Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice

Autor: Martin K.-H. Schäfer, Eberhard Weihe, Ursula Keber, Günter U. Höglinger, Martin Klietz, Thomas Carlsson, Wolfgang H. Oertel, Candan Depboylu
Rok vydání: 2015
Předmět:
Male
Dyskinesia
Drug-Induced
Parkinson's disease
adverse effects [Levodopa]
Striatum
Functional Laterality
Antiparkinson Agents
Levodopa
Mice
drug effects [Medial Forebrain Bundle]
injuries [Medial Forebrain Bundle]
etiology [Dyskinesia
Drug-Induced]
Medial forebrain bundle
Neurons
Serotonin Plasma Membrane Transport Proteins
metabolism [Serotonin Plasma Membrane Transport Proteins]
General Neuroscience
Parkinson Disease
metabolism [Neurons]
etiology [Parkinson Disease]
Proto-Oncogene Proteins c-fos
medicine.drug
pathology [Corpus Striatum]
Tyrosine 3-Monooxygenase
Slc6a4 protein
mouse
Biology
Serotonergic
Statistics
Nonparametric
Midbrain
pharmacology [Amphetamine]
Dopamine
adverse effects [Antiparkinson Agents]
medicine
Animals
ddc:610
Oxidopamine
pathology [Dyskinesia
Drug-Induced]
metabolism [Phosphopyruvate Hydratase]
Tyrosine hydroxylase
physiology [Functional Laterality]
Medial Forebrain Bundle
medicine.disease
toxicity [Oxidopamine]
drug therapy [Parkinson Disease]
Corpus Striatum
Abnormal involuntary movement
metabolism [Tyrosine 3-Monooxygenase]
Mice
Inbred C57BL
Amphetamine
Disease Models
Animal
nervous system
metabolism [Proto-Oncogene Proteins c-fos]
Phosphopyruvate Hydratase
Neuroscience
Zdroj: Neuroscience 298, 302-317 (2015). doi:10.1016/j.neuroscience.2015.04.021
ISSN: 0306-4522
DOI: 10.1016/j.neuroscience.2015.04.021
Popis: L-3,4-Dihydroxyphenylalanine (L-DOPA) is the therapeutic gold standard in Parkinson's disease. However, long-term treatment is complicated by the induction of debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesias (LIDs). Until today the underlying mechanisms of LID pathogenesis are not fully understood. The aim of this study was to reveal new factors, which may be involved in the induction of LID. We have focused on the expression of striatal tyrosine hydroxylase-positive (TH+) neurons, which are capable of producing either L-DOPA or dopamine (DA) in target areas of ventral midbrain DAergic neurons. To address this issue, a daily L-DOPA dose was administered over the course of 15 days to mice with unilateral 6-hydroxydopamine-induced lesions of the medial forebrain bundle and LIDs were evaluated. Remarkably, the number of striatal TH+ neurons strongly correlated with both induction and severity of LID as well as ΔFosB expression as an established molecular marker for LID. Furthermore, dyskinetic mice showed a marked augmentation of serotonergic fiber innervation in the striatum, enabling the decarboxylation of L-DOPA to DA. Axial, limb and orolingual dyskinesias were predominantly associated with TH+ neurons in the lateral striatum, whereas medially located TH+ neurons triggered locomotive rotations. In contrast, identified accumbal and cortical TH+ cells did not contribute to the generation of LID. Thus, striatal TH+ cells and serotonergic terminals may cooperatively synthesize DA and subsequently contribute to supraphysiological synaptic DA concentrations, an accepted cause in LID pathogenesis.
Databáze: OpenAIRE
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