Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT)

54739-18-3

CJOFXWAVKWHTFT-XSFVSMFZSA-N

Fluvoxamine

1-Pentanone, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-, O-(2-aminoethyl)oxime, (1E)-

DTXSID2044002

PR:000015189

PR sodium-dependent serotonin transporter

GO:0005576

GO extracellular region

CHEBI:28790

CHEBI serotonin

FMA:86594

FMA Surface of brain

PR:000001161

PR 5-hydroxytryptamine receptor 1A

PR:000001168

PR 5-hydroxytryptamine receptor 2C

GO:0098810

GO neurotransmitter reuptake

GO:0051610

GO serotonin uptake

MP:0010069

MP increased serotonin level

GO:0099589

GO serotonin receptor activity

GO:0007210

GO serotonin receptor signaling pathway

NBO:0000079

NBO feeding behavior

WIKI decreased

WIKI increased

SSRI (Selective serotonin reuptake inhibitor)

2017-04-13T15:32:43

Fluoxetine

2016-11-29T18:42:27

Fluvoxamine

2016-11-29T18:42:27

WikiUser_26

ApacheUser rodents

WikiUser_6

ApacheUser fish

33208

NCBI Animals

Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT)

Molecular

Inhibitors of the serotonin reuptake transporter (SERT; 5-hydroxytryptamine transporter; 5-HTT) block the reuptake of the neurotransmitter serotonin, increasing its residence time in synapses (McDonald 2017; Correira et al. 2023).  Selective serotonin reuptake inhibitor (SSRI) antidepressants are a class of compounds known to inhibit serotonin reuptake transporter activity (McDonald 2017).

<ul> <li>Toxcast assays that target the serotonin transporter (5-HTT; SERT) gene SLC6A4 include: NVS_TR_rSERT,NVS_TR_rSERT.  </li> <li>SERT activity can be measured by the rate of uptake of radiolabeled compounds into cells, with development of fluorescent dyes a recent development (Persson et al. 2023).  </li> <li>Real time PCR can be used to measure transcript abundance of genes for SERT, which is an indirect – and only semi-quantitative indicator of protein abundance.   </li> <li>Serotonin concentrations can be measured via microdialysis/high-performance liquid chromatography, fast-scan cyclic voltammetry, N-Shaped Multiple Cyclic Square Wave Voltammetry, and Fast-Scan Controlled-Adsorption Voltammetry (Rojas Cabrera et al. 2023).</li> </ul>

CL:0000100

CL motor neuron

High Unspecific

Moderate

All life stages

High High

Correia, D., Domingues, I., Faria, M., and Oliveira, M.  2023.  Effects of fluoxetine on fish: What do we know and where should we focus our efforts in the future?  Science of the Total Environment 857: 159486. McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. Persson, M., Vikingsson, S., Kronstrand, R., and Green, H. 2023.  Characterization of neurotransmitter inhibition for seven cathinones by a proprietary fluorescent dye method. Drug Testing and Analysis 16(4): 339-347. Rojas Cabrera, J.M., Oesterle, T.S., Rusheen, A.E., Goyal, A., Scheitler, K.M., Mandybur, I., Blaha, C.D., Bennet, K.E., Heien, M.L., Jang, D.P., Lee, K.H., Oh, Y., and Shin, H. 2023. Techniques for Measurement of Serotonin: Implications in Neuropsychiatric Disorders and Advances in Absolute Value Recording Methods. ACS Chemical Neuroscience 14(24): 4264-4273. NOTE: Italics indicate edits from John Frisch January 2025.   AOPWiki 2016-11-29T18:41:25

2025-02-24T08:34:09

Increased, extracellular serotonin

Molecular

Extracellular serotonin levels are determined by a balance between the synthesis from tryptophan in cells, release into the synaptic cleft, reuptake into cells by serotonin reuptake transporter (SERT; 5-hydroxytryptamine transporter; 5-HTT), and breakdown to 5-hydroxindile acetic acid (5-HIAA) (Conde et al. 2023).  Selective serotonin reuptake inhibitor (SSRI) antidepressants are a class of compounds known to inhibit serotonin reuptake transporter activity and increase extracellular serotonin levels (McDonald 2017).

Serotonin concentrations can be measured via microdialysis/high-performance liquid chromatography, fast-scan cyclic voltammetry, N-Shaped Multiple Cyclic Square Wave Voltammetry, and Fast-Scan Controlled-Adsorption Voltammetry (Rojas Cabrera et al. 2023).

Life Stage: Applies to all life stages with developed brain and central nervous systems. Sex: Applies to both males and females. Taxonomic: Primarily studied in laboratory rodents, humans, and fish.  Serotonin is present in diverse taxa from bacteria to plants to animals (Goncalves et al. 2022).

High Unspecific

Moderate

All life stages

High High

Conde, K., Fang, S. and Xu, Y. 2023.  Unraveling the serotonin saga: from discovery to weight regulation and beyond - a comprehensive scientific review. Cell and Bioscience 13: 143. Goncalves, S., Nunes-Costa, D.N., Cardoso, S.M., Empadinhas, N., and Marugg, J.D.  2022.  Enzyme Promiscuity in Serotonin Biosynthesis, From Bacteria to Plants and Humans.  Frontiers in Microbiology 13: 873555. McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. Rojas Cabrera, J.M., Oesterle, T.S., Rusheen, A.E., Goyal, A., Scheitler, K.M., Mandybur, I., Blaha, C.D., Bennet, K.E., Heien, M.L., Jang, D.P., Lee, K.H., Oh, Y., and Shin, H. 2023. Techniques for Measurement of Serotonin: Implications in Neuropsychiatric Disorders and Advances in Absolute Value Recording Methods. ACS Chemical Neuroscience 14(24): 4264-4273. NOTE: Italics indicate edits from John Frisch January 2025.   AOPWiki 2017-04-13T14:20:14

2025-02-13T14:30:44

Increased, stimulation of brain serotonin 5-HT1a, 5-HT2c receptors

Organ

Serotonin (5-HT) is a neurotransmitter which stimulates pathways resulting in a variety of downstream behavior effects (McDonald 2017; Ramsteijn et al. 2020).  Activation of different pathways is mediated by different receptors located in different tissue types, with serotonin receptors classified into 7 families and 14 receptor subtypes (McDonald 2017; Barnes et al. 2021).   Increased levels of serotonin result in increased stimulation of serotonin 5-HT1a, 5-HT2c receptors located in brain tissue.  In the brain, 5-HT1a receptors have been found in the septum, thalamus, hippocampus, entorhinal cortex, interpeduncular nucleus, olfactory bulb, amygdala, hypothalamic subnuclei, and subareas of the cortex and raphe nuclei (Barnes et al. 2021).  In the brain, 5-HT2c receptors have been found in choroid plexus, the basal ganglia, limbic system, and prefrontal cortex (Barnes et al. 2021).

