT polymorphism of the SLC6A4 gene is worth further investigation as a potential candidate gene in the IBS pathophysiology.
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Descarries, Laurent, and Mustaph Riad. "Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT 1A receptors and SERT." Philosophical Transactions of the Royal Society B: Biological Sciences 367, no. 1601 (September 5, 2012): 2416–25. http://dx.doi.org/10.1098/rstb.2011.0361.
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Serotonin (5-HT) 5-HT 1A autoreceptors (5-HT 1A autoR) and the plasmalemmal 5-HT transporter (SERT) are key elements in the regulation of central 5-HT function and its responsiveness to antidepressant drugs. Previous immuno-electron microscopic studies in rats have demonstrated an internalization of 5-HT 1A autoR upon acute administration of the selective agonist 8-OH-DPAT or the selective serotonin reuptake inhibitor antidepressant fluoxetine. Interestingly, it was subsequently shown in cats as well as in humans that this internalization is detectable by positron emission tomography (PET) imaging with the 5-HT 1A radioligand [ 18 F]MPPF. Further immunocytochemical studies also revealed that, after chronic fluoxetine treatment, the 5-HT 1A autoR, although present in normal density on the plasma membrane of 5-HT cell bodies and dendrites, do not internalize when challenged with 8-OH-DPAT. Resensitization requires several weeks after discontinuation of the chronic fluoxetine treatment. In contrast, the SERT internalizes in both the cell bodies and axon terminals of 5-HT neurons after chronic but not acute fluoxetine treatment. Moreover, the total amount of SERT immunoreactivity is then reduced, suggesting that SERT is not only internalized, but also degraded in the course of the treatment. Ongoing and future investigations prompted by these finding are briefly outlined by way of conclusion.
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Chen, Xiaoning, Kara J. Margolis, Michael D. Gershon, Gary J. Schwartz, and Ji Y. Sze. "Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake." PLoS ONE 7, no. 3 (March 8, 2012): e32511. http://dx.doi.org/10.1371/journal.pone.0032511.
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Barbaro, Maria Raffaella, Antonio Di Sabatino, Cesare Cremon, Paolo Giuffrida, Michelangelo Fiorentino, Annalisa Altimari, Lara Bellacosa, Vincenzo Stanghellini, and Giovanni Barbara. "Interferon-γ is increased in the gut of patients with irritable bowel syndrome and modulates serotonin metabolism." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 6 (March 15, 2016): G439—G447. http://dx.doi.org/10.1152/ajpgi.00368.2015.
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Mucosal immune activation and altered serotonin metabolism participate in the pathophysiology of irritable bowel syndrome (IBS). However, the reciprocal interplay between these two systems remains unknown. We evaluated the expression and release of interferon (IFN)-γ from the colonic mucosa of patients with IBS and its impact on serotonin reuptake transporter ( SERT) gene expression in Caco-2 cells. qPCR was used to evaluate IFN-γ gene expression in colonic mucosal biopsies, whereas IFN-γ protein amount was assessed by ELISA. Colonic T box expressed in T cells (T-bet) and phosphorylated signal transducer and activator of transcription 4 protein amount were evaluated by Western blot. The impact of colonic mucosal mediators on SERT gene expression was evaluated in Caco-2 cells using qPCR. IFN-γ receptor was silenced in Caco-2 cells to determine the effect of IFN-γ released by mucosal biopsies. Compared with asymptomatic controls (ACs), the expression of IFN-γ gene and its transcription factor T-bet were markedly increased in the colonic mucosa of patients with IBS. Compared with ACs, IFN-γ protein tissue levels and its release by mucosal biopsies were significantly increased in IBS. The exposure of Caco-2 cells to IBS supernatants induced a significant decrease in SERT gene expression, independently of IBS subtypes, compared with AC mucosal supernatants. In Caco-2 cells, IFN-γ receptor silencing reversed the reduction of SERT expression evoked by IBS supernatants vs. nonsilenced cell lines. IFN-γ gene, its transcription factor T-bet, IFN-γ protein expression, and its release are increased in the colonic mucosa of patients with IBS and downregulate SERT gene expression in vitro. These results suggest that IFN-γ downregulates SERT expression, hence likely playing a role in altered serotonin metabolism of patients with IBS.
