Autoreceptor control of serotonin dynamics

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 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.

A model of dopamine and serotonin-kynurenine metabolism in cortisolemia: Implications for depression

“…We have developed and parameterized a dynamic model to test the impact of elevated cortisol/ corticosterone levels and their consequences on serotonin, dopamine and kynurenine pathways, which are known to be associated with the etiology of MDD. Previous models have investigated the interplay of dopaminergic and serotonergic pathways in different contexts, such as the influence of firing and the roles of autoreceptors [47][48][49][50]. However, to the best of our knowledge, this is the first mathematical model integrating all pertinent biochemical pathways into a model of depression.…”

“…e ., > 100%) were adjusted based on data from experiments on chronic stress in animal models (see Table C in S2 Supplement ). Finally, the rate constants were calculated for the final set of power-law equations according to the methodology described in [ 30 ] and based on the flux partitioning ratios taken from other models in the literature [ 33 , 47 – 50 , 79 , 155 ].…”

“…Specifically, to estimate the parameter values related to corticosterone, all kinetic orders determined for the control state were fixed and only the kinetic orders for CORT (increased by a factor greater than 1, i.e., > 100%) were adjusted based on data from experiments on chronic stress in animal models (see Table C in S2 Supplement). Finally, the rate constants were calculated for the final set of power-law equations according to the methodology described in [30] and based on the flux partitioning ratios taken from other models in the literature [33,[47][48][49][50]79,155].…”

Mathematical Models of Serotonin, Histamine, and Depression

“…As discussed in Section 3, the experimental results in [11] and later papers revealed that various aspects of the 2010 model were naive and too simplistic. So, in 2020, the authors and collaborators expanded and revised the original model to take account of the new findings that we had learned [13]. Here we will briefly discuss the changes and some of the new results.…”

“…That paper changed our understanding of 5-HT 1b autoreceptors and showed that the way we modeled autoreceptors in 2010 [5] was wrong. Section 4 describes our 2017 paper [12] creating a mathematical model for histamine dynamics in the brain and Section 5 discusses our 2020 paper [13] revising and expanding our original 5-HT model. In Section 6 we briefly describe the techniques for measuring 5-HT and histamine in the extracellular space and in Section 7 we describe our ideas and speculations about depression.…”