Serotonin synthesis, release and reuptake in terminals: a mathematical model

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 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.MethodsWe 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.ResultsWe 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.ConclusionsSerotonergic 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.

Systems Biology of Phenotypic Robustness and Plasticity

“…The general structure of the model is similar to the model of DA, except that 5HT is made from tryptophan (instead of tyrosine), it is hydroxylated by tryptophan hydroxylase (TPH), instead of TH, and it is taken up from the extracellular space by serotonin reuptake transports (SERTs), instead of DATs. As in the case of DA, the concentration of 5HT in the extracellular space is stabilized against polymorphisms in TPH and SERTs by the 5HT autoreceptors (Best et al 2010a(Best et al , 2010b.…”

“…Using system population models, we can identify the characteristics of such subpopulations and using the underlying mathematical model we can determine the reasons why they react differently. We will give an example from serotonin (5HT) metabolism in the brain using an updated version of the mathematical model introduced in Best et al (2010b). The general structure of the model is similar to the model of DA, except that 5HT is made from tryptophan (instead of tyrosine), it is hydroxylated by tryptophan hydroxylase (TPH), instead of TH, and it is taken up from the extracellular space by serotonin reuptake transports (SERTs), instead of DATs.…”

“…We will use our work on dopamine (DA) metabolism (Best et al , 2010bReed et al 2009) to illustrate how system population models can give meaning and mechanistic understanding to the concept of "predisposition to disease," which emerges naturally from robustness mechanisms. Dopamine and serotonin are unusual neurotransmitters in that the system attempts to maintain a constant concentration in the extracellular space, a phenomenon known as volume transmission ).…”

5-HT2A receptor antagonist M100907 reduces serotonin synthesis: An autoradiographic study

“…The action through 5-HT 2A receptors is probably also related to 5-HT dopamine interaction because blocade of 5-HT 2A receptors on dopaminergic neurons could result in higher release of dopamine which could influence 5-HT synthesis [35]. The tryptophan hydroxylase (TPH) is "mostly" expressed in the cell bodies found in raphe nuclei (e.g., [36]), but there is also substantial evidence that TPH is present in the serotonergic terminals [62,18,59], and that the synthesis of 5-HT is occurring in those terminals (e.g., [49,33,11,51]). …”

Porodični i partnerski odnosi kao protektivni faktori suicidalnih misli

“…Seksualno zadovoljstvo se definiše kao posljedica privrženosti i kompatibilnosti, prije nego kao posljedica specifičnog seksualnog ponašanja [13], dok drugi nude definiciju seksualnosti kao sveukupnosti ideja o seksualnim odnosima, vrijednostima i značenjima koja pojedinac vezuje za taj pojam, kao i načinima na koje neko upražnjava, kontroliše ili inhibira seksualno ponašanje [14]. Serotonin (5-HT), neurotransmiter koji je odgovoran za seksualno ponašanje, takođe se dovodi u vezu i sa suicidalnim ponašanjem, jer utiče na povećanje impulsivnosti [15]. S obzirom na pol, muškarci češće izvrše, dok žene češće pokušaju izvršiti suicid.…”