Blockade of metabotropic glutamate receptors inhibits cognition and neurodegeneration in an MPTP-induced Parkinson's disease rat model

Pharmacol Biochem Behav. 2012 Jul;102(1):64-71. doi: 10.1016/j.pbb.2012.03.022. Epub 2012 Mar 31.


Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinson's disease (PD). Metabotropic glutamate receptor subtype 5 (mGluR5) modulates glutamatergic transmission and thus has been proposed as a potential target for neuroprotective drugs. The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an mGluR5 antagonist, on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were stereotaxically injected with MPTP into the substantia nigra pars compacta (SNc). Starting 1 day after lesioning (day 1), the rats were treated daily with MPEP (2mg/kg/day, i.p.) for 14 days and rats underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test and both effects were prevented by MPEP treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all inhibited by MPEP treatment. These data provide support for a role of mGluR5s in the pathophysiology of PD and suggest that MPEP is a promising pharmacological tool for the development of new treatments for dementia associated with PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / metabolism*
  • Cognition Disorders / psychology
  • Disease Models, Animal
  • Male
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / psychology
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / psychology
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / physiology


  • Pyridines
  • Receptors, Metabotropic Glutamate
  • 6-methyl-2-(phenylethynyl)pyridine