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dc.contributor.author Best, J
dc.contributor.author Nijhout, HF
dc.contributor.author Reed, M
dc.coverage.spatial England
dc.date.accessioned 2011-06-21T17:30:24Z
dc.date.issued 2010-08-19
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20723248
dc.identifier 1742-4682-7-34
dc.identifier.citation Theor Biol Med Model, 2010, 7 pp. 34 - ?
dc.identifier.uri http://hdl.handle.net/10161/4376
dc.description.abstract BACKGROUND: Serotonin 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 of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. 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 in the serotonergic signaling system. METHODS: We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. RESULTS: We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine. CONCLUSIONS: Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions.
dc.format.extent 34 - ?
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof Theor Biol Med Model
dc.relation.isversionof 10.1186/1742-4682-7-34
dc.subject Animals
dc.subject Autoreceptors
dc.subject Brain
dc.subject Fluoxetine
dc.subject Food
dc.subject Gene Knockdown Techniques
dc.subject Homeostasis
dc.subject Humans
dc.subject Kinetics
dc.subject Mice
dc.subject Models, Biological
dc.subject Presynaptic Terminals
dc.subject Protein Binding
dc.subject Rats
dc.subject Serotonin
dc.subject Serotonin Plasma Membrane Transport Proteins
dc.subject Serotonin Receptor Agonists
dc.subject Time Factors
dc.title Serotonin synthesis, release and reuptake in terminals: a mathematical model.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-8-19 en_US
duke.description.endpage 34 en_US
duke.description.issue en_US
duke.description.startpage 34 en_US
duke.description.volume 7 en_US
dc.relation.journal Theoretical Biology and Medical Modelling en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20723248
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Biology
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Mathematics
pubs.publication-status Published online
pubs.volume 7
dc.identifier.eissn 1742-4682

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