title: Striatal tyrosine hydroxylase-positive neurons are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice.
abstract: 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.
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps University Marburg, Marburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Keber
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps University Marburg, Marburg, Germany; Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Klietz
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps University Marburg, Marburg, Germany; Section of Pharmacology, Institute for Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden(†).
authors.forename: T
authors.initials: T
authors.lastname: Carlsson
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps University Marburg, Marburg, Germany.
authors.forename: W H
authors.initials: WH
authors.lastname: Oertel
authors.affiliation: Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Marburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Weihe
authors.affiliation: Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Marburg, Germany.
authors.forename: M K-H
authors.initials: MK
authors.lastname: Schäfer
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps University Marburg, Marburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany(†); Department of Neurology, Technical University, Munich, Germany.
authors.forename: G U
authors.initials: GU
authors.lastname: Höglinger
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps University Marburg, Marburg, Germany. Electronic address: depboylu@med.uni-marburg.de.
authors.forename: C
authors.initials: C
authors.lastname: Depboylu
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000473:pathology*; D007839:Functional Laterality / Q000502:physiology*; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D018709:Statistics, Nonparametric; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D016760:Proto-Oncogene Proteins c-fos; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase
keywords: Parkinson’s disease; TH; abnormal involuntary movement; accumbens; dopamine; striatum