l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation

Barbara Picconi, Vincent Paillé, Veronica Ghiglieri, Vincenza Bagetta, Ilaria Barone, Hanna S. Lindgren, Giorgio Bernardi, M. Angela Cenci, Paolo Calabresi

Research output: Contribution to journalArticlepeer-review

Abstract

The emergence of levodopa (l-DOPA)-induced dyskinesia and motor fluctuations represents a major clinical problem in Parkinson's disease (PD). While it has been suggested that the daily dose of l-DOPA can play a critical role, the mechanisms linking l-DOPA dosage to the occurrence of motor complications have not yet been explored. Using an experimental model of PD we have recently demonstrated that long-term l-DOPA treatment leading to the induction of abnormal involuntary movements (AIMs) alters corticostriatal bidirectional synaptic plasticity. Dyskinetic animals, in fact, lack the ability to reverse previously induced long-term potentiation (LTP). This lack of depotentiation has been associated to a defect in erasing unessential motor information. Here chronic l-DOPA treatment was administered at two different doses to hemiparkinsonian rats, and electrophysiological recordings were subsequently performed from striatal spiny neurons. Both low and high doses of l-DOPA restored normal LTP, which was disrupted following dopamine (DA) denervation. By the end of the chronic treatment, however, while the low l-DOPA dose induced AIMs only in half of the rats, the high dose caused motor complications in all the treated animals. Interestingly, the dose-related expression of motor complications was associated with a lack of synaptic depotentiation. Our study provides further experimental evidence to support a direct correlation between the daily dosage of l-DOPA and the induction of motor complications and establishes a critical pathophysiological link between the lack of synaptic depotentiation and the expression of AIMs.

Original languageEnglish
Pages (from-to)327-335
Number of pages9
JournalNeurobiology of Disease
Volume29
Issue number2
DOIs
Publication statusPublished - Feb 2008

Keywords

  • Dyskinesia
  • Electrophysiology
  • Levodopa
  • Parkinson's disease
  • Striatum
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neurology

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