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 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. Results We 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. Conclusions We 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.

中文翻译：

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血清素动力学的自身受体控制


背景 血清素是一种神经递质，与多种行为有关，包括进食和体重调节、社会等级、攻击性和自杀性、强迫症、酗酒、焦虑和情感障碍。充分的理解涉及基因组学、神经化学、电生理学和行为学。由于使用选择性血清素再摄取抑制剂和其他药物来治疗疾病，科学问题令人望而生畏，但对人类健康很重要。本文提出了一种新的血清素代谢确定性模型和一种新的系统群体模型，该模型考虑了酶和转运蛋白表达水平、色氨酸输入和自身受体功能的巨大变化。结果我们讨论了模型的稳态和在不同的自身受体假设下细胞外血清素的稳态分布，并显示了色氨酸输入对稳态的影响和膳食的影响。我们使用确定性模型来解释雄性和雌性小鼠海马反应的实验数据，并说明自身受体的短时动态。我们表明，血清素可能有两种再摄取机制，并且自身受体具有长期影响，并将我们的结果与黑质网状部血清素动态的测量结果进行比较。我们还展示了组胺如何影响血清素动态。我们检查了显示小鼠群体中变化很大的响应曲线的实验数据，并询问模型中的参数需要多大的变化才能产生观察到的数据变化。 最后，我们展示了系统群体模型如何可能用于研究特定的生物学和临床问题。结论 我们已经证明，我们的新模型可用于研究色氨酸输入和膳食的影响以及不同脑核中实验反应曲线的行为。系统群体模型包含个体差异，可用于研究临床问题和药物功效的变化。作者可以提供确定性模型和系统群体模型的代码，其他研究人员可以使用它们来研究血清素系统。