title: L-Dopa induced dyskinesias in Parkinsonian mice: Disease severity or L-Dopa history.
abstract: In Parkinson's disease, the efficacy of l-Dopa treatment changes over time, as dyskinesias emerge with previously beneficial doses. Using MitoPark mice, that models mitochondrial failure in dopamine (DA) neurons and mimics the progressive loss of dopamine observed in Parkinson's disease, we found that the severity of DA denervation and associated adaptations in striatal neurotransmission at the time of initiation of l-Dopa treatment determines development of l-Dopa induced dyskinesias. We treated 20-week, and 28-week old MitoPark mice with l-Dopa (10mg/kg i.p. twice a day) and found locomotor responses to be significantly different. While all MitoPark mice developed sensitization to l-Dopa treatment over time, 28-week old MitoPark mice with extensive striatal DA denervation developed abnormal involuntary movements rapidly and severely after starting l-Dopa treatment, as compared to a more gradual escalation of movements in 20-week old animals that started treatment at earlier stages of degeneration. Our data support that it is the extent of loss of DA innervation that determines how soon motor complications develop with l-Dopa treatment. Gene array studies of striatal neurotransmitter receptors revealed changes in mRNA expression levels for DA, serotonin, glutamate and GABA receptors in striatum of 28-week old MitoPark mice. Our results support that delaying l-Dopa treatment until Parkinson's disease symptoms become more severe does not delay the development of l-Dopa-induced dyskinesias. MitoPark mice model genetic alterations known to impair mitochondrial function in a subgroup of Parkinson patients and provide a platform in which to study treatments to minimize the development of dyskinesia.
authors.affiliation: Integrative Neuroscience Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Lufei
authors.initials: L
authors.lastname: Shan
authors.affiliation: Integrative Neuroscience Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz
authors.affiliation: Integrative Neuroscience Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.affiliation: Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Jean-Lud
authors.initials: JL
authors.lastname: Cadet
authors.affiliation: Graduate Program on Neuroregeneration, Taipei Medical University, Taipei, Taiwan, ROC. Electronic address: ychiang@tmu.edu.tw.
authors.forename: Yung-Hsiao
authors.initials: YH
authors.lastname: Chiang
authors.affiliation: Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: Lars.Olson@ki.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Olson
authors.affiliation: Graduate Program on Neuroregeneration, Taipei Medical University, Taipei, Taiwan, ROC; Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44124, USA. Electronic address: barry.hoffer@case.edu.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Hoffer
authors.affiliation: Integrative Neuroscience Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA. Electronic address: Cristina.Backman@nih.gov.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Bäckman
mesh_terms: D000818:Animals; D000930:Antidiarrheals / Q000009:adverse effects*; D001545:Benserazide / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects*; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D051379:Mice; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D000930:Antidiarrheals; D017981:Receptors, Neurotransmitter; D007980:Levodopa; D001545:Benserazide; D004298:Dopamine
keywords: Basal ganglia; Behavior; MitoPark mouse; Motor complication; Nigrostriatal function; Sensitization