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.
Highlights
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, alcohol‐ ism, anxiety, and affective disorders
The question is how should we model the release of serotonin over the 30 s period—the first term in the differential equation for eht? The question is complicated by the existence of serotonin binding protein (SBP) that is attached to the inner wall of vesicles and binds serotonin tightly [55, 56]
We have created a new model of serotonin metabolism including transport of tryptophan from the blood, synthesis of serotonin, packaging into vesicles, release, reuptake and control by autoreceptors
Summary
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, alcohol‐ ism, anxiety, and affective disorders. Serotonin rises rapidly in the extracellular space in the projection regions and typically plunges substantially below basal levels within 30 s [7]. This almost certainly is because inhibition of release by the autoreceptor continues well after the serotonin concentration in the extracellular space has returned to basal levels. In our 2010 model, the autoreceptor effect was modeled by high extracellular serotonin instantaneously inhibiting release, and the Hashemi experiments showed that this is wrong. In this paper we include a full model of a histamine H3 receptor on the serotonin varicosity that changes the dynamics of serotonin release. We make stochastic systems population models from our deterministic model (see below) and use these systems population models to investigate certain aspects of the serotonin system
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