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Modulation of l-DOPA-induced abnormal involuntary movements by clinically tested compounds: Further validation of the rat dyskinesia model.

Dekundy, Andrzej; Lundblad, Martin LU ; Danysz, Wojciech and Cenci Nilsson, Angela LU (2007) In Behavioural Brain Research 179(1). p.76-89
Abstract
l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's Disease. A model of LID has recently been described in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In the present study, the model was used in order to compare the efficacies of some clinically available compounds that have shown antidyskinetic effects in nonhuman primate models of LID and/or in patients, namely, amantadine (20 and 40 mg/kg), buspirone (1, 2 and 4 mg/kg), clonidine (0.01, 0.1 and 1 mg/kg), clozapine (4 and 8 mg/kg), fluoxetine (2.5 and 5 mg/kg), propranolol (5, 10 and 20 mg/kg), riluzole (2 and 4 mg/kg), and yohimbine (2 and 10 mg/kg). Rats were treated for 3 weeks with l-DOPA for an induction and monitoring of... (More)
l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's Disease. A model of LID has recently been described in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In the present study, the model was used in order to compare the efficacies of some clinically available compounds that have shown antidyskinetic effects in nonhuman primate models of LID and/or in patients, namely, amantadine (20 and 40 mg/kg), buspirone (1, 2 and 4 mg/kg), clonidine (0.01, 0.1 and 1 mg/kg), clozapine (4 and 8 mg/kg), fluoxetine (2.5 and 5 mg/kg), propranolol (5, 10 and 20 mg/kg), riluzole (2 and 4 mg/kg), and yohimbine (2 and 10 mg/kg). Rats were treated for 3 weeks with l-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs) prior to the drug screening experiments. The antidyskinetic drugs or their vehicles were administered together with l-DOPA, and their effects were evaluated according to a randomized cross-over design both on the AIM rating scale and on the rotarod test. Most of the compounds under investigation attenuated the l-DOPA-induced axial, limb and orolingual AIM scores. However, the highest doses of many of these substances (but for amantadine and riluzole) had also detrimental motor effects, producing a reduction in rotarod performance and locomotor scores. Since the present results correspond well to existing clinical and experimental data, this study indicates that axial, limb and orolingual AIMs possess predictive validity for the preclinical screening of novel antidyskinetic treatments. Combining tests of general motor performance with AIMs ratings in the same experiment allows for selecting drugs that specifically reduce dyskinesia without diminishing the anti-akinetic effect of l-DOPA. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
5HT1A, Serotonin, Glutamate, Motor complications, Levodopa, Nicotinic, Adrenergic, Receptor
in
Behavioural Brain Research
volume
179
issue
1
pages
76 - 89
publisher
Elsevier
external identifiers
  • wos:000246033300009
  • scopus:33947302427
ISSN
0166-4328
DOI
10.1016/j.bbr.2007.01.013
language
English
LU publication?
yes
id
a860e62f-308a-4fe9-b99d-c87283e22f87 (old id 165641)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17306893&dopt=Abstract
date added to LUP
2007-07-11 12:49:40
date last changed
2017-10-01 03:54:43
@article{a860e62f-308a-4fe9-b99d-c87283e22f87,
  abstract     = {l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's Disease. A model of LID has recently been described in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In the present study, the model was used in order to compare the efficacies of some clinically available compounds that have shown antidyskinetic effects in nonhuman primate models of LID and/or in patients, namely, amantadine (20 and 40 mg/kg), buspirone (1, 2 and 4 mg/kg), clonidine (0.01, 0.1 and 1 mg/kg), clozapine (4 and 8 mg/kg), fluoxetine (2.5 and 5 mg/kg), propranolol (5, 10 and 20 mg/kg), riluzole (2 and 4 mg/kg), and yohimbine (2 and 10 mg/kg). Rats were treated for 3 weeks with l-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs) prior to the drug screening experiments. The antidyskinetic drugs or their vehicles were administered together with l-DOPA, and their effects were evaluated according to a randomized cross-over design both on the AIM rating scale and on the rotarod test. Most of the compounds under investigation attenuated the l-DOPA-induced axial, limb and orolingual AIM scores. However, the highest doses of many of these substances (but for amantadine and riluzole) had also detrimental motor effects, producing a reduction in rotarod performance and locomotor scores. Since the present results correspond well to existing clinical and experimental data, this study indicates that axial, limb and orolingual AIMs possess predictive validity for the preclinical screening of novel antidyskinetic treatments. Combining tests of general motor performance with AIMs ratings in the same experiment allows for selecting drugs that specifically reduce dyskinesia without diminishing the anti-akinetic effect of l-DOPA.},
  author       = {Dekundy, Andrzej and Lundblad, Martin and Danysz, Wojciech and Cenci Nilsson, Angela},
  issn         = {0166-4328},
  keyword      = {5HT1A,Serotonin,Glutamate,Motor complications,Levodopa,Nicotinic,Adrenergic,Receptor},
  language     = {eng},
  number       = {1},
  pages        = {76--89},
  publisher    = {Elsevier},
  series       = {Behavioural Brain Research},
  title        = {Modulation of l-DOPA-induced abnormal involuntary movements by clinically tested compounds: Further validation of the rat dyskinesia model.},
  url          = {http://dx.doi.org/10.1016/j.bbr.2007.01.013},
  volume       = {179},
  year         = {2007},
}