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Autoreceptor control of serotonin dynamics

Authors
  • Best, Janet1
  • Duncan, William2
  • Sadre-Marandi, Farrah3
  • Hashemi, Parastoo4
  • Nijhout, H. Frederik2
  • Reed, Michael2
  • 1 The Ohio State University, 231 W 18th Ave., Columbus, OH, 43210, USA , Columbus (United States)
  • 2 Duke University, Durham, NC, 27708, USA , Durham (United States)
  • 3 qPharmetra, LLC, Denver, CO, 80203, USA , Denver (United States)
  • 4 Imperial College, London, SW7 2AZ, UK , London (United Kingdom)
Type
Published Article
Journal
BMC Neuroscience
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Sep 23, 2020
Volume
21
Issue
1
Identifiers
DOI: 10.1186/s12868-020-00587-z
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundSerotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding involves genomics, neurochemistry, electrophysiology, and behavior. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders. This paper presents a new deterministic model of serotonin metabolism and a new systems population model that takes into account the large variation in enzyme and transporter expression levels, tryptophan input, and autoreceptor function.ResultsWe discuss the steady state of the model and the steady state distribution of extracellular serotonin under different hypotheses on the autoreceptors and we show the effect of tryptophan input on the steady state and the effect of meals. We use the deterministic model to interpret experimental data on the responses in the hippocampus of male and female mice, and to illustrate the short-time dynamics of the autoreceptors. We show there are likely two reuptake mechanisms for serotonin and that the autoreceptors have long-lasting influence and compare our results to measurements of serotonin dynamics in the substantia nigra pars reticulata. We also show how histamine affects serotonin dynamics. We examine experimental data that show very variable response curves in populations of mice and ask how much variation in parameters in the model is necessary to produce the observed variation in the data. Finally, we show how the systems population model can potentially be used to investigate specific biological and clinical questions.ConclusionsWe have shown that our new models can be used to investigate the effects of tryptophan input and meals and the behavior of experimental response curves in different brain nuclei. The systems population model incorporates individual variation and can be used to investigate clinical questions and the variation in drug efficacy. The codes for both the deterministic model and the systems population model are available from the authors and can be used by other researchers to investigate the serotonergic system.

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