Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity

Giuseppe Battaglia, Francesco Fornai, Carla L. Busceti, Gabriella Aloisi, Franca Cerrito, Antonio De Blasi, Daniela Melchiorri, Ferdinando Nicoletti

Research output: Contribution to journalArticlepeer-review

Abstract

Methamphetamine (MA), a widely used drug of abuse, produces oxidative damage of nigrostriatal dopaminergic terminals. We examined the effect of subtype-selective ligands of metabotropic glutamate (mGlu) receptors on MA neurotoxicity in mice. MA (5 mg/kg, i.p.; injected three times, every 2 hr) induced, 5 d later, a substantial degeneration of striatal dopaminergic terminals associated with reactive gliosis. MA toxicity was primarily attenuated by the coinjection of the noncompetitive mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine and (E)-2-methyl-6-styrylpyridine both at 10 mg/kg, i.p.). In contrast, the mGlu1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (10 mg/kg, i.p.), and the mGlu2/3 receptor agonist (-)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (1 mg/kg, i.p.), failed to affect MA toxicity. mGlu5 receptor antagonists reduced the production of reactive oxygen species but did not reduce the acute stimulation of dopamine release induced by MA both in striatal synaptosomes and in the striatum of freely moving mice. We conclude that endogenous activation of mGlu5 receptors enables the development of MA neurotoxicity and that mGlu5 receptor antagonists are neuroprotective without interfering with the primary mechanism of action of MA.

Original languageEnglish
Pages (from-to)2135-2141
Number of pages7
JournalJournal of Neuroscience
Volume22
Issue number6
Publication statusPublished - Mar 15 2002

Keywords

  • Methamphetamine toxicity
  • MGlu5 antagonists
  • Microdialysis
  • Neuroprotection
  • Reactive oxygen species
  • Striatal dopaminergic terminals

ASJC Scopus subject areas

  • Neuroscience(all)

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