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l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation

Picconi, B; Paille, V; Ghiglieri, V; Bagetta, V; Barone, I; Lindgren, Hanna LU ; Bernardi, G; Cenci Nilsson, Angela LU and Calabresi, P (2008) In Neurobiology of Disease 29(2). p.327-335
Abstract
The emergence of levodopa (l-DOPA)-induced dyskinesia and motor fluctuations represents a major clinical problem in Parkinson's disease (PD). While it has been suggested that the daily dose of l-DOPA can play a critical role, the mechanisms linking l-DOPA dosage to the occurrence of motor complications have not yet been explored. Using an experimental model of PD we have recently demonstrated that long-term l-DOPA treatment leading to the induction of abnormal involuntary movements (AIMs) alters corticostriatal bidirectional synaptic plasticity. Dyskinetic animals, in fact, lack the ability to reverse previously induced long-term potentiation (LTP). This lack of depotentiation has been associated to a defect in erasing unessential motor... (More)
The emergence of levodopa (l-DOPA)-induced dyskinesia and motor fluctuations represents a major clinical problem in Parkinson's disease (PD). While it has been suggested that the daily dose of l-DOPA can play a critical role, the mechanisms linking l-DOPA dosage to the occurrence of motor complications have not yet been explored. Using an experimental model of PD we have recently demonstrated that long-term l-DOPA treatment leading to the induction of abnormal involuntary movements (AIMs) alters corticostriatal bidirectional synaptic plasticity. Dyskinetic animals, in fact, lack the ability to reverse previously induced long-term potentiation (LTP). This lack of depotentiation has been associated to a defect in erasing unessential motor information. Here chronic l-DOPA treatment was administered at two different doses to hemiparkinsonian rats, and electrophysiological recordings were subsequently performed from striatal spiny neurons. Both low and high doses of l-DOPA restored normal LTP, which was disrupted following dopamine (DA) denervation. By the end of the chronic treatment, however, while the low l-DOPA dose induced AIMs only in half of the rats, the high dose caused motor complications in all the treated animals. Interestingly, the dose-related expression of motor complications was associated with a lack of synaptic depotentiation. Our study provides further experimental evidence to support a direct correlation between the daily dosage of l-DOPA and the induction of motor complications and establishes a critical pathophysiological link between the lack of synaptic depotentiation and the expression of AIMs. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neurobiology of Disease
volume
29
issue
2
pages
327 - 335
publisher
Elsevier
external identifiers
  • pmid:17997101
  • wos:000252647000016
  • scopus:38149033506
ISSN
0969-9961
DOI
10.1016/j.nbd.2007.10.001
language
English
LU publication?
yes
id
91006694-8026-4f1d-aa62-5057f24bfa9e (old id 1143371)
date added to LUP
2008-07-30 12:22:29
date last changed
2017-10-22 03:57:09
@article{91006694-8026-4f1d-aa62-5057f24bfa9e,
  abstract     = {The emergence of levodopa (l-DOPA)-induced dyskinesia and motor fluctuations represents a major clinical problem in Parkinson's disease (PD). While it has been suggested that the daily dose of l-DOPA can play a critical role, the mechanisms linking l-DOPA dosage to the occurrence of motor complications have not yet been explored. Using an experimental model of PD we have recently demonstrated that long-term l-DOPA treatment leading to the induction of abnormal involuntary movements (AIMs) alters corticostriatal bidirectional synaptic plasticity. Dyskinetic animals, in fact, lack the ability to reverse previously induced long-term potentiation (LTP). This lack of depotentiation has been associated to a defect in erasing unessential motor information. Here chronic l-DOPA treatment was administered at two different doses to hemiparkinsonian rats, and electrophysiological recordings were subsequently performed from striatal spiny neurons. Both low and high doses of l-DOPA restored normal LTP, which was disrupted following dopamine (DA) denervation. By the end of the chronic treatment, however, while the low l-DOPA dose induced AIMs only in half of the rats, the high dose caused motor complications in all the treated animals. Interestingly, the dose-related expression of motor complications was associated with a lack of synaptic depotentiation. Our study provides further experimental evidence to support a direct correlation between the daily dosage of l-DOPA and the induction of motor complications and establishes a critical pathophysiological link between the lack of synaptic depotentiation and the expression of AIMs.},
  author       = {Picconi, B and Paille, V and Ghiglieri, V and Bagetta, V and Barone, I and Lindgren, Hanna and Bernardi, G and Cenci Nilsson, Angela and Calabresi, P},
  issn         = {0969-9961},
  language     = {eng},
  number       = {2},
  pages        = {327--335},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation},
  url          = {http://dx.doi.org/10.1016/j.nbd.2007.10.001},
  volume       = {29},
  year         = {2008},
}