Stimulation of brain 5-HT1a, 5-HT2c receptors have been studied by a variety of techniques including radiolabeled compounds, receptor binding, real time PCR, in situ hybridization, Western and Northern blotting, and immunohistochemistry (Barnes et al. 2021).  Stimulation of brain 5-HT1a, 5-HT2c receptors by serotonin (5-HT) is often measured indirectly by use of antagonist compounds to block activation of receptors (methysergide for 5-HT1/5-HT2 in Ortega et al. 2013, 8-OH-DPAT for 5-HT1a in Perez-Maceira et al. 2014 and Perez-Maceria et al. 2016; MK212 for 5-HT2c in Perez-Maceira et al. 2014 and Perez-Maceria et al. 2016; WAY 161503 for 5-HT2c in Perez-Maceria et al. 2016; overview of compounds in Barnes et al. 2021).

Life Stage: Applies to all life stages with developed brain and central nervous systems. Sex: Applies to both males and females. Taxonomic: Primarily studied in laboratory rodents, humans, and fish.  Plausible to be applicable in a wide variety of invertebrate and vertebrate taxa due to functional conservation of serotonin pathways (Bacque-Cazenave et al. 2020).

UBERON:0000955

UBERON brain

High Unspecific

Moderate

All life stages

Moderate Moderate

Bacque-Cazenave, J., Bharatiya, R., Barriere, G., Delbecque, J.-P., Bouguiyoud, N., Di Giovanni, G., Cattaert, D., and De Deurwaerdere, P.  2020. Serotonin in Animal Cognition and Behavior.  International Journal of Molecular Sciences 21(5): 1649. Barnes, N.M., Ahern, G.P., Becamel, C., Bockaert, J., Camilleri, M., Chaumont-Dubel, S., Claeysen, S., Cunningham, K.A., Fone, K.C., Gershon, M., Di Giovanni, G., Goodfellow, N.M., Halberstadt, A.L., Hartley, R.M., Hassaine, G., Herrick-Davis, K., Hovius, R., Lacivita, E., Lambe, E..K, Leopoldo, M., Levy, F.O., Lummis, S.C.R, Marin, P., Maroteaux, L., McCreary, A.C., Nelson, D.L., Neumaier, J.F., Newman-Tancredi, A., Nury, H., Roberts, A., Roth, B.L., Roumier, A., Sanger, G.J., Teitler, M., Sharp, T., Villalon, C.M., Vogel, H., Watts, S.W., and  Hoyer, D. 2021.  International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function. Pharmacological Reviews 73(1): 310-520. McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. Ortega, V.A., Lovejoy, D.A., and Bernier, N.J.  2013.   Appetite-suppressing effects and interactions of centrally administered corticotropin-releasing factor, urotensin I and serotonin in rainbow trout (Oncorhynchus mykiss).  Frontiers in Neuroscience 7: 196. Perez-Maceira, J.J., Mancebo, M.J., and Aldegunde, M.  2014.  The involvement of 5-HT-like receptors in the regulation of food intake in rainbow trout (Oncorhynchus mykiss).  Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 161: 1–6. Perez-Maceira, J.J., Otero-Rodino, C., Mancebo, M.J., Soengas, J.L., and Aldegunde, M.  2016.  Food intake inhibition in rainbow trout induced by activation of serotonin 5‑HT2C receptors is associated with increases in POMC, CART and CRF mRNA abundance in hypothalamus.  Comparative Biochemistry and Physiology, Part B-Biochemical Systems and Environmental Physiology 186(3): 313-321. Ramsteijn A.S., Van de Wijer, L., Rando, J., van Luijk, J., Homberg, J.R., and Olivier, J.D.A. 2020.  Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies. Neuroscience and Biobehavior Reviews 114: 53–69. NOTE: Italics symbolize edits from John Frisch January 2025.   AOPWiki 2025-01-14T08:44:13

2025-02-13T15:57:40

Inhibition, Feeding

Individual

Inhibition of feeding is caused by appetite suppression from brain signals, a reduced ability to capture prey, increased lethargy, and reduction in locomotion activity (McDonald 2017).

Inhibition of feeding is measured in the short-term by decreased consumption of available food by weight of food ingested, and for extended periods by decreased weight gain or weight loss.

Life Stage: All life stages. Sex: Applies to both males and females. Taxonomic: Animals.

High Unspecific

Moderate

All life stages

High

McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. NOTE: Italics indicate edits from John Frisch January 2025.   AOPWiki 2016-11-29T18:41:28

2025-01-14T10:26:08

<upstream-id>599e2ded-f838-4e06-9c72-e0592ded6736</upstream-id> <downstream-id>84a01831-42b8-496c-86fd-6c3898c03ad9</downstream-id> 5-hydroxytryptamine transporter (5-HTT; SERT) is responsible for transporting serotonin through presynaptic receptors into nerve cells (Correia et al. 2023).  When 5-hydroxytryptamine transporter activity is inhibited, serotonin reuptake is diminished, resulting in increased extracellular serotonin levels.

