Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: Effects of combined treatment and possible mechanisms of action.
Iderberg, Hanna LU ; Rylander, Daniella LU ; Bimpisidis, Zisis LU and Cenci Nilsson, Angela LU
(2013)
In Experimental Neurology
250.
p.116-124
- Abstract
- l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's disease. Emerging approaches to the treatment of LID include negative modulation of metabotropic glutamate receptor type 5 (mGluR5) and positive modulation of serotonin receptors 5-HT1A/1B. We set out to compare the efficacy of these two approaches in alleviating the dyskinesias induced by either l-DOPA or a D1 receptor agonist. Rats with unilateral 6-OHDA lesions were treated chronically with either l-DOPA or the selective D1-class receptor agonist SKF38393 to induce abnormal involuntary movements (AIMs). Rats with stable AIM scores received challenge doses of the mGluR5 antagonist, MTEP (2.5 and 5mg/kg), or the 5-HT1A/1B agonists... (More)
- l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's disease. Emerging approaches to the treatment of LID include negative modulation of metabotropic glutamate receptor type 5 (mGluR5) and positive modulation of serotonin receptors 5-HT1A/1B. We set out to compare the efficacy of these two approaches in alleviating the dyskinesias induced by either l-DOPA or a D1 receptor agonist. Rats with unilateral 6-OHDA lesions were treated chronically with either l-DOPA or the selective D1-class receptor agonist SKF38393 to induce abnormal involuntary movements (AIMs). Rats with stable AIM scores received challenge doses of the mGluR5 antagonist, MTEP (2.5 and 5mg/kg), or the 5-HT1A/1B agonists 8-OH-DPAT/CP94253 (0.035/0.75 and 0.05/1.0mg/kg). Treatments were given either alone or in combination. In agreement with previous studies, 5mg/kg MTEP and 0.05/1.0mg/kg 8-OH-DPAT/CP94253 significantly reduced l-DOPA-induced AIM scores. The two treatments in combination achieved a significantly greater effect than each treatment alone. Moreover, a significant attenuation of l-DOPA-induced AIM scores was achieved when combining doses of MTEP (2.5mg/kg) and 8-OH-DPAT/CP94253 (0.035/0.75mg/kg) that did not have a significant effect if given alone. SKF38393-induced AIM scores were reduced by MTEP at both doses tested, but not by 0.05/1.0mg/kg 8-OH-DPAT/CP94253. The differential efficacy of MTEP and 8-OH-DPAT/CP94253 in reducing l-DOPA- versus SKF38393-induced dyskinesia indicates that these treatments have different mechanisms of action. This contention is supported by the efficacy of subthreshold doses of these compounds in reducing l-DOPA-induced AIMs. Combining negative modulators of mGluR5 with positive modulators of 5-HT1A/1B receptors may therefore achieve greater than additive antidyskinetic effects and reduce the dose requirement for these drugs in Parkinson's disease. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4065941
- author
- Iderberg, Hanna
LU
; Rylander, Daniella
LU
; Bimpisidis, Zisis
LU
and Cenci Nilsson, Angela
LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Experimental Neurology
- volume
- 250
- pages
- 116 - 124
- publisher
- Elsevier
- external identifiers
-
- wos:000328305600012
- pmid:24029003
- scopus:84885345968
- pmid:24029003
- ISSN
- 0014-4886
- DOI
- 10.1016/j.expneurol.2013.09.003
- language
- English
- LU publication?
- yes
- id
- f3a81cd2-ca3e-47ec-8002-d64a72acbe20 (old id 4065941)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/24029003?dopt=Abstract
- date added to LUP
- 2016-04-01 10:22:24
- date last changed
- 2022-05-13 08:16:40
@article{f3a81cd2-ca3e-47ec-8002-d64a72acbe20,
abstract = {{l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's disease. Emerging approaches to the treatment of LID include negative modulation of metabotropic glutamate receptor type 5 (mGluR5) and positive modulation of serotonin receptors 5-HT1A/1B. We set out to compare the efficacy of these two approaches in alleviating the dyskinesias induced by either l-DOPA or a D1 receptor agonist. Rats with unilateral 6-OHDA lesions were treated chronically with either l-DOPA or the selective D1-class receptor agonist SKF38393 to induce abnormal involuntary movements (AIMs). Rats with stable AIM scores received challenge doses of the mGluR5 antagonist, MTEP (2.5 and 5mg/kg), or the 5-HT1A/1B agonists 8-OH-DPAT/CP94253 (0.035/0.75 and 0.05/1.0mg/kg). Treatments were given either alone or in combination. In agreement with previous studies, 5mg/kg MTEP and 0.05/1.0mg/kg 8-OH-DPAT/CP94253 significantly reduced l-DOPA-induced AIM scores. The two treatments in combination achieved a significantly greater effect than each treatment alone. Moreover, a significant attenuation of l-DOPA-induced AIM scores was achieved when combining doses of MTEP (2.5mg/kg) and 8-OH-DPAT/CP94253 (0.035/0.75mg/kg) that did not have a significant effect if given alone. SKF38393-induced AIM scores were reduced by MTEP at both doses tested, but not by 0.05/1.0mg/kg 8-OH-DPAT/CP94253. The differential efficacy of MTEP and 8-OH-DPAT/CP94253 in reducing l-DOPA- versus SKF38393-induced dyskinesia indicates that these treatments have different mechanisms of action. This contention is supported by the efficacy of subthreshold doses of these compounds in reducing l-DOPA-induced AIMs. Combining negative modulators of mGluR5 with positive modulators of 5-HT1A/1B receptors may therefore achieve greater than additive antidyskinetic effects and reduce the dose requirement for these drugs in Parkinson's disease.}},
author = {{Iderberg, Hanna and Rylander, Daniella and Bimpisidis, Zisis and Cenci Nilsson, Angela}},
issn = {{0014-4886}},
language = {{eng}},
pages = {{116--124}},
publisher = {{Elsevier}},
series = {{Experimental Neurology}},
title = {{Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: Effects of combined treatment and possible mechanisms of action.}},
url = {{http://dx.doi.org/10.1016/j.expneurol.2013.09.003}},
doi = {{10.1016/j.expneurol.2013.09.003}},
volume = {{250}},
year = {{2013}},
}