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Bertrand, Paul P., Xiaoya Hu, John Mach, and Rebecca L. Bertrand. "Serotonin (5-HT) release and uptake measured by real-time electrochemical techniques in the rat ileum." American Journal of Physiology-Gastrointestinal and Liver Physiology 295, no. 6 (December 2008): G1228—G1236. http://dx.doi.org/10.1152/ajpgi.90375.2008.
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Serotonin (5-HT) is released from the enterochromaffin cells and plays an important role in regulating intestinal function. Although the release of 5-HT is well documented, the contribution of the serotonin reuptake transporter (SERT) to the levels and actions of 5-HT in the intestine is unclear. This study aimed to demonstrate real-time SERT activity in ileal mucosa and to assess the effects of SERT inhibition using fluoxetine. Electrochemical recordings were made from the mucosa in full-thickness preparations of rat ileum using a carbon fiber electrode to measure 5-HT oxidation current and a force transducer to record circular muscle (CM) tension. Compression of the mucosa stimulated a peak 5-HT release of 12 ± 6 μM, which decayed to 7 ± 4 μM. Blockade of SERT with fluoxetine (1 μM) increased the peak compression-evoked release to 19 ± 9 μM, and the background levels of 5-HT increased to 11 ± 7 μM ( P < 0.05, n = 7). When 5-HT was exogenously applied to the mucosa, fluoxetine caused a significant increase in the time to 50% and 80% decay of the oxidation current. Fluoxetine also increased the spontaneous CM motility ( P < 0.05; n = 7) but did not increase the CM contraction-evoked 5-HT release ( P > 0.05, n = 5). In conclusion, this is the first characterization of the real-time uptake of 5-HT into the rat intestine. These data suggest that SERT plays an important role in the modulation of 5-HT concentrations that reach intestinal 5-HT receptors.
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Bertrand, R. L., S. Senadheera, I. Markus, L. Liu, L. Howitt, H. Chen, T. V. Murphy, S. L. Sandow, and P. P. Bertrand. "A Western Diet Increases Serotonin Availability in Rat Small Intestine." Endocrinology 152, no. 1 (January 1, 2011): 36–47. http://dx.doi.org/10.1210/en.2010-0377.
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Abstract Diet-induced obesity is associated with changes in gastrointestinal function and induction of a mild inflammatory state. Serotonin (5-HT) containing enterochromaffin (EC) cells within the intestine respond to nutrients and are altered by inflammation. Thus, our aim was to characterize the uptake and release of 5-HT from EC cells of the rat ileum in a physiologically relevant model of diet-induced obesity. In chow-fed (CF) and Western diet–fed (WD) rats electrochemical methods were used to measure compression evoked (peak) and steady state (SS) 5-HT levels with fluoxetine used to block the serotonin reuptake transporter (SERT). The levels of mRNA for tryptophan hydroxylase 1 (TPH1) and SERT were determined by quantitative PCR, while EC cell numbers were determined immunohistochemically. In WD rats, the levels of 5-HT were significantly increased (SS: 19.2±3.7 μm; peak: 73.5±14.1 μm) compared with CF rats (SS: 12.3±1.8 μm; peak: 32.2±7.2 μm), while SERT-dependent uptake of 5-HT was reduced (peak WD: 108% of control versus peak CF: 212% control). In WD rats, there was a significant increase in TPH1 mRNA, a decrease in SERT mRNA and protein, and an increase in EC cells. In conclusion, our data show that foods typical of a Western diet are associated with an increased 5-HT availability in the rat ileum. Increased 5-HT availability is driven by the up-regulation of 5-HT synthesis genes, decreased re-uptake of 5-HT, and increased numbers and/or 5-HT content of EC cells which are likely to cause altered intestinal motility and sensation in vivo.