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  McDonald (2017) focused on using an Adverse Outcome Pathway framework to examine inhibition of 5-hydroxytryptamine transporters in fish by selective serotonin reuptake inhibitor (SSRI) toxicants, to review known roles of serotonin receptors to explore mechanisms of action, and to determine toxicity endpoints.  McDonald (2017) used the Read-Across Hypothesis, which postulates that pharmaceuticals will cause comparable effects in different taxa if the pathways and targets are evolutionarily and functionally conserved (Rand-Weaver et al. 2013), to link effects of serotonin pathways in fish and mammals.   Cited empirical studies are focused on inhibition of 5-hydroxytryptamine transporter and resulting increased extracellular serotonin levels in fish, in support of development of AOP 568 for McDonald (2017) content.  Authors of KER 3474 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

Inhibition of 5-hydroxytryptamine transporter and resulting increased extracellular levels of serotonin has been studied in a limited number of fish systems, primarily in the laboratory of McDonald.  It can be difficult and expensive to measure small extracellular concentrations of serotonin, and measurements of serotonin and the metabolite 5-hydroxyindoleactetic acid in tissue allows for the introduction of metabolism as possible influence on serotonin concentrations in addition to inhibition of transport by 5-hydroxytryptamine transporter (McDonald 2017).  There has been more extensive study in laboratory mammals (see Ramsteijn et al. 2020 for review).  In fish, SSRI injection studies have shown a consistent response in inhibition of 5-hydroxytryptamine transporter leading to increased extracellular levels of serotonin.  Empirical mammal studies show additional support for the mechanism of inhibition of 5-hydroxytryptamine transporter leading to increased extracellular levels of serotonin because of the evolutionarily and functionally conserved pathways modulated by the neurotransmitter serotonin.

<table cellspacing="0" class="Table" style="border-collapse:collapse; width:683px"> <tbody> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:92px"> Species </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:61px"> Duration </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:91px"> Dose </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:77px"> Decreased 5-HTT; SERT activity? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:76px"> Increased extracellular serotonin? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:186px"> Summary </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:101px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Gulf toadfish (Opsanus beta) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:61px"> 1 day </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> 25 and 50 ug/g fluoxetine by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:186px"> Fish injected with known SSRI inhibitor fluoxetine had statistically significant increased plasma serotonin concentrations at both 25 and 50 ug/g doses tested. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> Morando et al. (2009) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Gulf toadfish (Opsanus beta) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:61px"> 1 day </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> 10 and 25 ug/g fluoxetine by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:186px"> Fish injected with known SSRI inhibitor fluoxetine had statistically significant increased plasma serotonin concentrations at both 10 and 25 ug/g doses tested. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> McDonald et al. (2011) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Gulf toadfish (Opsanus beta) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:61px"> 1 day </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> 1, 10 and 50 ug/g fluoxetine by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:186px"> Fish injected with known SSRI inhibitor fluoxetine had statistically significant increased plasma serotonin concentrations at 10 and 50 ug/g between 15-120 minutes. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> Amador and McDonald (2018) </td> </tr> </tbody> </table>

High Unspecific

Moderate

All life stages

High

Life Stage: Applies to all life stages with developed brain and central nervous systems. Sex: Applies to both males and females. Taxonomic: Studied in fish, with similarities expected in laboratory mammals and humans due to evolutionary and functional conservation of serotonin-induced pathways.

Amador, M.H.B. and McDonald, M.D.  2018.  Molecular and functional characterization of the Gulf toadfish serotonin transporter SLC6A4.  Journal of Experimental Biology 221: jeb170928. Correia, D., Domingues, I., Faria, M., and Oliveira, M.  2023.  Effects of fluoxetine on fish: What do we know and where should we focus our efforts in the future?  Science of the Total Environment 857: 159486. McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. McDonald,M.D., Gonzalez, A., and Sloman, K.A. 2011.  Higher levels of aggression are observed in socially dominant toadfish treated with the selective serotonin reuptake inhibitor, fluoxetine. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 153: 107–112. Morando, M.B., Medeiros, L.R., and McDonald, M.D.  2009. Fluoxetine treatment affects nitrogen waste excretion and osmoregulation in a marine teleost fish. Aquatic Toxicology 95: 164–171. Ramsteijn A.S., Van de Wijer, L., Rando, J., van Luijk, J., Homberg, J.R., and Olivier, J.D.A. 2020.  Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies. Neuroscience and Biobehavior Reviews 114: 53–69. Rand-Weaver, M., Margiotta-Casaluci, L., Patel, A., Panter, G.H., Owen, S.F., and Sumpter, J.P.  2013. The read-across hypothesis and environmental risk assessment of pharmaceuticals. Environmental Science Technology 47: 11384–11395. NOTE: Italics indicate edits from John Frisch January 2025.   AOPWiki 2025-01-14T09:09:24

2025-02-13T15:48:23

<upstream-id>84a01831-42b8-496c-86fd-6c3898c03ad9</upstream-id> <downstream-id>dd6c892c-d8f4-46d2-9971-c9be542ba609</downstream-id> Serotonin (5-HT) is a neurotransmitter with multiple classes of cellular receptors that regulates a variety of organism functions (for review see Barnes et al. 2021).  Increased extracellular serotonin leads to increased stimulation of brain 5-HT1a, 5-HT2c receptors.  Stimulation of brain serotonin 5-HT1a, 5-HT2c receptors leads to an anorexigenic response inhibiting feeding.

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  McDonald (2017) focused on using an Adverse Outcome Pathway framework to examine inhibition of 5-hydroxytryptamine transporters in fish by selective serotonin reuptake inhibitor (SSRI) toxicants, to review known roles of serotonin receptors to explore mechanisms of action, and to determine toxicity endpoints.  McDonald (2017) used the Read-Across Hypothesis, which postulates that pharmaceuticals will cause comparable effects in different taxa if the pathways and targets are evolutionarily and functionally conserved (Rand-Weaver et al. 2013), to link effects of serotonin pathways in fish and mammals. Cited empirical studies are focused on increased extracellular serotonin levels, resulting increased stimulation of brain 5-HT1a, 5-HT2c receptors, and inhibition of feeding in fish, in support of development of AOP 568 for McDonald  (2017) content.  Authors of KER 3489 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

Stimulation of brain 5-HT1a, 5-HT2c receptors by serotonin (5-HT) is often measured indirectly by use of antagonist compounds to block activation of receptors (methysergide for 5-HT1/5-HT2 in Ortega et al. 2013, 8-OH-DPAT for 5-HT1a in Perez-Maceira et al. 2014 and Perez-Maceria et al. 2016; MK212 for 5-HT2c in Perez-Maceira et al. 2014 and Perez-Maceria et al. 2016; WAY 161503 for 5-HT2c in Perez-Maceria et al. 2016).  Often the relationship between increased levels of serotonin and increased simulation of serotonin receptors is assumed and focus placed on downstream effects of activation of serotonin pathways and/or behavior effects (ex. feeding), with more extensive study in laboratory mammals than fish (see Ramsteijn et al. 2020 for review of mammal studies).  Empirical mammal studies show additional support for the mechanism of stimulation of brain 5-HT1a, 5-HT2c receptors by serotonin because of the evolutionarily and functionally conserved pathways modulated by the neurotransmitter serotonin.

