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Brain Advance Access published online on December 2, 2008
Brain, doi:10.1093/brain/awn322
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients

I. A. Prescott1, J. O. Dostrovsky1,2, E. Moro2, M. Hodaie2, A. M. Lozano2 and W. D. Hutchison1,2

1Department of Physiology, University of Toronto, Canada and 2Division of Neurosurgery, Department of Surgery, Toronto Western Research Institute and Krembil Neuroscience Centre, Canada

Correspondence to: W. D. Hutchison, PhD, Associate Professor of Surgery and Physiology, University of Toronto, and Senior Scientist, Toronto Western Research Institute, 399 Bathurst Street, MP11-308, Toronto, Canada M5T 2S8. E-mail: whutch{at}uhnres.utoronto.ca

Parkinson's disease, caused by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease characterized by bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-dopa) is the most effective treatment for the amelioration of Parkinson's disease signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-dopa -induced dyskinesias (LIDs). Studies in rat striatal slices have shown dopamine to be an essential component of activity-dependent synaptic plasticity at the input to the basal ganglia, but dopamine is also released from ventrally projecting dendrites of the substantia nigra pars compacta (SNc) on the substantia nigra pars reticulata (SNr), a major output structure of the basal ganglia. We characterized synaptic plasticity in the SNr using field potentials evoked with a nearby microelectrode (fEPs), in 18 Parkinson's disease patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN). High frequency stimulation (HFS—four trains of 2 s at 100 Hz) in the SNr failed to induce a lasting change in test fEPs (1 Hz) amplitudes in patients OFF medication (decayed to baseline by 160 s). Following oral L-dopa administration, HFS induced a potentiation of the fEP amplitudes (+29.3% of baseline at 160 s following a plateau). Our findings suggest that extrastriatal dopamine modulates activity-dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of Parkinson's disease.

Key Words: Parkinson's disease; substantia nigra; synaptic plasticity; microelectrode recordings; basal ganglia

Abbreviations: DBS, deep brain stimulating; fEP, field evoked potential; HFS, high frequency stimulation; LTP, long-term potentiation; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus

Received August 13, 2008. Revised October 1, 2008. Accepted October 24, 2008.


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