A Mathematical Model of Presynaptic Dopamine Homeostasis: Implications for Schizophrenia

Abstract

Several lines of evidence implicate altered dopamine neurotransmission in schizophrenia. Current drugs for schizophrenia focus on postsynaptic sites of the dopamine signaling pathways, but do not target presynaptic dopamine metabolism. We have begun to develop a mathematical model of dopamine homeostasis, which will aid our understanding of how genetic, environmental, and pharmacological factors alter the functioning of the presynaptic dopamine neuron. Formulated within the modeling framework of BIOCHEMICAL SYSTEMS THEORY, the mathematical model integrates relevant metabolites, enzymes, transporters, and regulators involved in the control of the biochemical environment within the dopamine neuron. In this report we use the model to assess several components and factors that affect the dopamine neuron and have been implicated in schizophrenia. These include the enzymes COMT, MAO, and TH, different dopamine transporters, as well as administration of amphetamine or cocaine. We also investigate scenarios that could increase (or decrease) dopamine neurotransmission and thus exacerbate (or alleviate) symptoms of schizophrenia. Our results indicate that the model predicts the effects of various factors related to schizophrenia on the homeostasis of the presynaptic dopamine neuron rather well. Upon further refinements and testing, the model has the potential of serving as a tool for screening novel therapeutics aimed at altering presynaptic dopamine function and thereby potentially ameliorating some of the symptomology of schizophrenia.

The Tolerability of rTMS Treatment in Schizophrenia with Respect to Cognitive Function

“…Schizophrenia patients appear to have abnormal cortical inhibition. Several lines of evidence implicate altered dopamine neurotransmission in schizophrenia [32] consistent with GABA abnormalities. GABA abnormalities in schizophrenia patients may relate to cognitive defi cits and negative symptoms [39] .…”

Systems Biology and Addiction

“…For addiction, interaction between metabolic pathways of transmitter systems, such as glutamate, dopamine, GABA, acetylcholine, norepinephrine and serotonin is of great interest. First steps in modeling the dopamine-synthesis with the aim to understand pathological processes such as Parkinsonism or Schizophrenia and also addiction could be explored by computer models (comp [60] ). Also the study of processes with diff erent time scales, such as transmitter release, receptor adaptation to high or low concentrations of the transmitter in the synaptic cleft, internalization of receptors after stimulation by agonists etc.…”

Model-based optimization approaches for precision medicine: A case study in presynaptic dopamine overactivity

“…The mathematical model of the nigrostriatal dopamine network accessed from Qi et al [42, 43] is expressed as the generalized mass action framework that consisted of 34 metabolites, 18 independent variables, and 68 target enzymes. The detailed definition of the model is expressed in supporting information (S3 File).…”