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Bertrand, R. L., S. Senadheera, A. Tanoto, K. L. Tan, L. Howitt, H. Chen, T. V. Murphy, S. L. Sandow, L. Liu, and P. P. Bertrand. "Serotonin availability in rat colon is reduced during a Western diet model of obesity." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 3 (August 1, 2012): G424—G434. http://dx.doi.org/10.1152/ajpgi.00048.2012.
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Constipation and slowed transit are associated with diet-induced obesity, although the mechanisms by which this occurs are unclear. Enterochromaffin (EC) cells within the intestinal epithelium respond to mechanical stimulation with the release of serotonin [5-hydroxytryptamine (5-HT)], which promotes transit. Thus our aim was to characterize 5-HT availability in the rat colon of a physiologically relevant model of diet-induced obesity. EC cell numbers were determined immunohistochemically in chow-fed (CF) and Western diet-fed (WD) rats, while electrochemical methods were used to measure mechanically evoked (peak) and steady-state (SS) 5-HT levels. Fluoxetine was used to block the 5-HT reuptake transporter (SERT), and the levels of mRNA for tryptophan hydroxylase 1 and SERT were determined by quantitative PCR, and SERT protein was determined by Western blot. In WD rats, there was a significant decrease in the total number of EC cells per crypt (0.86 ± 0.06 and 0.71 ± 0.05 in CF and WD, respectively), which was supported by a reduction in the levels of 5-HT in WD rats (2.9 ± 1.0 and 10.5 ± 2.6 μM at SS and peak, respectively) compared with CF rats (7.3 ± 0.4 and 18.4 ± 3.4 μM at SS and peak, respectively). SERT-dependent uptake of 5-HT was unchanged, which was supported by a lack of change in SERT protein levels. In WD rats, there was no change in tryptophan hydroxylase 1 mRNA but an increase in SERT mRNA. In conclusion, our data show that foods typical of a WD are associated with decreased 5-HT availability in rat colon. Decreased 5-HT availability is driven primarily by a reduction in the numbers and/or 5-HT content of EC cells, which are likely to be associated with decreased intestinal motility in vivo.
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Martín, Abraham, Boguslaw Szczupak, Vanessa Gómez-Vallejo, Sandra Plaza, Daniel Padró, Ainhoa Cano, and Jordi Llop. "PET Imaging of Serotoninergic Neurotransmission with [11C]DASB and [18F]altanserin after Focal Cerebral Ischemia in Rats." Journal of Cerebral Blood Flow & Metabolism 33, no. 12 (August 28, 2013): 1967–75. http://dx.doi.org/10.1038/jcbfm.2013.156.
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The use of selective serotonin reuptake inhibitors has shown functional improvement after stroke. Despite this, the role of serotoninergic neurotransmission after cerebral ischemia evolution and its involvement in functional recovery processes are still largely unknown. For this purpose, we performed in parallel in vivo magnetic resonance imaging and positron emission tomography (PET) with [11C]DASB and [18F]altanserin at 1, 3, 7, 14, 21, and 28 days after middle cerebral artery occlusion (MCAO) in rats. In the ischemic territory, PET with [11C]DASB and [18F]altanserin showed a dramatic decline in serotonin transporter (SERT) and 5-HT2A binding potential in the cortex and striatum after cerebral ischemia. Interestingly, a slight increase in [11C]DASB binding was observed from days 7 to 21 followed by the uppermost binding at day 28 in the ipsilateral midbrain. In contrast, no changes were observed in the contralateral hemisphere by using both radiotracers. Likewise, both functional and behavior testing showed major impaired outcome at day 1 after ischemia onset followed by a recovery of the sensorimotor function and dexterity from day 21 to day 28 after cerebral ischemia. Taken together, these results might evidence that SERT changes in the midbrain could have a key role in the functional recovery process after cerebral ischemia.
