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

Ulusoy, Ayse LU ; Sahin, Gurdal LU and Kirik, Deniz LU (2010) In Proceedings of the National Academy of Sciences 107(29). p.13159-13164
Abstract
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... (More)
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. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
107
issue
29
pages
13159 - 13164
publisher
National Acad Sciences
external identifiers
  • wos:000280144500081
  • pmid:20615977
  • scopus:77955625476
ISSN
1091-6490
DOI
10.1073/pnas.1003432107
language
English
LU publication?
yes
id
c7c8bc74-82a1-4da6-9d67-2046c2356c5b (old id 1645174)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20615977?dopt=Abstract
date added to LUP
2010-08-02 10:52:17
date last changed
2018-05-29 11:34:00
@article{c7c8bc74-82a1-4da6-9d67-2046c2356c5b,
  abstract     = {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.},
  author       = {Ulusoy, Ayse and Sahin, Gurdal and Kirik, Deniz},
  issn         = {1091-6490},
  language     = {eng},
  number       = {29},
  pages        = {13159--13164},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats.},
  url          = {http://dx.doi.org/10.1073/pnas.1003432107},
  volume       = {107},
  year         = {2010},
}