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Maladaptive striatal plasticity in L-DOPA-induced dyskinesia.

Cenci Nilsson, Angela LU and Konradi, Christine (2010) In Progress in Brain Research 183. p.209-233
Abstract
Dopamine (DA) replacement therapy with l-DOPA remains the most effective treatment for Parkinson's disease, but causes dyskinesia (abnormal involuntary movements) in the vast majority of the patients. The basic mechanisms of l-DOPA-induced dyskinesia (LID) have become the object of intense research focusing on neurochemical and molecular adaptations in the striatum. Here we review this vast literature and highlight trends that converge into a unifying pathophysiological interpretation. We propose that the core molecular alteration of striatal neurons in LID consists in an inability to turn down supersensitive signaling responses downstream of DA D1 receptors (where supersensitivity is primarily caused by DA denervation). The sustained... (More)
Dopamine (DA) replacement therapy with l-DOPA remains the most effective treatment for Parkinson's disease, but causes dyskinesia (abnormal involuntary movements) in the vast majority of the patients. The basic mechanisms of l-DOPA-induced dyskinesia (LID) have become the object of intense research focusing on neurochemical and molecular adaptations in the striatum. Here we review this vast literature and highlight trends that converge into a unifying pathophysiological interpretation. We propose that the core molecular alteration of striatal neurons in LID consists in an inability to turn down supersensitive signaling responses downstream of DA D1 receptors (where supersensitivity is primarily caused by DA denervation). The sustained activation of intracellular signaling pathways induced by each dose of l-DOPA leads to abnormal cellular plasticity and high bioenergetic expenditure. The over-exploitation of signaling pathways and energy reserves during treatment impairs the ability of striatal neurons to dynamically gate cortically driven motor commands. LID thus exemplifies a disorder where 'too much' molecular plasticity leads to plasticity failure in the striatum. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Progress in Brain Research
volume
183
pages
209 - 233
publisher
Elsevier
external identifiers
  • WOS:000287859500011
  • PMID:20696322
  • Scopus:77955380256
ISSN
1875-7855
DOI
10.1016/S0079-6123(10)83011-0
language
English
LU publication?
yes
id
d815d0e2-a106-4e85-94f2-a15081c6d32c (old id 1665430)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20696322?dopt=Abstract
date added to LUP
2010-09-02 10:57:32
date last changed
2016-12-04 04:37:33
@misc{d815d0e2-a106-4e85-94f2-a15081c6d32c,
  abstract     = {Dopamine (DA) replacement therapy with l-DOPA remains the most effective treatment for Parkinson's disease, but causes dyskinesia (abnormal involuntary movements) in the vast majority of the patients. The basic mechanisms of l-DOPA-induced dyskinesia (LID) have become the object of intense research focusing on neurochemical and molecular adaptations in the striatum. Here we review this vast literature and highlight trends that converge into a unifying pathophysiological interpretation. We propose that the core molecular alteration of striatal neurons in LID consists in an inability to turn down supersensitive signaling responses downstream of DA D1 receptors (where supersensitivity is primarily caused by DA denervation). The sustained activation of intracellular signaling pathways induced by each dose of l-DOPA leads to abnormal cellular plasticity and high bioenergetic expenditure. The over-exploitation of signaling pathways and energy reserves during treatment impairs the ability of striatal neurons to dynamically gate cortically driven motor commands. LID thus exemplifies a disorder where 'too much' molecular plasticity leads to plasticity failure in the striatum.},
  author       = {Cenci Nilsson, Angela and Konradi, Christine},
  issn         = {1875-7855},
  language     = {eng},
  pages        = {209--233},
  publisher    = {ARRAY(0x98cd568)},
  series       = {Progress in Brain Research},
  title        = {Maladaptive striatal plasticity in L-DOPA-induced dyskinesia.},
  url          = {http://dx.doi.org/10.1016/S0079-6123(10)83011-0},
  volume       = {183},
  year         = {2010},
}