Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats.
Author
Summary, in English
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.
Department/s
Publishing year
2010
Language
English
Pages
13159-13164
Publication/Series
Proceedings of the National Academy of Sciences
Volume
107
Issue
29
Links
Document type
Journal article
Publisher
National Academy of Sciences
Topic
- Neurosciences
Status
Published
Research group
- Brain Repair and Imaging in Neural Systems (BRAINS)
ISBN/ISSN/Other
- ISSN: 1091-6490