AUTHOR=Reed Michael C., Best Janet A., Nijhout H. F.

TITLE=Mathematical Insights into the Effects of Levodopa

JOURNAL=Frontiers in Integrative Neuroscience

VOLUME=Volume 6 - 2012

YEAR=2012

URL=https://www.frontiersin.org/journals/integrative-neuroscience/articles/10.3389/fnint.2012.00021

DOI=10.3389/fnint.2012.00021

ISSN=1662-5145

ABSTRACT=Parkinson's disease has been traditionally thought of as a dopaminergic disease in which
cells of the substantia nigra pars compacta (SNc) die. However, accumulating evidence implies
an important role for the serotonergic system in Parkinson's disease in general and in
physiological responses to levodopa therapy, the fi□rst line of treatment. We use a mathematical
model to investigate the consequences of levodopa therapy on the serotonergic system
and on the pulsatile release of dopamine from dopaminergic and serotonergic terminals in the
striatum. Levodopa competes with tyrosine and tryptophan at the blood-brain barrier and is
taken up by serotonin neurons in which it competes for aromatic amino acid decarboxylase.
The dopamine produced competes with serotonin for packaging into vesicles. We study how
this competition aff□ects the release of dopamine into the striatum during a levodopa dose
and how the time course of extracellular dopamine changes as SNc cells die. We explain
the shortening of the therapeutic time window for the effi□cacy of levodopa as Parkinson's
disease progresses. Finally, we study the eff□ects 5HT1a and 5HT1b autoreceptor agonists
and explain why they have a synergistic eff□ect and why they lengthen the therapeutic time
window.