Mass spectrometry imaging identifies abnormally elevated brain l -DOPA levels and extrastriatal monoaminergic dysregulation in l -DOPA–induced dyskinesia
Sci. Adv.. 2021-01-06; 7(2):
DOI: 10.1126/sciadv.abe5948
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Fridjonsdottir E(1), Shariatgorji R(1)(2), Nilsson A(1)(2), Vallianatou T(1), Odell LR(3), Schembri LS(1)(2), Svenningsson P(4), Fernagut PO(5)(6)(7), Crossman
AR(8), Bezard E(9)(6)(10), Andrén PE(11)(2).
Author information:
(1)Medical Mass Spectrometry Imaging, Department of Pharmaceutical Biosciences,
Uppsala University, Uppsala, Sweden.
(2)Science for Life Laboratory, National Resource for Mass Spectrometry Imaging,
Uppsala University, Uppsala, Sweden.
(3)Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
(4)Section of Neurology, Department of Clinical Neuroscience, Karolinska
Institutet, Stockholm, Sweden.
(5)Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
France.
(6)CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.
(7)Université de Poitiers, INSERM, U0-1084, Laboratoire de Neurosciences
Expérimentales et Cliniques, Poitiers, France.
(8)University of Manchester, Manchester M13 9PL, UK.
(9)Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
France. .
(10)Motac Neuroscience, Manchester M15 6WE, UK.
(11)Medical Mass Spectrometry Imaging, Department of Pharmaceutical Biosciences,
Uppsala University, Uppsala, Sweden.
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l-DOPA treatment for Parkinson’s disease frequently leads to dyskinesias, the
pathophysiology of which is poorly understood. We used MALDI-MSI to map the
distribution of l-DOPA and monoaminergic pathways in brains of dyskinetic and
nondyskinetic primates. We report elevated levels of l-DOPA, and its metabolite
3-O-methyldopa, in all measured brain regions of dyskinetic animals and increases
in dopamine and metabolites in all regions analyzed except the striatum. In
dyskinesia, dopamine levels correlated well with l-DOPA levels in extrastriatal
regions, such as hippocampus, amygdala, bed nucleus of the stria terminalis, and
cortical areas, but not in the striatum. Our results demonstrate that
l-DOPA-induced dyskinesia is linked to a dysregulation of l-DOPA metabolism
throughout the brain. The inability of extrastriatal brain areas to regulate the
formation of dopamine during l-DOPA treatment introduces the potential of
dopamine or even l-DOPA itself to modulate neuronal signaling widely across the
brain, resulting in unwanted side effects.
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