title: Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: effects of combined treatment and possible mechanisms of action.
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.
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Sciences, Lund University, BMC F11, 221 84 Lund, Sweden. Electronic address: Hanna.Iderberg@med.lu.se.
authors.forename: Hanna
authors.initials: H
authors.lastname: Iderberg
authors.forename: Daniella
authors.initials: D
authors.lastname: Rylander
authors.forename: Zisis
authors.initials: Z
authors.lastname: Bimpisidis
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D018491:Dopamine Agonists / Q000494:pharmacology; D004357:Drug Synergism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D007980:Levodopa / Q000009:adverse effects; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D044302:Receptor, Serotonin, 5-HT1B; D017447:Receptors, Dopamine D1; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin
keywords: 5-HT1A/1B agonists; 6-OHDA rat model; DA agonist; Metabotropic glutamate receptor 5; Parkinson's disease; l-DOPA-induced dyskinesia