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Milind Thorat, Vandana, Chitra C Khanwelkar, Somnath Mallikarjun Matule, Pratibha Satish Salve, Smita Ajit Surle-Patil, and Seshla Sadanandan. "Effect of Duloxetine Pretreatment on 5-HTP and Dexfenfluramine Induced Behaviours in Albino Rats." Biomedical & Pharmacology Journal 12, no. 3 (August 30, 2019): 1339–43. http://dx.doi.org/10.13005/bpj/1762.
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Activation of central brain serotonergic receptors viz 5-HT1A and 5-HT2A by serotonin (5-HT) induces the 5-HT behavioural syndrome in rats. 5-HTP and dexfenfluramine produce 5-HT mediated behaviours. We have carried out the experiment with the aim to study the effect of duloxetine pretreatment on 5-hydroxytryptophan and dexfenfluramine induced behaviours in albino rats. Pre-treatment with 20 mg/kg duloxetine, a SNRI was found to potentiate 75 mg/kg 5-HTP mediated behavioural syndrome. However, 5, 10 and 20 mg/kg duloxetine had decreased the intensity of the behavioral syndrome produced by 10 mg/kg dexfenfluramine significantly. Duloxetine at 5, 10 and 20 mg/kg had produced inhibition of serotonin transporter (SERT) and inhibited dexfenfluramine uptake which had significantly antagonised its behavioural syndrome. Duloxetine at 5 and 10 mg/kg did not affect 5-HTP induced behavioral syndrome significantly where as 20 mg/kg duloxetine did significantly potentiate 5-HTP induced behavioral syndrome. This indicates 20 mg/kg dose of duloxetine blocks neuronal reuptake of 5-HT by blocking SERT and effectively increase its concentration to greater level in the synaptic gap which causes synergistic stimulation of the central postsynaptic 5-HT1A and 5-HT2A receptors and potentiation of 5-HTP behavioral syndrome.
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Olusakin, Jimmy, Imane Moutkine, Sylvie Dumas, Evgeni Ponimaskin, Eleni Paizanis, Mariano Soiza-Reilly, and Patricia Gaspar. "Implication of 5-HT7 receptor in prefrontal circuit assembly and detrimental emotional effects of SSRIs during development." Neuropsychopharmacology 45, no. 13 (July 20, 2020): 2267–77. http://dx.doi.org/10.1038/s41386-020-0775-z.
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Abstract Altered development of prefrontal cortex (PFC) circuits can have long-term consequences on adult emotional behavior. Changes in serotonin homeostasis during critical periods produced by genetic or pharmacological inactivation of the serotonin transporter (SERT, or Slc6a4), have been involved in such developmental effects. In mice, selective serotonin reuptake inhibitors (SSRIs), administered during postnatal development cause exuberant synaptic connectivity of the PFC to brainstem dorsal raphe nucleus (DRN) circuits, and increase adult risk for developing anxiety and depressive symptoms. SERT is transiently expressed in the glutamate neurons of the mouse PFC, that project to the DRN. Here, we find that 5-HTR7 is transiently co-expressed with SERT by PFC neurons, and it plays a key role in the maturation of PFC-to-DRN synaptic circuits during early postnatal life. 5-HTR7-KO mice show reduced PFC-to-DRN synaptic density (as measured by array-tomography and VGLUT1/synapsin immunocytochemistry). Conversely, 5-HTR7 over-expression in the developing PFC increased PFC-to-DRN synaptic density. Long-term consequences on depressive-like and anxiogenic behaviors were observed in adults. 5-HTR7 over-expression in the developing PFC, results in depressive-like symptoms in adulthood. Importantly, the long-term depressive-like and anxiogenic effects of SSRIs (postnatal administration of fluoxetine from P2 to P14) were not observed in 5-HTR7-KO mice, and were prevented by co-administration of the selective inhibitor of 5-HTR7, SB269970. This study identifies a new role 5-HTR7 in the postnatal maturation of prefrontal descending circuits. Furthermore, it shows that 5-HTR7 in the PFC is crucially required for the detrimental emotional effects caused by SSRI exposure during early postnatal life.
