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Relationship: 3489

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, extracellular serotonin leads to Inhibition, Feeding

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, extracellular serotonin

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Inhibition, Feeding

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Inhibition, Feeding	non-adjacent	Moderate	Not Specified	John Frisch (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
fish	fish	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

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.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Species	Duration	Dose	Increased extracellular serotonin?	Inhibition feeding?	Summary	Citation
Rainbow trout (Oncorhynchus mykiss)	2 hours	1,10, 100 ng/g body weight serotonin, 200 ng/g body weight methysergide by intracerebroventricular injection.	yes	yes	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.	Ortega et al. (2013)
Rainbow trout (Oncorhynchus mykiss)	24 hours	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.	yes	yes	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.	Perez-Maceira et al. (2014)
Rainbow trout (Oncorhynchus mykiss)	2 hours	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.	yes	yes	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.	Perez-Maceira et al. (2016)

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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.

References

List of the literature that was cited for this KER description. More help

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.