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The Journal of Neuroscience, March 15, 2002, 22(6):2135-2141

Selective Blockade of mGlu5 Metabotropic Glutamate Receptors Is Protective against Methamphetamine Neurotoxicity

Giuseppe Battaglia¹, Francesco Fornai^{1, 2}, Carla L. Busceti¹, Gabriella Aloisi³, Franca Cerrito³, Antonio De Blasi¹, Daniela Melchiorri⁴, and Ferdinando Nicoletti^{1, 4}

¹ Instituto Neuromed Mediterraneo, Pozzilli (Isernia) 86077, Italy, ² Department of Human Morphology and Applied Biology, University of Pisa, Pisa 56126, Italy, ³ Department of Experimental Medicine, University of L'Aquila, L'Aquila 67100, Italy, and ⁴ Department of Human Physiology and Pharmacology, University of Roma "La Sapienza", 00185 Rome, Italy

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.

Key words: neuroprotection; methamphetamine toxicity; mGlu5 antagonists; microdialysis; striatal dopaminergic terminals; reactive oxygen species

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2262135-07$05.00/0

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