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Antagonizing L-type Ca2+ Channel Reduces Development of Abnormal Involuntary Movement in the Rat Model of L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

Schuster, Stefan; Doudnikoff, Evelyne; Rylander, Daniella LU ; Berthet, Amandine; Aubert, Incarnation; Ittrich, Carina; Bloch, Bertrand; Cenci, M. Angela; Surmeier, D. James and Hengerer, Bastian, et al. (2009) In Biological Psychiatry 65(6). p.518-526
Abstract
Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral... (More)
Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. Results: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. Conclusions: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD. (Less)
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Contribution to journal
publication status
published
subject
keywords
medium spiny neurons, isradipine, Parkinson's, disease, Electron microscopy
in
Biological Psychiatry
volume
65
issue
6
pages
518 - 526
publisher
Society of Biological Psychiatry Published by Elsevier Inc.
external identifiers
  • wos:000263895900010
  • scopus:60349126440
ISSN
0006-3223
DOI
10.1016/j.biopsych.2008.09.008
language
English
LU publication?
yes
id
bad59941-7931-41e2-9800-36bc0fbc027a (old id 1370791)
date added to LUP
2009-05-07 14:30:01
date last changed
2017-11-19 03:32:13
@article{bad59941-7931-41e2-9800-36bc0fbc027a,
  abstract     = {Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. Results: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. Conclusions: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.},
  author       = {Schuster, Stefan and Doudnikoff, Evelyne and Rylander, Daniella and Berthet, Amandine and Aubert, Incarnation and Ittrich, Carina and Bloch, Bertrand and Cenci, M. Angela and Surmeier, D. James and Hengerer, Bastian and Bezard, Erwan},
  issn         = {0006-3223},
  keyword      = {medium spiny neurons,isradipine,Parkinson's,disease,Electron microscopy},
  language     = {eng},
  number       = {6},
  pages        = {518--526},
  publisher    = {Society of Biological Psychiatry Published by Elsevier Inc.},
  series       = {Biological Psychiatry},
  title        = {Antagonizing L-type Ca2+ Channel Reduces Development of Abnormal Involuntary Movement in the Rat Model of L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia},
  url          = {http://dx.doi.org/10.1016/j.biopsych.2008.09.008},
  volume       = {65},
  year         = {2009},
}