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The Journal of Neuroscience, May 18, 2005, 25(20):5079-5086; doi:10.1523/JNEUROSCI.0360-05.2005

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Neurobiology of Disease
Pallidal Origin of GABA Release within the Substantia Nigra Pars Reticulata during High-Frequency Stimulation of the Subthalamic Nucleus

François Windels, Carole Carcenac, Annie Poupard, and Marc Savasta

Dynamique des Réseaux Neuronaux, Unité Mixte de Recherche, Institut National de la Santé et de la Recherche Médicale, Unité 704, Université Joseph Fourier, Unité de Formation par la Recherche en Biologie, 38041 Grenoble Cedex 09, France

High-frequency stimulation of the subthalamic nucleus (HFS-STN) is an effective treatment for alleviating the motor symptoms of parkinsonian patients. However, the neurochemical basis of its effects remains unknown. We showed previously that 1 h of HFS-STN in normal rats increases extracellular glutamate (Glu) level in the output nuclei of the STN, the globus pallidus (GP), and the substantia nigra pars reticulata (SNr), consistent with an increase in the activity of STN neurons. HFS-STN also increases GABA levels in the SNr, but the origin of this increase is unclear. We investigated the effectiveness of HFS-STN for improving Parkinson's disease symptoms, using intracerebral microdialysis to determine the extracellular Glu and GABA levels of the GP and SNr in response to HFS-STN in anesthetized hemiparkinsonian rats [6-hydroxydopamine lesion of the substantia nigra pars compacta (SNc)]. Basal levels of Glu and GABA in the GP and SNr were significantly higher in hemiparkinsonian than in intact rats. HFS-STN did not affect extracellular Glu level in the SNr of hemiparkinsonian rats but doubled the level of GABA. Ibotenic acid lesion of the GP abolished the increase in GABA levels in the SNr induced by HFS-STN in SNc-lesioned rats. These results provide neurochemical confirmation of the hyperactivity of the STN after dopaminergic denervation and suggest that the therapeutic effects of HFS-STN may result partly from the stimulation of pallidonigral fibers, thereby revealing a potential role for pallidal GABA in the inhibition of basal ganglial output structures during HFS-STN.

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

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Received Sep 29, 2004; revised April 13, 2005; accepted April 13, 2005.

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