<table cellspacing="0" class="Table" style="border-collapse:collapse; width:683px"> <tbody> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:92px"> Species </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:59px"> Duration </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:139px"> Dose </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:77px"> Increased extracellular serotonin? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:74px"> Inhibition feeding? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:157px"> Summary </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:86px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Rainbow trout (Oncorhynchus mykiss) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> 2 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> 1,10, 100 ng/g body weight serotonin, 200 ng/g body weight methysergide by intracerebroventricular injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:74px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:157px"> Immature male and female fish injected with serotonin led to statistically significant decreased food intake by 10, 100 ng/g body weight serotonin; effect was blocked by injection of 5-HT1/5-HT2 receptor antagonist methysergide. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Ortega et al. (2013) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Rainbow trout (Oncorhynchus mykiss) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> 24 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> 30 ug/kg body weight 8-OH-DPAT, 60 ug/kg body weight MK212 by intracerebroventricular injection, 1 mg/kg body weight 8-OH-DPAT by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:74px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:157px"> Immature fish injected with 5-HT1a receptor agonist 8-OH-DPAT led to statistically significant decreased food intake at 2 hours from 1 mg/kg body weight 8-OH-DPAT by intraperitoneal injection, and statistically significant decreased food intake at 4 hours from 30 ug/kg body weight 8-OH-DPAT by intracerebroventricular injection.  Immature fish injected with 5-HT2c receptor agonist MK212 led to statistically significant decreased food intake at 2 and 4 hours from 60 ug/kg body weight MK212 by intracerebroventricular injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Perez-Maceira et al. (2014) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Rainbow trout (Oncorhynchus mykiss) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> 2 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> 30 ug/kg body weight 8-OH-DPAT, 60 ug/kg body weight MK212 by intracerebroventricular injection, 1 mg/kg body weight 8-OH-DPAT, 1 mg/kg body weight WAY 161503 by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:74px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:157px"> Immature fish injected with 5-HT1a receptor agonist 8-OH-DPAT led to statistically significant decreased food intake at 2 hours from 1 mg/kg body weight 8-OH-DPAT by intraperitoneal injection and from 30 ug/kg body weight 8-OH-DPAT by intracerebroventricular injection.  Immature fish injected with 5-HT2c receptor agonists led to statistically significant decreased food intake at 2 hours from 60 ug/kg body weight MK212 by intracerebroventricular injection and from 1 mg/kg body weight WAY 161503 by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Perez-Maceira et al. (2016) </td> </tr> </tbody> </table>

High Unspecific

Moderate

All life stages

High

Life Stage: Applies to all life stages with developed brain and central nervous systems. Sex: Applies to both males and females. Taxonomic: Studied in fish, with similarities expected in laboratory mammals and humans due to evolutionary and functional conservation of serotonin-induced pathways.

Barnes, N.M., Ahern, G.P., Becamel, C., Bockaert, J., Camilleri, M., Chaumont-Dubel, S., Claeysen, S., Cunningham, K.A., Fone, K.C., Gershon, M., Di Giovanni, G., Goodfellow, N.M., Halberstadt, A.L., Hartley, R.M., Hassaine, G., Herrick-Davis, K., Hovius, R., Lacivita, E., Lambe, E..K, Leopoldo, M., Levy, F.O., Lummis, S.C.R, Marin, P., Maroteaux, L., McCreary, A.C., Nelson, D.L., Neumaier, J.F., Newman-Tancredi, A., Nury, H., Roberts, A., Roth, B.L., Roumier, A., Sanger, G.J., Teitler, M., Sharp, T., Villalon, C.M., Vogel, H., Watts, S.W., and  Hoyer, D. 2021.  International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function. Pharmacological Reviews 73(1): 310-520.  McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. Ortega, V.A., Lovejoy, D.A., and Bernier, N.J.  2013.   Appetite-suppressing effects and interactions of centrally administered corticotropin-releasing factor, urotensin I and serotonin in rainbow trout (Oncorhynchus mykiss).  Frontiers in Neuroscience 7: 196. Perez-Maceira, J.J., Mancebo, M.J., and Aldegunde, M.  2014.  The involvement of 5-HT-like receptors in the regulation of food intake in rainbow trout (Oncorhynchus mykiss).  Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 161: 1–6. Perez-Maceira, J.J., Otero-Rodino, C., Mancebo, M.J., Soengas, J.L., and Aldegunde, M.  2016.  Food intake inhibition in rainbow trout induced by activation of serotonin 5‑HT2C receptors is associated with increases in POMC, CART and CRF mRNA abundance in hypothalamus.  Comparative Biochemistry and Physiology, Part B-Biochemical Systems and Environmental Physiology 186(3): 313-321. Ramsteijn A.S., Van de Wijer, L., Rando, J., van Luijk, J., Homberg, J.R., and Olivier, J.D.A. 2020.  Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies. Neuroscience and Biobehavior Reviews 114: 53–69. NOTE: Italics indicate edits from John Frisch February 2025.   AOPWiki 2025-02-20T11:42:35

2025-02-20T11:58:03

<upstream-id>84a01831-42b8-496c-86fd-6c3898c03ad9</upstream-id> <downstream-id>5af0b46e-63ac-4945-9872-47c28afd597b</downstream-id> Serotonin (5-HT) is a neurotransmitter with multiple classes of cellular receptors that regulates a variety of organism functions (for review see Barnes et al. 2021).  Increased extracellular serotonin leads to increased stimulation of brain 5-HT1a, 5-HT2c receptors.

