Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

Abstract

The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients.

• Authors: Paolo Calabresi, Veronica Ghiglieri, Petra Mazzocchetti, Ilenia Corbelli, Barbara Picconi
• Journal: Philosophical transactions of the Royal Society of London. Series B, Biological sciences (Philos Trans R Soc Lond B Biol Sci) Vol. 370 Issue 1672 (Jul 05 2015) ISSN: 1471-2970 [Electronic] England
• PMID: 26009763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Chemical References

• Levodopa
• Dopamine

Topics

• Cerebral Cortex (physiopathology)
• Corpus Striatum (physiopathology)
• Dopamine (metabolism)
• Dose-Response Relationship, Drug
• Hippocampus (physiopathology)
• Humans
• Levodopa (adverse effects, pharmacology)
• Neuronal Plasticity (drug effects, physiology)
• Parkinson Disease (drug therapy, physiopathology)