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The Journal of Neuroscience, October 18, 2006, 26(42):10768-10776; doi:10.1523/JNEUROSCI.3065-06.2006

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Neurobiology of Disease
Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

Sabrina Boulet,^1,2 Emilie Lacombe,^1,2 Carole Carcenac,^1,2 Claude Feuerstein,^1,2 Véronique Sgambato-Faure,^1,2 Annie Poupard,^1,2 and Marc Savasta^1,2

¹Dynamique des Réseaux Neuronaux, Institut National de la Santé et de la Recherche Médicale, Unité 704, F-38041 Grenoble, France, and ²Université Joseph Fourier, F-38041 Grenoble, France

Correspondence should be addressed to Dr. Marc Savasta, Dynamique des Réseaux Neuronaux, Institut National de la Santé et de la Recherche Médicale, Unité 704, Université Joseph Fourier, Unité de Formation par la Recherche en Biologie, Bâtiment B, Domaine Universitaire, 2280 rue de la Piscine, Boîte Postale 53, 38041 Grenoble Cedex 09, France. E-mail: Email: marc.savasta{at}ujf-grenoble.fr

The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN–HFS) alleviates the motor symptoms of Parkinson's disease (PD) remain unclear. In this study, we analyzed the effects of STN–HFS on motor behavior in intact or hemiparkinsonian rats (6-hydroxydopamine lesion of the substantia nigra pars compacta) and investigated the correlation between these effects and extracellular glutamate (Glu) and GABA levels, assessed by intracerebral microdialysis in the substantia nigra pars reticulata (SNr). STN–HFS at an intensity corresponding to the threshold inducing contralateral forelimb dyskinesia, increased Glu levels in the SNr of both intact and hemiparkinsonian rats. In contrast, STN–HFS at half this intensity did not affect Glu levels in the SNr in intact or hemiparkinsonian rats but increased GABA levels in hemiparkinsonian rats only. STN–HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr. These new neurochemical data suggest that STN–HFS-induced forelimb dyskinesia is mediated by glutamate, probably via the direct activation of STN axons, shedding light on the mechanisms of STN–HFS in PD.

Key words: subthalamic nucleus; substantia nigra pars reticulata; glutamate; GABA; high-frequency deep brain stimulation; Parkinson's disease; dyskinesia

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Received May 15, 2006; revised Sept. 1, 2006; accepted Sept. 4, 2006.

Correspondence should be addressed to Dr. Marc Savasta, Dynamique des Réseaux Neuronaux, Institut National de la Santé et de la Recherche Médicale, Unité 704, Université Joseph Fourier, Unité de Formation par la Recherche en Biologie, Bâtiment B, Domaine Universitaire, 2280 rue de la Piscine, Boîte Postale 53, 38041 Grenoble Cedex 09, France. E-mail: Email: marc.savasta{at}ujf-grenoble.fr

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