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

• Published in: Brain (London, England : 1878) Vol. 132; no. 2; pp. 309 - 318
• Main Authors: Prescott, I. A., Dostrovsky, J. O., Moro, E., Hodaie, M., Lozano, A. M., Hutchison, W. D.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2009; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Antiparkinson Agents - therapeutic use; basal ganglia; Basal Ganglia - physiopathology; Biological and medical sciences; Deep Brain Stimulation; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Evoked Potentials - drug effects; Female; Humans; Levodopa - therapeutic use; Male; Medical sciences; microelectrode recordings; Microelectrodes; Middle Aged; Neurology; Neuronal Plasticity - drug effects; Parkinson Disease - drug therapy; Parkinson Disease - physiopathology; Parkinson Disease - therapy; Parkinson's disease; Stimulation, Chemical; substantia nigra; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - physiopathology; synaptic plasticity; substantia nigra; Parkinson's disease; basal ganglia; synaptic plasticity; microelectrode recordings; Human; Nervous system diseases; Central nervous system; Parkinson disease; Basal ganglion; Encephalon; Cerebral disorder; Locus niger; Central nervous system disease; Synaptic plasticity; Microelectrode; Degenerative disease; Levodopa; Extrapyramidal syndrome
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awn322

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.