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  McDonald (2017) focused on using an Adverse Outcome Pathway framework to examine inhibition of 5-hydroxytryptamine transporters in fish by selective serotonin reuptake inhibitor (SSRI) toxicants, to review known roles of serotonin receptors to explore mechanisms of action, and to determine toxicity endpoints.  McDonald (2017) used the Read-Across Hypothesis, which postulates that pharmaceuticals will cause comparable effects in different taxa if the pathways and targets are evolutionarily and functionally conserved (Rand-Weaver et al. 2013), to link effects of serotonin pathways in fish and mammals. Cited empirical studies are focused on increased extracellular serotonin levels and resulting increased stimulation of brain 5-HT1a, 5-HT2c receptors in fish, in support of development of AOP 568 for McDonald  (2017) content.  Authors of KER 3475 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

Stimulation of brain 5-HT1a, 5-HT2c receptors by serotonin (5-HT) is often measured indirectly by use of antagonist compounds to block activation of receptors (methysergide for 5-HT1/5-HT2 in Ortega et al. 2013, 8-OH-DPAT for 5-HT1a in Perez-Maceira et al. 2014 and Perez-Maceria et al. 2016; MK212 for 5-HT2c in Perez-Maceira et al. 2014 and Perez-Maceria et al. 2016; WAY 161503 for 5-HT2c in Perez-Maceria et al. 2016).  Often the relationship between increased levels of serotonin and increased simulation of serotonin receptors is assumed and focus placed on downstream effects of activation of serotonin pathways and/or behavior effects, with more extensive study in laboratory mammals than fish (see Ramsteijn et al. 2020 for review of mammal studies).  Empirical mammal studies show additional support for the mechanism of stimulation of brain 5-HT1a, 5-HT2c receptors by serotonin because of the evolutionarily and functionally conserved pathways modulated by the neurotransmitter serotonin.

High Unspecific

Moderate

All life stages

High

Life Stage: Applies to all life stages with developed brain and central nervous systems. Sex: Applies to both males and females. Taxonomic: Studied in fish, with similarities expected in laboratory mammals and humans due to evolutionary and functional conservation of serotonin-induced pathways.

Barnes, N.M., Ahern, G.P., Becamel, C., Bockaert, J., Camilleri, M., Chaumont-Dubel, S., Claeysen, S., Cunningham, K.A., Fone, K.C., Gershon, M., Di Giovanni, G., Goodfellow, N.M., Halberstadt, A.L., Hartley, R.M., Hassaine, G., Herrick-Davis, K., Hovius, R., Lacivita, E., Lambe, E..K, Leopoldo, M., Levy, F.O., Lummis, S.C.R, Marin, P., Maroteaux, L., McCreary, A.C., Nelson, D.L., Neumaier, J.F., Newman-Tancredi, A., Nury, H., Roberts, A., Roth, B.L., Roumier, A., Sanger, G.J., Teitler, M., Sharp, T., Villalon, C.M., Vogel, H., Watts, S.W., and  Hoyer, D. 2021.  International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function. Pharmacological Reviews 73(1): 310-520.  McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. Ortega, V.A., Lovejoy, D.A., and Bernier, N.J.  2013.   Appetite-suppressing effects and interactions of centrally administered corticotropin-releasing factor, urotensin I and serotonin in rainbow trout (Oncorhynchus mykiss).  Frontiers in Neuroscience 7: 196. Perez-Maceira, J.J., Mancebo, M.J., and Aldegunde, M.  2014.  The involvement of 5-HT-like receptors in the regulation of food intake in rainbow trout (Oncorhynchus mykiss).  Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 161: 1–6. Perez-Maceira, J.J., Otero-Rodino, C., Mancebo, M.J., Soengas, J.L., and Aldegunde, M.  2016.  Food intake inhibition in rainbow trout induced by activation of serotonin 5‑HT2C receptors is associated with increases in POMC, CART and CRF mRNA abundance in hypothalamus.  Comparative Biochemistry and Physiology, Part B-Biochemical Systems and Environmental Physiology 186(3): 313-321. Ramsteijn A.S., Van de Wijer, L., Rando, J., van Luijk, J., Homberg, J.R., and Olivier, J.D.A. 2020.  Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies. Neuroscience and Biobehavior Reviews 114: 53–69. NOTE: Italics indicate edits from John Frisch January 2025.   AOPWiki 2025-01-14T09:09:48

2025-02-20T15:41:38

<upstream-id>5af0b46e-63ac-4945-9872-47c28afd597b</upstream-id> <downstream-id>dd6c892c-d8f4-46d2-9971-c9be542ba609</downstream-id> Stimulation of brain serotonin 5-HT1a, 5-HT2c receptors leads to an anorexigenic response inhibiting feeding.

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  McDonald (2017) focused on using an Adverse Outcome Pathway framework to examine inhibition of 5-hydroxytryptamine transporters in fish by selective serotonin reuptake inhibitor (SSRI) toxicants, to review known roles of serotonin receptors to explore mechanisms of action, and to determine toxicity endpoints.  McDonald (2017) used the Read-Across Hypothesis, which postulates that pharmaceuticals will cause comparable effects in different taxa if the pathways and targets are evolutionarily and functionally conserved (Rand-Weaver et al. 2013), to link effects of serotonin pathways in fish and mammals. Cited empirical studies are focused on increased stimulation of brain 5-HT1a, 5-HT2c receptors and resulting inhibition of feeding in fish, in support of development of AOP 568 for McDonald (2017) content.  Authors of KER 3476 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

Given the difficulty in measuring neurotransmitter activity in living organisms, and established activation of serotonin receptors by serotonin, often the relationship between increased levels of serotonin and increased simulation of serotonin receptors is assumed, and focus placed on downstream effects of activation of serotonin pathways and/or behavior effects, with more extensive study in laboratory mammals than fish (see Ramsteijn et al. 2020 for review of mammal studies).  Empirical mammal studies show additional support for the mechanism of stimulation of brain 5-HT1a, 5-HT2c receptors leading to inhibition of feeding because of the evolutionarily and functionally conserved pathways modulated by the neurotransmitter serotonin.  Use of antagonist compounds to block serotonin receptors (methysergide for 5-HT1/5-HT2 in Ortega et al. 2013, 8-OH-DPAT for 5-HT1a in Perez-Maceira et al. 2014 and Perez-Maceria 2016; MK212 for 5-HT2c in Perez-Maceira et al. 2014 and Perez-Maceria 2016; WAY 161503 for 5-HT2c in Perez-Maceria 2016) have been used to study behavioral effects on feeding.