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Javkar, T., M. Paul, A. Stanisz, and P. Forsythe. "A119 AN EX VIVO MODEL TO STUDY THE GUT SEROTONERGIC SYSTEM RESPONSE TO LIVE AND HEAT-KILLED LACTOBACILLUS RHAMNOSUS STRAIN JB-1." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 138–40. http://dx.doi.org/10.1093/jcag/gwz047.118.
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Abstract Background Enterochromaffin (EC) cells are one of the most abundant enteroendocrine cells in the intestinal epithelium, responsible for producing and storing the largest pool of serotonin or 5-hydroxytryptamine (5-HT) in the body. 5-HT has been shown to be important for modulating a large number of gastrointestinal reflexes in health and disease. 5-HT can stimulate extrinsic (vagal and spinal afferents) or intrinsic primary afferent neurons (IPANs) which are involved in motility, secretion and vasodilation within the intestines. Where EC cell localized enzyme tryptophan hydroxylase (TpH) isoform 1 is responsible for 5-HT synthesis, serotonin reuptake transporter (Sert) and monoamine oxidase A (Mao A) are responsible for termination by uptake and metabolism of 5-HT respectively. Our previous research has demonstrated the effects Lactobacillus rhamnosus (JB-1) on the firing frequency of spinal nerve fibres and motility. Increasing interest is being focused on potential health benefits of heat-inactivated microbes and purified bacterial components. However, the effect of these heat-killed bacteria on the intestinal epithelium cells, particularly on EC cells, is unknown. Aims Small intestinal organoids are shown to recapitulate in vivo characteristics of the small intestine epithelium. The present study aims to assess the suitability of intestinal organoids to study bacterial effects on the serotonergic system in the gut. Here we determined changes in the gene expression of key mediators in the serotonergic system [serotonin reuptake transporter (Sert), tryptophan hydroxylase-1 (Tph-1) and monoamine oxidase A (Mao A)] in response to live and heat-killed JB-1. Methods Male C57bl/6 mice aged 6–8 weeks were used for both ex vivo and in vivo experiments. Jejunal organoids were grown from whole crypts isolated using DTT-EDTA solution. Live and heat-killed JB-1 bacteria were used as treatments. Gene expression analysis was performed on jejunal organoids and jejunum tissue using qRT-PCR. Results JB-1 induced a significant increase in gene expression of Sert, Mao A and Tph-1. No significant difference was observed between the effects of live and heat-killed bacteria. In contrast the JB-1 increased expression of the peptide hormone CCK. Effects of JB-1 on gene expression in organoid culture were reflective of changes observed in in vivo experiments involving feeding of the bacteria. Conclusions Ex vivo organoid culture could be a useful tool in studying mechanisms underlying bacterial effects on serotonergic signalling. The observation that heat-killed bacteria produced comparable effects to the live organism suggests the possibility of isolating active 5-HT modulating components from these strains. Future research will focus on identifying such bacterial components and how their effects on gene expression influence serotonin availability Funding Agencies None
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Owens, Michael J., and Jerrold F. Rosenbaum. "Escitalopram: A Second-Generation SSRI." CNS Spectrums 7, S1 (April 2002): 34–39. http://dx.doi.org/10.1017/s1092852900028583.
