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Molecular mechanisms of L-DOPA-induced dyskinesia

Nature Reviews Neuroscience volume 9, pages 665–677 (2008)Cite this article

Key Points

  • Involuntary movements (dyskinesia) develop in the course of Parkinson's disease (PD) and can be treatment-limiting. Two processes seem to be important: the 'priming' of motor systems for the initiation of dyskinesia and the processes that are responsible for its expression.

  • Dyskinesia has been associated with an imbalance in the output of the basal ganglia, but the pathophysiology of the involuntary movements remains unclear.

  • Loss of dopaminergic neurons in the substantia nigra is essential for dyskinesia induction, and the extent of denervation determines the vulnerability to non-physiological replacement of dopamine that occurs in the drug treatment of PD.

  • Attempts to define dyskinesia at the biochemical or molecular level have proved difficult. However, alterations in glutamatergic transmission seem to be key.

  • The basal ganglia are structurally and functionally abnormal in PD as a result of the loss of striatal dopaminergic input. Connectivity with the motor cortex is diminished, and the consequence is the abnormal motor response to drug treatment that comprises dyskinesia.

  • Novel approaches to treatment that alter intracellular signalling cascades and so normalize the integration of sensory and motor inputs to the basal ganglia and result in the restoration of normal movement (without dyskinesia induction or expression) in response to dopamine-replacement therapy might now be possible.

Abstract

L-DOPA (L-3,4-dihydroxyphenylalanine) remains the most effective drug for the treatment of Parkinson's disease. However, chronic use causes dyskinesia, a complex motor phenomenon that consists of two components: the execution of involuntary movements in response to drug administration, and the 'priming' phenomenon that underlies these movements' establishment and persistence. A reinterpretation of recent data suggests that priming for dyskinesia results from nigral denervation and the loss of striatal dopamine input, which alters glutamatergic synaptic connectivity in the striatum. The subsequent response of the abnormal basal ganglia to dopaminergic drugs determines the manner and timing of dyskinesia expression. The combination of nigral denervation and drug treatment establishes inappropriate signalling between the motor cortex and the striatum, leading to persistent dyskinesia.

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Figure 1: Time course of events in PD and L-DOPA-induced dyskinesia.
Figure 2: Classical model of the basal ganglia changes that underlie L-DOPA-induced dyskinesia.
Figure 3: Altered transmission in the striatum that leads to dyskinesia expression.

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Acknowledgements

The author has been supported by the Parkinson's Disease Society and by the National Parkinson Foundation for many aspects of this work.

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Authors and Affiliations

  1. King's College London, Guy's Campus, School of Health and Biomedical Sciences, SE1 1UL, London, UK

    Peter Jenner

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Peter Jenner has a 9% stockholding in Proximogen Neuroscience Ltd, which is developing novel drug treatments for Parkinson's Disease.

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DATABASES

OMIM

Parkinson's disease

Glossary

MPTP

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). A neurotoxin that, on systemic administration to mice or non-human primates, induces motor disability that closely resembles PD. MPTP is commonly used to study cellular and molecular aspects of PD, as it specifically induces the degeneration of dopaminergic neurons in the substantia nigra.

Priming

The abnormality in the basal ganglia that leads to the expression of dyskinesia following administration of dopaminergic agents. An analogy might be when an active process such as electrical stimulation leads to an epileptic focus.

Plasma half-life

The length of time that it takes for the concentration of a drug in the plasma to decline by 50%.

6-OHDA

(6-hydroxydopamine). A neurotoxin that, when it is administered unilaterally to the substantia nigra of rodents, causes degeneration of the nigrostriatal dopaminergic pathway. Subsequent administration of dopaminergic drugs causes motor asymmetry in the form of rotational behaviour.

Long-term potentiation

(LTP). A persistent strengthening of synaptic transmission in response to strong, correlated input.

Long-term depression

(LTD). A long-lasting decrease in the response of neurons to stimulation of their afferents following a brief patterned stimulus (for example, a 1 Hz stimulus).

Striatal medium spiny neurons

Medium sized, spiny GABAergic neurons that are found in the striatum. The spines are the points of synaptic input from other transmitter systems, notably glutamatergic input from the cortex.

Synaptic depotentiation

A reversal of LTP by low-frequency synaptic stimulation.

Pallidotomy

A surgical procedure involving electrocoagulation of the GPi. It is carried out to relieve drug-resistant tremor or dyskinesia in PD.

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Jenner, P. Molecular mechanisms of L-DOPA-induced dyskinesia. Nat Rev Neurosci 9, 665–677 (2008). https://doi.org/10.1038/nrn2471

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