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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1645174
- author
- Ulusoy, Ayse
LU
; Sahin, Gurdal
LU
and Kirik, Deniz
LU
- organization
- publishing date
- 2010
- 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 Academy of 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
- 2016-04-04 08:12:40
- date last changed
- 2022-05-16 21:02:50
@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 Academy of 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}},
doi = {{10.1073/pnas.1003432107}},
volume = {{107}},
year = {{2010}},
}