Best2009 - Homeostatic mechanisms in dopamine synthesis and release

Best2009 - Homeostatic mechanisms in dopamine
synthesis and release

Encoded non-curated model. Issues:

- Initial concentrations for hva, tyrpool, NADPH and NADP
are missing
- Reaction VMAT requires two substrates to match the formula
proposed in the article

This model is described in the article:

Homeostatic mechanisms in
dopamine synthesis and release: a mathematical model.

Best JA, Nijhout HF, Reed MC.
Theor Biol Med Model 2009; 6: 21
Abstract:

BACKGROUND: Dopamine is a catecholamine that is used as a
neurotransmitter both in the periphery and in the central
nervous system. Dysfunction in various dopaminergic systems is
known to be associated with various disorders, including
schizophrenia, Parkinson's disease, and Tourette's syndrome.
Furthermore, microdialysis studies have shown that addictive
drugs increase extracellular dopamine and brain imaging has
shown a correlation between euphoria and
psycho-stimulant-induced increases in extracellular dopamine 1.
These consequences of dopamine dysfunction indicate the
importance of maintaining dopamine functionality through
homeostatic mechanisms that have been attributed to the
delicate balance between synthesis, storage, release,
metabolism, and reuptake. METHODS: We construct a mathematical
model of dopamine synthesis, release, and reuptake and use it
to study homeostasis in single dopaminergic neuron terminals.
We investigate the substrate inhibition of tyrosine hydroxylase
by tyrosine, the consequences of the rapid uptake of
extracellular dopamine by the dopamine transporters, and the
effects of the autoreceoptors on dopaminergic function. The
main focus is to understand the regulation and control of
synthesis and release and to explicate and interpret
experimental findings. RESULTS: We show that the substrate
inhibition of tyrosine hydroxylase by tyrosine stabilizes
cytosolic and vesicular dopamine against changes in tyrosine
availability due to meals. We find that the autoreceptors
dampen the fluctuations in extracellular dopamine caused by
changes in tyrosine hydroxylase expression and changes in the
rate of firing. We show that short bursts of action potentials
create significant dopamine signals against the background of
tonic firing. We explain the observed time courses of
extracellular dopamine responses to stimulation in wild type
mice and mice that have genetically altered dopamine
transporter densities and the observed half-lives of
extracellular dopamine under various treatment protocols.
CONCLUSION: Dopaminergic systems must respond robustly to
important biological signals such as bursts, 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 tyrosine hydroxylase, the dopamine transporters, and the
dopamine autoreceptors.

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