<table cellspacing="0" class="Table" style="border-collapse:collapse; width:683px"> <tbody> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:92px"> Species </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:59px"> Duration </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:139px"> Dose </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:77px"> Increased stimulation 5-HT1a, 5-HT2c? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:74px"> Inhibition feeding? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:157px"> Summary </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:86px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Rainbow trout (Oncorhynchus mykiss) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> 2 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> 1,10, 100 ng/g body weight serotonin, 200 ng/g body weight methysergide by intracerebroventricular injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:74px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:157px"> Immature male and female fish injected with serotonin had increased brain 5-HT1a and 5-HT2c stimulation leading to statistically significant decreased food intake by 10, 100 ng/g body weight serotonin; effect was blocked by injection of 5-HT1/5-HT2 receptor antagonist methysergide. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Ortega et al. (2013) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Rainbow trout (Oncorhynchus mykiss) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> 24 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> 30 ug/kg body weight 8-OH-DPAT, 60 ug/kg body weight MK212 by intracerebroventricular injection, 1 mg/kg body weight 8-OH-DPAT by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:74px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:157px"> Immature fish injected with 5-HT1a receptor agonist 8-OH-DPAT had decreased brain 5-HT1a stimulation leading to statistically significant decreased food intake at 2 hours from 1 mg/kg body weight 8-OH-DPAT by intraperitoneal injection, and statistically significant decreased food intake at 4 hours from 30 ug/kg body weight 8-OH-DPAT by intracerebroventricular injection.  Immature fish injected with 5-HT2c receptor agonist MK212 had decreased brain 5-HT2c stimulation leading to significant decreased food intake at 2 and 4 hours from 60 ug/kg body weight MK212 by intracerebroventricular injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Perez-Maceira et al. (2014) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Rainbow trout (Oncorhynchus mykiss) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> 2 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> 30 ug/kg body weight 8-OH-DPAT, 60 ug/kg body weight MK212 by intracerebroventricular injection, 1 mg/kg body weight 8-OH-DPAT, 1 mg/kg body weight WAY 161503 by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:74px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:157px"> Immature fish injected with 5-HT1a receptor agonist 8-OH-DPAT had decreased brain 5-HT1a stimulation leading to statistically significant decreased food intake at 2 hours from 1 mg/kg body weight 8-OH-DPAT by intraperitoneal injection and from 30 ug/kg body weight 8-OH-DPAT by intracerebroventricular injection.  Immature fish injected with 5-HT2c receptor agonists had decreased brain 5-HT2c stimulation leading to statistically significant decreased food intake at 2 hours from 60 ug/kg body weight MK212 by intracerebroventricular injection and from 1 mg/kg body weight WAY 161503 by intraperitoneal injection. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Perez-Maceira et al. (2016) </td> </tr> </tbody> </table>

High Unspecific

Moderate

All life stages

High

Life Stage: Applies to all life stages with developed brain and central nervous systems. Sex: Applies to both males and females. Taxonomic: Studied in fish, with similarities expected in laboratory mammals and humans due to evolutionary and functional conservation of serotonin-induced pathways.

McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. Ortega, V.A., Lovejoy, D.A., and Bernier, N.J.  2013.   Appetite-suppressing effects and interactions of centrally administered corticotropin-releasing factor, urotensin I and serotonin in rainbow trout (Oncorhynchus mykiss).  Frontiers in Neuroscience 7: 196. Perez-Maceira, J.J., Mancebo, M.J., and Aldegunde, M.  2014.  The involvement of 5-HT-like receptors in the regulation of food intake in rainbow trout (Oncorhynchus mykiss).  Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 161: 1–6. Perez-Maceira, J.J., Otero-Rodino, C., Mancebo, M.J., Soengas, J.L., and Aldegunde, M.  2016.  Food intake inhibition in rainbow trout induced by activation of serotonin 5‑HT2C receptors is associated with increases in POMC, CART and CRF mRNA abundance in hypothalamus.  Comparative Biochemistry and Physiology, Part B-Biochemical Systems and Environmental Physiology 186(3): 313-321. Ramsteijn A.S., Van de Wijer, L., Rando, J., van Luijk, J., Homberg, J.R., and Olivier, J.D.A. 2020.  Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies. Neuroscience and Biobehavior Reviews 114: 53–69. NOTE: Italics indicate edits from John Frisch January 2025.   AOPWiki 2025-01-14T09:10:01

2025-02-20T16:04:35

Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Inhibition, Feeding

John Frisch

Of the originating work: M. Danielle McDonald, University of Miami, Florida. Of the content populated in the AOP-Wiki:  John R. Frisch and Travis Karschnik, General Dynamics Information Technology; Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division.

