L-Dopa induced dyskinesias in Parkinsonian mice

Disease severity or l-Dopa history

Lufei Shan, Oscar Diaz, Yajun Zhang, Bruce Ladenheim, Jean Lud Cadet, Yung Hsiao Chiang, Lars Olson, Barry J. Hoffer, Cristina M. Bäckman

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 (10 mg/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.

Original languageEnglish
Pages (from-to)261-269
Number of pages9
JournalBrain Research
Volume1618
DOIs
Publication statusPublished - Aug 27 2015

Fingerprint

Dihydroxyphenylalanine
Dyskinesias
Parkinsonian Disorders
Levodopa
History
Corpus Striatum
Dopamine
Parkinson Disease
Denervation
Therapeutics
Neurotransmitter Receptor
GABA Receptors
Serotonin Receptors
Dopaminergic Neurons
Genetic Models
Dopamine Receptors
Glutamate Receptors
Synaptic Transmission
Messenger RNA

Keywords

  • Basal ganglia
  • Behavior
  • MitoPark mouse
  • Motor complication
  • Nigrostriatal function
  • Sensitization

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Shan, L., Diaz, O., Zhang, Y., Ladenheim, B., Cadet, J. L., Chiang, Y. H., ... Bäckman, C. M. (2015). L-Dopa induced dyskinesias in Parkinsonian mice: Disease severity or l-Dopa history. Brain Research, 1618, 261-269. https://doi.org/10.1016/j.brainres.2015.06.005

L-Dopa induced dyskinesias in Parkinsonian mice : Disease severity or l-Dopa history. / Shan, Lufei; Diaz, Oscar; Zhang, Yajun; Ladenheim, Bruce; Cadet, Jean Lud; Chiang, Yung Hsiao; Olson, Lars; Hoffer, Barry J.; Bäckman, Cristina M.

In: Brain Research, Vol. 1618, 27.08.2015, p. 261-269.

Research output: Contribution to journalArticle

Shan, L, Diaz, O, Zhang, Y, Ladenheim, B, Cadet, JL, Chiang, YH, Olson, L, Hoffer, BJ & Bäckman, CM 2015, 'L-Dopa induced dyskinesias in Parkinsonian mice: Disease severity or l-Dopa history', Brain Research, vol. 1618, pp. 261-269. https://doi.org/10.1016/j.brainres.2015.06.005
Shan, Lufei ; Diaz, Oscar ; Zhang, Yajun ; Ladenheim, Bruce ; Cadet, Jean Lud ; Chiang, Yung Hsiao ; Olson, Lars ; Hoffer, Barry J. ; Bäckman, Cristina M. / L-Dopa induced dyskinesias in Parkinsonian mice : Disease severity or l-Dopa history. In: Brain Research. 2015 ; Vol. 1618. pp. 261-269.
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