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Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: effects of combined treatment and possible mechanisms of action.
Exp Neurol. 2013 Dec; 250:116-24.EN

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 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.

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Authors+Show Affiliations

Iderberg H
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Sciences, Lund University, BMC F11, 221 84 Lund, Sweden. Electronic address: Hanna.Iderberg@med.lu.se.
Rylander D
No affiliation info available
Bimpisidis Z
No affiliation info available
Cenci MA
No affiliation info available

MeSH

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine8-Hydroxy-2-(di-n-propylamino)tetralinAnimalsAntiparkinson AgentsDopamine AgonistsDrug SynergismDyskinesia, Drug-InducedLevodopaParkinsonian DisordersPyridinesRatsReceptor, Metabotropic Glutamate 5Receptor, Serotonin, 5-HT1AReceptor, Serotonin, 5-HT1BReceptors, Dopamine D1Serotonin Receptor AgonistsThiazoles

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24029003

Citation

Iderberg, Hanna, et al. "Modulating mGluR5 and 5-HT1A/1B Receptors to Treat l-DOPA-induced Dyskinesia: Effects of Combined Treatment and Possible Mechanisms of Action." Experimental Neurology, vol. 250, 2013, pp. 116-24.
Iderberg H, Rylander D, Bimpisidis Z, et al. Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: effects of combined treatment and possible mechanisms of action. Exp Neurol. 2013;250:116-24.
Iderberg, H., Rylander, D., Bimpisidis, Z., & Cenci, M. A. (2013). Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: effects of combined treatment and possible mechanisms of action. Experimental Neurology, 250, 116-24. https://doi.org/10.1016/j.expneurol.2013.09.003
Iderberg H, et al. Modulating mGluR5 and 5-HT1A/1B Receptors to Treat l-DOPA-induced Dyskinesia: Effects of Combined Treatment and Possible Mechanisms of Action. Exp Neurol. 2013;250:116-24. PubMed PMID: 24029003.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: effects of combined treatment and possible mechanisms of action. AU - Iderberg,Hanna, AU - Rylander,Daniella, AU - Bimpisidis,Zisis, AU - Cenci,M Angela, Y1 - 2013/09/10/ PY - 2013/06/07/received PY - 2013/08/24/revised PY - 2013/09/01/accepted PY - 2013/9/14/entrez PY - 2013/9/14/pubmed PY - 2014/1/31/medline KW - 5-HT1A/1B agonists KW - 6-OHDA rat model KW - DA agonist KW - Metabotropic glutamate receptor 5 KW - Parkinson's disease KW - l-DOPA-induced dyskinesia SP - 116 EP - 24 JF - Experimental neurology JO - Exp Neurol VL - 250 N2 - 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 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. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/24029003/Modulating_mGluR5_and_5_HT1A/1B_receptors_to_treat_l_DOPA_induced_dyskinesia:_effects_of_combined_treatment_and_possible_mechanisms_of_action_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(13)00271-9 DB - PRIME DP - Unbound Medicine ER -