BY-SA

2.7

Serotonin reuptake transporter (SERT; 5-hydroxytryptamine transporter; 5-HTT) is a member of the neurotransmitter sodium symporter (NSS) family that includes the dopamine (DAT), norepinephrine (NET), and Gamma-aminobutyric acid (GABA) transporters (Yang and Gouaux 2021).  SERT transports the neurotransmitter serotonin from the synaptic cleft back into presynaptic neurons, a process commonly referred to as reuptake.  SERT binds to sodium, then serotonin, then chloride in order to allow transport of serotonin into the neuron, and binding to potassium allows SERT to be released by the cell in outward configuration available for transport of serotonin (Yang and Gouaux 2021).  Selective serotonin reuptake inhibitor (SSRI) antidepressants are a class of compounds known to inhibit serotonin reuptake transporter activity resulting in increased extracellular serotonin levels, and enter the aquatic environment when not removed by wastewater treatment (McDonald 2017). Serotonin (5-HT) is a neurotransmitter which stimulates pathways resulting in a variety of downstream behavior effects including increased stress, increased anxiety, decreased aggression, decreased appetite, increased lethargy, decreased locomotion, learning inhibition, and decreased reproduction (McDonald 2017; Ramsteijn et al. 2020).  Activation of different pathways is modulated by different receptors located in different tissue types, with serotonin receptors classified into 7 families and 14 receptor subtypes (McDonald 2017; Barnes et al. 2021).    Inhibition of feeding can be caused by appetite suppression from brain signals, a reduced ability to capture prey, increased lethargy, and reduction in locomotion activity.  Increased stimulation of brain serotonin 5-HT1a, 5-HT2c receptors is one mechanism that has been shown to decrease feeding by appetite suppression, in empirical studies that used agonist compounds that block specific serotonin receptors (Ortega et al. 2013; Perez-Maceira et al. 2014; Perez-Maceria et al. 2016; Barnes et al. 2021). This Adverse Outcome Pathway (AOP) was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  The originating work for this AOP was: McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31.   This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.  The focus of the originating work was to use an AOP framework to examine inhibition of 5-hydroxytryptamine transporters in fish by selective serotonin reuptake inhibitor (SSRI) toxicants, to review known roles of serotonin receptors to explore mechanisms of action, and to determine toxicity endpoints.  McDonald (2017) used the Read-Across Hypothesis, which postulates that pharmaceuticals will cause comparable effects in different taxa if the pathways and targets are evolutionarily and functionally conserved (Rand-Weaver et al. 2013), to link effects of serotonin pathways in fish and mammals.

The originating authors used an AOP framework to develop pathways related to SSRI exposure in fish, and Read-Across hypothesis to link empirical studies in laboratory mammals to functionally conserved effects in fish. The scope of the aforementioned EPA project was limited to re-representing the AOP(s) as presented in the originating publication. The literature used to support this AOP and its constituent pages began with the originating publication and followed to the primary, secondary, and tertiary works cited therein. KE and KER page creation and re-use was determined using Handbook principles where page re-use was preferred.     <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/07/16/2spzwstnyk_Citation_workflow_graphic.png" style="height:729px; width:592px" />

adjacent

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High adjacent

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High adjacent

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Moderate non-adjacent

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Moderate

High Unspecific

Moderate

All life stages

High

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top"> 1. Support for Biological Plausibility of Key Event Relationships: Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event Relationship (KER) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support   Strong = Extensive understanding of the KER based on extensive previous documentation and broad acceptance. Moderate = Support of the relationship based on limited empirical studies, with some uncertainty of the exclusivity of the receptors involved, and acknowledgement of the involvement of additional signaling molecules. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3474: Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, extracellular serotonin </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  The relationship between inhibition of 5-hydroxytryptamine transporter (5-HTT; SERT) and increased extracellular serotonin is broadly accepted and supported among fish, laboratory mammal, and fish data. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3475: Increased, extracellular serotonin leads to Increased, stimulation of brain 5-HT1a, 5-HT2c receptors </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  The relationship between increased extracellular serotonin and increased stimulation of brain 5-HT1a, 5-HT2c receptors is broadly accepted and supported among fish, laboratory mammal, and fish data. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3476: Increased, stimulation of brain 5-HT1a, 5-HT2c receptors leads to Inhibition, feeding </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate support. The relationship between increased stimulation of brain 5-HT1a, 5-HT2c receptors and inhibition of feeding is consistent with established empirical studies.  The number of studies that link inhibition of feeding to brain 5-HT1a, 5-HT2c receptors is limited, with the stimulation of other serotonin receptors a possible influence on feeding response.  In addition, activation of serotonin-induced pathways stimulates production of appetite-regulating neuropeptides, with the observed behavioral effect of reduced feeding. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate to strong support.  Extensive understanding of the relationships between events from empirical studies from fish, laboratory mammals, and humans.   More limited support for the exclusivity of brain 5-HT1a, 5-HT2c receptors in inducing inhibition of feeding, and an acknowledgment of the involvement of additional signaling molecules. </td> </tr> </tbody> </table> Life Stage: Applies to all life stages with developed brain and central nervous systems. Sex: Applies to both males and females. Taxonomic: Studied in fish, with similarities expected in laboratory mammals and humans due to evolutionary and functional conservation of serotonin-induced pathways.

<table cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:775px"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> 2. Essentiality of Key Events: Are downstream KEs and/or the AO prevented if an upstream KE is blocked? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event (KE) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support Strong = Direct evidence from specifically designed experimental studies illustrating essentiality and direct relationship between key events. Moderate = Some evidence from experimental studies supporting the relationship, with additional internal and external environmental factors impacting the relationship. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 619 Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Inhibition of 5-hydroxytryptamine transporter (SERT) leads to increased extracellular serotonin.  Evidence is available from studies of radiolabeled compounds, enzyme immunoassay, and toxicant studies measuring enzyme activity, protein levels, and movement of serotonin into nerve cells.  Best evidence for the essentiality of activation of 5-hydroxytryptamine transporter is through toxicant studies of selective serotonin reuptake inhibitors (SSRIs) that inhibit 5-hydroxytryptamine transporter activity and lead to increased levels of extracellular serotonin, with normal 5-hydroxytryptamine transporter activity in the absence of the SSRI compound.  The mechanism in which SERT binds to sodium, then serotonin, then chloride in order to allow transport of serotonin into neurons has been established. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 1320 Increased, extracellular serotonin </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Increased extracellular serotonin (5-HT) leads to increased stimulation of brain 5-HT1a and 5-HT2c receptors.  Evidence is available from serotonin addition, enzyme immunoassay, and toxicant studies measuring enzyme activity and protein levels.  Families and subclasses of receptors that are stimulated by serotonin have been well-established.  Best evidence for the essentiality of increased stimulation specific to brain 5-HT1a and 5-HT2c receptors is in the use of agonist compounds known to block a specific serotonin receptor, and contrasting to treatment without the agonist agent.  In some cases the relationship between increased levels of serotonin and increased simulation of serotonin receptors is assumed and study focus placed on downstream effects of activation of serotonin pathways and/or behavior effects. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 2308 Increased, stimulation of brain 5-HT1a, 5-HT2c receptors </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate support.  Increased stimulation of brain 5-HT1a and 5-HT2c receptors leads to inhibition of feeding.  Evidence is available from serotonin addition, enzyme immunoassay, toxicant, and behavior studies.   Best evidence for essentiality of simulation of brain 5-HT1a and 5-HT2c receptors is in the use of agonist compounds known to block a specific serotonin receptor and observed inhibition of feeding by rate of food intake, and contrasting to treatment without the agonist agent where normal feeding is maintained.  Empirical evidence has the caveat that additional signaling molecules are involved in modulating feeding response, and that feeding rate is influenced by both internal and external environmental factors. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 1016 Inhibition, feeding </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> This is the final event of the AOP. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate to strong support.  Direct evidence from empirical studies from fish, laboratory mammals, and humans for all key events.   Moderate support for the relationship between simulation of brain 5-HT1a, 5-HT2c receptors and inhibition of feeding because of the influence of additional internal and external environmental factors. </td> </tr> </tbody> </table>