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ABSTRACTSerotonin (5-hydroxytryptamine, 5-HT) has long been suspected to play a role in the etiology of depression, and modern neurochemical techniques have confirmed this suspicion. Furthermore, all drugs known to be selective (a relative term) serotonin transporter (SERT) inhibitors are effective antidepressants. Of the selective serotonin reuptake inhibitors (SSRIs) approved in a number of countries for use in depression, panic disorder, and obsessive-compulsive disorder, citalopram is the most selective. Citalopram has been used worldwide to treat an estimated 35 million patients, with an excellent safety record. Citalopram is a racemic drug, and its effects on serotonin transport are thought to reside in the S-enantiomer, known as (S)-citalopram or escitalopram. Escitalopram is the most selective SSRI yet developed. Its receptor binding properties and activity in preclinical animal models of depression predict that escitalopram would be effective in the treatment of depression, with approximately twice the potency of the racemate. The pivotal clinical trials of escitalopram not only support this conclusion, but also suggest escitalopram possesses advantages over citalopram in terms of both efficacy and safety. In conclusion, escitalopram is a promising candidate for use as a first-line antidepressant.
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Cirrito, John R., Clare E. Wallace, Ping Yan, Todd A. Davis, Woodrow D. Gardiner, Brookelyn M. Doherty, Diana King, Carla M. Yuede, Jin-Moo Lee, and Yvette I. Sheline. "Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model." Neurology 95, no. 19 (September 10, 2020): e2666-e2674. http://dx.doi.org/10.1212/wnl.0000000000010733.
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BackgroundSeveral neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into β-amyloid (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aβ levels in mice.ObjectivesWe hypothesized that acute treatment with escitalopram would reduce Aβ generation, which would be reflected chronically with a significant reduction in Aβ plaque load.MethodsWe performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically.ResultsEscitalopram acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.ConclusionsEscitalopram significantly reduced Aβ in mice, similar to previous findings in humans treated with acute dosing of an SSRI.
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Zhang, Shiquen, Baoman Li, Ditte Lovatt, Junnan Xu, Dan Song, Steven A. Goldman, Maiken Nedergaard, Leif Hertz, and Liang Peng. "5-HT2B receptors are expressed on astrocytes from brain and in culture and are a chronic target for all five conventional ‘serotonin-specific reuptake inhibitors’." Neuron Glia Biology 6, no. 2 (May 2010): 113–25. http://dx.doi.org/10.1017/s1740925x10000141.
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In well-differentiated primary cultures of mouse astrocytes, which express no serotonin transporter (SERT), the ‘serotonin-specific reuptake inhibitor’ (SSRI) fluoxetine leads acutely to 5-HT2B receptor-mediated, transactivation-dependent phosphorylation of extracellular regulated kinases 1/2 (ERK1/2) with an EC50 of ~5 μM, and chronically to ERK1/2 phosphorylation-dependent upregulation of mRNA and protein expression of calcium-dependent phospholipase A2 (cPLA2) with ten-fold higher affinity. This affinity is high enough that fluoxetine given therapeutically may activate astrocytic 5-HT2B receptors (Li et al., 2008, 2009). We now confirm the expression of 5-HT2B receptors in astrocytes freshly dissociated from mouse brain and isolated by fluorescence-activated cell sorting (FACS) and investigate in cultured cells if the effects of fluoxetine are shared by all five conventional SSRIs with sufficiently high affinity to be relevant for mechanism(s) of action of SSRIs. Phosphorylated and total ERK1/2 and mRNA and protein expression of cPLA2a were determined by Western blot and reverse transcription polymerase chain reaction (RT-PCR). Paroxetine, which differs widely from fluoxetine in affinity for SERT and for another 5-HT2 receptor, the 5-HT2C receptor, acted acutely and chronically like fluoxetine. One micromolar of paroxetine, fluvoxamine or sertraline increased cPLA2a expression during chronic treatment; citalopram had a similar effect at 0.1–0.5 μM; these are therapeutically relevant concentrations.
