Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats.

Drug-induced dyskinesias in dopamine-denervated animals are known to depend on both pre- and postsynaptic changes of the nigrostriatal circuitry. In lesion models used thus far, changes occur in both of these compartments and, therefore, it has not been possible to dissect the individual contribution of each compartment in the pathophysiology of dyskinesias. Here we silenced the nigrostriatal dopamine neurotransmission without affecting the anatomical integrity of the presynaptic terminals using a short-hairpin RNA-mediated knockdown of tyrosine hydroxylase enzyme (shTH). This treatment resulted in significant reduction (by about 70%) in extracellular dopamine concentration in the striatum as measured by on-line microdialysis. Under these conditions, the animals remained nondyskinetic after chronic L-DOPA treatment, whereas partial intrastriatal 6-hydoxydopamine lesioned rats with comparable reduction in extracellular dopamine levels developed dyskinesias. On the other hand, apomorphine caused moderate to severe dyskinesias in both groups. Importantly, single-dose L-DOPA challenge in apomorphine-primed shTH animals failed to activate the already established abnormal postsynaptic responses. Taken together, these data provide direct evidence that the status of the presynaptic, DA releasing compartment is a critical determinant of both the induction and maintenance of L-DOPA-induced dyskinesias.
AuthorsAyse Ulusoy, Gurdal Sahin, Deniz Kirik
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 29 Pg. 13159-64 (Jul 20 2010) ISSN: 1091-6490 [Electronic] United States
PMID20615977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Fosb protein, rat
  • Proto-Oncogene Proteins c-fos
  • RNA, Small Interfering
  • Levodopa
  • Tyrosine 3-Monooxygenase
  • Apomorphine
  • Dopamine
  • Animals
  • Apomorphine (pharmacology)
  • Chromatography, High Pressure Liquid
  • Dependovirus (genetics)
  • Disease Susceptibility
  • Dopamine (metabolism)
  • Down-Regulation (drug effects)
  • Dyskinesia, Drug-Induced (metabolism, pathology)
  • Female
  • Gene Knockdown Techniques
  • Levodopa
  • Microdialysis
  • Neostriatum (drug effects, metabolism)
  • Neurons (drug effects, enzymology)
  • Presynaptic Terminals (drug effects, metabolism)
  • Proto-Oncogene Proteins c-fos (metabolism)
  • RNA, Small Interfering (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Recombination, Genetic (genetics)
  • Substantia Nigra (drug effects, enzymology)
  • Time Factors
  • Tyrosine 3-Monooxygenase (metabolism)

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