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> 3. Empirical Support for Key Event Relationship: Does empirical evidence support that a change in KEup leads to an appropriate change in KEdown? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event Relationship (KER) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support  Strong =  Experimental evidence from exposure to toxicant shows consistent change in both events across taxa and study conditions.  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3474: Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Increased, extracellular serotonin </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Inhibition of 5-hydroxytryptamine transporter (SERT) leads to increased extracellular serotonin.  Evidence is available from studies of radiolabeled compounds, enzyme immunoassay, and toxicant studies measuring enzyme activity, protein levels, and movement of serotonin into nerve cells.  Inhibition of 5-hydroxytryptamine transporter (SERT) occurred earlier in the time-course of exposure than increased extracellular serotonin, and the concentrations that inhibited 5-hydroxytryptamine transporter were equal to or lower than the concentrations that increased extracellular serotonin.   Therefore, the data support a causal relationship. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3475: Increased, extracellular serotonin leads to Increased, stimulation of brain 5-HT1a, 5-HT2c receptors </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Increased extracellular serotonin (5-HT) leads to increased stimulation of brain 5-HT1a and 5-HT2c receptors.  Evidence is available from serotonin addition, enzyme immunoassay, and toxicant studies measuring enzyme activity and protein levels.  Increased extracellular serotonin occurred earlier in the time-course of exposure than increased stimulation of brain 5-HT1a and 5-HT2c receptors, and the concentrations that increased extracellular serotonin were equal to or lower than the concentrations that increased stimulation of brain 5-HT1a and 5-HT2c receptors.  Therefore, the data support a causal relationship. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3476: Increased, stimulation of brain 5-HT1a, 5-HT2c receptors leads to Inhibition, feeding </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Increased stimulation of brain 5-HT1a and 5-HT2c receptors leads to inhibition of feeding.  Evidence is available from serotonin addition, enzyme immunoassay, toxicant, and behavior studies.  Increased stimulation of brain 5-HT1a and 5-HT2c receptors occurred earlier in the time-course of exposure than inhibition of feeding, and the concentrations that increased stimulation of brain 5-HT1a and 5-HT2c receptors were equal to or lower than the concentrations that inhibited feeding.  Therefore, the data support a causal relationship. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Evidence from empirical studies shows consistent change in both events including frequent testing in fish and lab mammals, with upstream events occurring earlier in the time-course of exposure and at equal or lower concentrations than downstream events, supporting causal relationships. </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td>Selective Serotonin Reuptake Inhibitor (SSRI)</td> <td>Inhibits reuptake of serotonin by nerve cells by blocking receptors, increases extracellular serotonin.</td> <td>3474</td> </tr> </tbody> </table> </div>

Not Specified

Barnes, N.M., Ahern, G.P., Becamel, C., Bockaert, J., Camilleri, M., Chaumont-Dubel, S., Claeysen, S., Cunningham, K.A., Fone, K.C., Gershon, M., Di Giovanni, G., Goodfellow, N.M., Halberstadt, A.L., Hartley, R.M., Hassaine, G., Herrick-Davis, K., Hovius, R., Lacivita, E., Lambe, E..K, Leopoldo, M., Levy, F.O., Lummis, S.C.R, Marin, P., Maroteaux, L., McCreary, A.C., Nelson, D.L., Neumaier, J.F., Newman-Tancredi, A., Nury, H., Roberts, A., Roth, B.L., Roumier, A., Sanger, G.J., Teitler, M., Sharp, T., Villalon, C.M., Vogel, H., Watts, S.W., and  Hoyer, D. 2021.  International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function. Pharmacological Reviews 73(1): 310-520. McDonald, M.D.  2017.  An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish. Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 197: 19–31. Ortega, V.A., Lovejoy, D.A., and Bernier, N.J.  2013.   Appetite-suppressing effects and interactions of centrally administered corticotropin-releasing factor, urotensin I and serotonin in rainbow trout (Oncorhynchus mykiss).  Frontiers in Neuroscience 7: 196. Perez-Maceira, J.J., Mancebo, M.J., and Aldegunde, M.  2014.  The involvement of 5-HT-like receptors in the regulation of food intake in rainbow trout (Oncorhynchus mykiss).  Comparative Biochemistry and Physiology, Part C-Toxicology and Pharmacology 161: 1–6. Perez-Maceira, J.J., Otero-Rodino, C., Mancebo, M.J., Soengas, J.L., and Aldegunde, M.  2016.  Food intake inhibition in rainbow trout induced by activation of serotonin 5‑HT2C receptors is associated with increases in POMC, CART and CRF mRNA abundance in hypothalamus.  Comparative Biochemistry and Physiology, Part B-Biochemical Systems and Environmental Physiology 186(3): 313-321. Ramsteijn A.S., Van de Wijer, L., Rando, J., van Luijk, J., Homberg, J.R., and Olivier, J.D.A. 2020.  Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies. Neuroscience and Biobehavior Reviews 114: 53–69. Rand-Weaver, M., Margiotta-Casaluci, L., Patel, A., Panter, G.H., Owen, S.F., and Sumpter, J.P.  2013. The read-across hypothesis and environmental risk assessment of pharmaceuticals. Environmental Science Technology 47: 11384–11395. Yang, D. and Gouaux, E. 2021.  Illumination of serotonin transporter mechanism and role of the allosteric site. Science Advances 7(49): eabl3857. AOPWiki 2025-01-14T08:59:38

2025-02-20T11:42:35