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NEUROPHARMACOLOGY

Group III Metabotropic Glutamate-Receptor-Mediated Modulation of Excitatory Transmission in Rodent Substantia Nigra Pars Compacta Dopamine Neurons

Neuroscience Drug Discovery, Movement Disorders, Merck Research Laboratories, West Point, Pennsylvania (O.V., G.R.S., M.J.M.); Department of Pharmacology, University of Florence, Florence, Italy (G.M.); and Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee (P.J.C.)

Glutamate plays an important role in the regulation of dopamine neuron activity. In particular, the glutamatergic input from the subthalamic nucleus is thought to provide control over dopamine neuron firing patterns. The degeneration of dopamine neurons in the substantia nigra pars compacta (SNc) observed in Parkinson's disease (PD) is believed to be due to a complex interplay of factors, including oxidative stress and mitochondrial dysfunction. Although glutamate is not the primary cause of cell death in PD, there is evidence suggesting excessive glutamate release onto dopamine neurons may play a role in continued degeneration. Although many studies have focused on the role of glutamate in the SNc, little work has been directed at exploring the modulatory control of glutamate release in this region. Previous studies have found a high-potency inhibitory effect of nonselective group III mGluR agonist on glutamatergic transmission in the SNc. Using whole-cell patch-clamp methods and novel pharmacological tools, we have determined that mGluR4 mediates the group III mGluR modulation of excitatory transmission in the rat SNc. The group III mGluR-selective agonist L-(+)-2-amino-4-phosphonobutyric acid inhibits excitatory transmission in the SNc at low micromolar concentrations with a maximal inhibition occurring at 3 µM. This effect was potentiated by the mGluR4-selective allosteric modulator N-phenyl-7-(hydroxymino)cyclopropa[b]chromen-1a-carboxamide and was not mimicked by the mGluR8-selective agonist (S)-3,4-dicarboxyphenylglycine. Interestingly, in an attempt to employ knockout mice to confirm the role of mGluR4, we discovered an apparent species difference suggesting that in mice, both mGluR4 and mGluR8 modulate excitatory transmission in the SNc.

Address correspondence to: Dr. Michael J. Marino, Neuroscience Drug Discovery, Movement Disorders, Merck Research Laboratories, Merck and Co., Inc., WP46-300, 770 Sumneytown Pike, West Point, PA 19486. E-mail michael_marino{at}merck.com

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