Impact of Delays and Noise on Dopamine Signal Transduction - Biological Petri Nets - page 222

Biological Petri Nets
Impact of Delays and Noise on Dopamine
Signal Transduction
Jialiang Wu a , Zhen Qi b and Eberhard O. Voit b ,∗
a School of Mathematics, Georgia Institute of Technology, Atlanta, Georgia, USA
b Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School,
Atlanta, Georgia, USA
ABSTRACT: Dopamine is a critical neurotransmitter for the normal functioning of the central nervous system. Abnormal
dopamine signal transmission in the brain has been implicated in diseases such as Parkinson's disease (PD) and schizophrenia,
as well as in various types of drug addition. It is therefore important to understand the dopamine signaling dynamics in the
presynaptic neuron of the striatum and the synaptic cleft, where dopamine synthesis, degradation, compartmentalization, release,
reuptake, and numerous regulatory processes occur. The biochemical and biological processes governing this dynamics consist
of interacting discrete and continuous components, operate at different time scales, and must function effectively in spite of
intrinsic stochasticity and external perturbations. Not fitting into the realm of purely deterministic phenomena, the hybrid nature
of the system requires special means of mathematical modeling, simulation and analysis. We show here how hybrid functional
Petri-nets (HFPNs) and the software Cell Illustrator facilitate computational analyses of systems that simultaneously contain
deterministic, stochastic, and delay components. We evaluate the robustness of dopamine signaling in the presence of delays
and noise and discuss implications for normal and abnormal states of the system.
KEYWORDS: Amphetamine, Biochemical System Theory (BST), delay, dopamine signaling, HFPN, hybrid modeling, Parkin-
son's disease, Petri nets, schizophrenia, stochasticity
INTRODUCTION
Dopamine is a neurotransmitter of enormous physiological, pathological, and pharmacological impor-
tance. It is a crucial contributor to several diseases, such as Parkinson's disease (PD) and schizophrenia.
Dopamine is furthermore associated with addiction to a variety of drugs, because it has a direct effect
on the body's reward system. PD is the most common neurodegenerative movement disorder, affecting
more than 1% of the world population of age 65 or higher [1,2]. Because loss of dopaminergic neurons is
responsible for the majority of the motor symptoms of Parkinson's disease, treatment options have mostly
targeted the restoration of dopamine function by replacement of dopamine precursors, administration of
dopamine agonists, or inhibition of its degradative enzymes.
Schizophrenia is a mental disorder with a worldwide lifetime prevalence of about 0.7%. As with PD,
the large number of schizophrenia cases translates into enormous economical and societal losses [3].
While the root causes of schizophrenia are still obscure, the so-called dopamine hypothesis suggests
∗ Corresponding author. Fax: [phone]; E-mail: [e-mail] .