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. doi: 10.1016/j.expneurol.2013.09.003. Epub 2013 Sep 10.

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.

Keywords: 5-HT1A/1B agonists; 6-OHDA rat model; DA agonist; Metabotropic glutamate receptor 5; Parkinson's disease; l-DOPA-induced dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Antiparkinson Agents / adverse effects
  • Dopamine Agonists / pharmacology
  • Drug Synergism
  • Dyskinesia, Drug-Induced / drug therapy*
  • Levodopa / adverse effects
  • Parkinsonian Disorders / drug therapy*
  • Pyridines / pharmacology*
  • Rats
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT1B / metabolism
  • Receptors, Dopamine D1 / agonists
  • Serotonin Receptor Agonists / pharmacology*
  • Thiazoles / pharmacology*

Substances

  • 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine
  • Antiparkinson Agents
  • Dopamine Agonists
  • Grm5 protein, rat
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Dopamine D1
  • Serotonin Receptor Agonists
  • Thiazoles
  • Receptor, Serotonin, 5-HT1A
  • Levodopa
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • 8-Hydroxy-2-(di-n-propylamino)tetralin