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Xiong, Tingting, Jun Gao, Gintautas Grabauskas, and Chung Owyang. "Mo1565 MUCOSAL SEROTONIN REUPTAKE TRANSPORTER (SERT) EXPRESSION IS MODULATED BY GUT MICROBIOTA VIA MAST CELL-COX2 PATHWAY IN IBS." Gastroenterology 158, no. 6 (May 2020): S—897. http://dx.doi.org/10.1016/s0016-5085(20)32930-9.
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McEuen, Jonathan G., Katharine A. Semsar, Maria A. Lim, and Tracy L. Bale. "Influence of Sex and Corticotropin-Releasing Factor Pathways as Determinants in Serotonin Sensitivity." Endocrinology 150, no. 8 (April 2, 2009): 3709–16. http://dx.doi.org/10.1210/en.2008-1721.
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Stress sensitivity and sex are predictive factors in affective disorder susceptibility. Serotonin (5-HT) pathway recruitment by corticotropin-releasing factor (CRF) during stress is necessary in adaptive coping behaviors, but sex differences in such responses have not been investigated. Using selective 5-HT reuptake inhibitor (SSRI) administration to acutely elevate 5-HT in a genetic model of stress sensitivity, we examined behavioral and physiological responses in male and female stress-sensitive CRF receptor-2-deficient (R2KO) mice. Chronic SSRI treatment was used to confirm outcomes were specific to acute 5-HT elevation and not antidepressant efficacy. We hypothesized that R2KO mice would show a greater sensitivity to acute changes in 5-HT and that, because females typically are more stress sensitive, R2KO females would be the most responsive. Our results supported this hypothesis because females of both genotypes and R2KO males showed a greater sensitivity to an acute 10 mg/kg dose of citalopram in a tail suspension test, displaying decreased immobile time and increased latency to immobility. Furthermore, acute citalopram promoted significant anxiogenic-like effects that were specific to R2KO females in the elevated plus maze and light-dark box tests. Chronic citalopram did not produce these behavioral changes, supporting specificity to acute 5-HT modulation. Mechanistically, females had decreased hippocampal 5-HT transporter (SERT) levels, whereas R2KO mice showed reduced SERT in the prefrontal cortex, supporting a possible intersection of sex and genotype where R2KO females would have the lowest SERT to be blocked by the SSRI. This sensitivity to 5-HT-mediated anxiety in females may underlie a heightened vulnerability to stress-related affective disorders.
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Uebelhack, K., L. Franke, N. Herold, M. Plotkin, H. Amthauer, and R. Uebelhack. "Gender Differences in [123I]-ADAM Binding to Serotonin Transporters in Patients with Major Depression Before and After Treatment with Citalopram." European Psychiatry 24, S1 (January 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70937-x.
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Aims:The aim was to determine the relation between characteristics of [123I]-ADAM binding to serotonin transporters (SERT) in several brain regions to different symptoms in patients diagnosed with major depressive disorder (MDD) and to analyze data for males and females separately. Differences of [123I]-ADAM binding in patients before and after treatment with Selective Serotonin Reuptake Inhibitor (SSRI) antidepressant Citalopram were assessed.Method:12 non medicated patients (5 females and 7 males) diagnosed with MDD were examined by SPECT with specific Serotonin transporter radioligand [123I]-ADAM before and after treatment with SSRI Citalopram. We administered the dose of 10 mg Citalopram per day intravenously at first day, followed by a 6 days period of oral application. After 7 days of treatment patients were examined for second time with SPECT. The relationships between [123I]-ADAM binding and different aspects of major depression represented by HAMD items, assessed twice by Hamilton Depression-Scale (HAMD) once at baseline and second after treatment period, were evaluated.Results:We found significant correlations with significant gender differences between singular sub items of HAMD and indices of [123I]-ADAM binding in midbrain before and after treatment. These findings points to the need of data analysis separately in males and females. No correlations between HAMD total scores at baseline and indices were found.Conclusion:SERT availability for 123-ADAM binding in the midbrain in drug naives as well as in treated patients with major depression disorder seems to be related to intensity of sub items in the HAMD and the outcome of treatment.