Endogenous Activation of mGlu5 Metabotropic Glutamate Receptors Contributes to the Development of Nigro-Striatal Damage Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in Mice

Giuseppe Battaglia, Carla L. Busceti, Gemma Molinaro, Francesca Biagioni, Marianna Storto, Francesco Fornai, Ferdinando Nicoletti, Valeria Bruno

Research output: Contribution to journalArticle

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Abstract

We combined the use of knock-out mice and subtype-selective antagonists [2-methyl-6-(phenylethynyl)pyridine (MPEP) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB1893)] to examine whether endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the pathophysiology of nigro-striatal damage in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. High doses of MPTP (four injections of 20 mg/kg, i.p., every 2 hr) induced a high mortality rate and a nearly total degeneration of the nigro-striatal pathway in wild-type mice. mGlu5 knock-out mice were less sensitive to MPTP toxicity, as shown by a higher survival and a milder nigro-striatal damage. Protection against MPTP (80 mg/kg) toxicity was also observed after MPEP injections (four injections of 5 mg/kg, i.p., 30 min before each MPTP injection). MPEP treatment did not further increase neuroprotection against 80 mg/kg of MPTP in mGlu5 knock-out mice, indicating that the drug acted by inhibiting mGlu5 receptors. In wild-type mice, MPEP was also neuroprotective when challenged against lower doses of MPTP (either 30 mg/kg, single injection, or four of 10 mg/kg injections). The action of MPEP was mimicked by SIB1893 but not by the mGlu1 receptor antagonist 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester. MPEP did not change the kinetics of 1-methyl-4-phenylpyridinium ion formation in the striatum of mice injected with MPTP. We conclude that mGlu5 receptors act as amplifiers of MPTP toxicity and that mGlu5 receptor antagonists maylimit the extent of nigro-striatal damage in experimental models of parkinsonism.

Original languageEnglish (US)
Pages (from-to)828-835
Number of pages8
JournalJournal of Neuroscience
Volume24
Issue number4
DOIs
StatePublished - Jan 28 2004

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Corpus Striatum
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Metabotropic Glutamate Receptors
Injections
Knockout Mice
Parkinsonian Disorders
1-Methyl-4-phenylpyridinium
4-phenyl-1,2,3,6-tetrahydropyridine
Carboxylic Acids
Esters
Theoretical Models
pyridine
Mortality

Keywords

  • Basal ganglia
  • Dopamine
  • Experimental parkinsonism
  • mGlu5 receptors
  • MPTP toxicity
  • Neuroprotection

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Endogenous Activation of mGlu5 Metabotropic Glutamate Receptors Contributes to the Development of Nigro-Striatal Damage Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in Mice. / Battaglia, Giuseppe; Busceti, Carla L.; Molinaro, Gemma; Biagioni, Francesca; Storto, Marianna; Fornai, Francesco; Nicoletti, Ferdinando; Bruno, Valeria.

In: Journal of Neuroscience, Vol. 24, No. 4, 28.01.2004, p. 828-835.

Research output: Contribution to journalArticle

Battaglia, Giuseppe ; Busceti, Carla L. ; Molinaro, Gemma ; Biagioni, Francesca ; Storto, Marianna ; Fornai, Francesco ; Nicoletti, Ferdinando ; Bruno, Valeria. / Endogenous Activation of mGlu5 Metabotropic Glutamate Receptors Contributes to the Development of Nigro-Striatal Damage Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in Mice. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 4. pp. 828-835.
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AU - Battaglia, Giuseppe

AU - Busceti, Carla L.

AU - Molinaro, Gemma

AU - Biagioni, Francesca

AU - Storto, Marianna

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AU - Nicoletti, Ferdinando

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