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The Journal of Neuroscience, July 5, 2006, 26(27):7222-7229; doi:10.1523/JNEUROSCI.1595-06.2006

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Neurobiology of Disease
Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Reduces Nigrostriatal Degeneration in Mice Treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine

Giuseppe Battaglia,¹ Carla L. Busceti,¹ Gemma Molinaro,¹ Francesca Biagioni,¹ Anna Traficante,¹ Ferdinando Nicoletti,^1,2 and Valeria Bruno^1,2

¹Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy, and ²Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," 00185 Rome, Italy

Correspondence should be addressed to Dr. Valeria Bruno, Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," Piazzale Aldo Moro 5, 00185 Rome, Italy. Email: nicoletti{at}neuromed.it

We examined whether selective activation of mGlu4 metabotropic glutamate receptors attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage in mice. C57BL mice were treated with a single dose of MPTP (30 mg/kg, i.p.) preceded, 30 min earlier, by a systemic injection of the mGlu4 receptor enhancer N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). PHCCC was injected either subcutaneously in cremophor EL or intraperitoneally in saline containing 50% DMSO. PHCCC treatment (3 or 10 mg/kg) significantly reduced MPTP toxicity, as assessed by measurements of the striatal levels of dopamine and its metabolites and by tyrosine hydroxylase, dopamine transporter, and glial fibrillary acidic protein immunostaining in the corpus striatum and substantia nigra. In another set of experiments, a higher cumulative dose of MPTP (80 mg/kg divided into four injections with 2 h of interval) was injected to mGlu4^–/– mice and their Sv129/CD1 wild-type controls. A higher dose was used in these experiments because Sv129/CD1 mice are less sensitive to MPTP toxicity. Systemic administration of PHCCC was protective in wild-type mice but failed to affect nigrostriatal damage in mGlu4^–/– mice. Finally, unilateral infusion of PHCCC in the external globus pallidus protected the ipsilateral nigrostriatal pathway against MPTP toxicity. These data support the view that mGlu4 receptors are potential targets for the experimental treatment of parkinsonism.

Key words: basal ganglia; dopamine; MPTP toxicity; mGlu4 receptors; neuroprotection; experimental parkinsonism

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Received Sept. 29, 2005; revised May 19, 2006; accepted May 20, 2006.

Correspondence should be addressed to Dr. Valeria Bruno, Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," Piazzale Aldo Moro 5, 00185 Rome, Italy. Email: nicoletti{at}neuromed.it

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