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Pathophysiology of levodopa-induced dyskinesia: Potential for new therapies

Key Points

  • Levodopa-induced dyskinesia (LID) is a common complication after dopamine-replacement therapy in Parkinson's disease. The neural mechanisms underlying LID are far from clear, although significant advances have been made in recent years.

  • It is commonly assumed that levodopa induces dyskinesia by excessive inhibition of neurons of the projection from the putamen to the external segment of the globus pallidus (GPe), and subsequent disinhibition of the GPe. This dishinibition leads, in turn, to overinhibition of the subthalamic nucleus (STN) and to subsequent hypoactivity in output neurons of the basal ganglia. The net effect of these imbalances would be reduced inhibition of thalamocortical neurons and overactivation of cortical motor areas.

  • Marked abnormalities of neuronal function seem to accompany LID. They include changes in blood flow in the basal ganglia and in cortical motor areas, metabolic changes in the motor thalamus and internal segment of the globus pallidus (GPi), and alterations in the frequency and pattern of firing of GPi neurons.

  • Denervation supersensitivity of dopamine receptors has been widely suggested as the most plausible mechanism to underlie LID. This supersensitivity might be the result of changes in receptor number and cellular distribution, or changes in the signalling pathways downstream of receptor activation. As enhanced D1 dopamine receptor function might accompany the generation of dyskinesia, it is possible that the mechanisms underlying LID involve the direct pathway. This finding is surprising because, as described above, the neural mechanisms of dyskinesia are generally thought to involve the indirect rather than the direct pathway. Whereas the indirect pathway influences the output structures indirectly through a series of connections that involves the GPe and STN, the direct pathway comprises striatal neurons that project directly to the GPi and the substantia nigra.

  • Other neurotransmitters could also participate in the pathogenesis and treatment of LID. They include glutamate, enkephalins and opioid peptides. In fact, significant attention has been focused on the possibility that, in addition to the conventional dopamine-related therapeutic approaches, new pharmacological agents that are effective against these other neurotransmitter systems might be effective in treating LID.

Abstract

Involuntary movements — or dyskinesias — are a debilitating complication of levodopa therapy for Parkinson's disease that is experienced by most patients. Despite the importance of this problem, little was known about the cause of dyskinesia until recently; however, this situation has changed significantly in the past few years. Our increased understanding of levodopa-induced dyskinesia is not only valuable for improving patient care, but also in providing us with new insights into the functional organization of the basal ganglia and motor systems.

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Figure 1: Functional connectivity in the basal ganglia–thalamo–cortical circuit in Parkinson's disease and levodopa-induced dyskinesia.
Figure 2: Densitometric analysis of 2-deoxyglucose accumulation within the subthalamic nucleus of normal, choreic and dystonic monkeys.

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Acknowledgements

We thank S. Fox for helpful discussion and comments during the preparation of the manuscript. E.B. was supported by a grant from the Société de Secours des Amis des Sciences. J.M.B. is supported by the Medical Research Council (UK) and the Parkinson's Disease Society (UK). The University of Manchester, the CNRS and the IFR of Neuroscience funded this review. Our apologies to the many authors whose work could not be quoted because of space limitations.

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41583_2001_BF35086062_MOESM1_ESM.htm

Links to patents referred to in Table 1 | Patent applications related to the treatment of levodopa-induced dyskinesia (HTM 2 kb)

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DATABASE LINKS

Parkinson's disease

substance P

preproenkephalin B

D1

D2

Huntington's disease

D3

iGluRs

mGluRs

δ-opioid receptor

μ-opioid receptor

κ-opioid receptor

D5

D4

A2a

H3

CB1

α2-adrenoceptors

Glossary

BRADYKINESIA

Slowing of and difficulty in initiating movement that is characteristic of Parkinson's disease.

ON–OFF FLUCTUATIONS

A sudden loss of levodopa-induced benefit ('on' state) and onset of the parkinsonian state ('off' state). The term 'on–off' depicts well the speed of this change in therapeutic benefit, which has been likened to switching a light on and off.

WEARING-OFF PHENOMENON

A decrease in the duration of levodopa action, also known as the 'end-of-dose' deterioration. It is characterized by the gradual reappearance of the 'off' state, and shortening of the 'on' state.

MEDIUM SPINY NEURONS

The main cell population of the ventral and dorsal striatum; these GABA-containing projection neurons form the two main outputs of these structures, called the direct and indirect pathways.

BALLISM

Large-amplitude flinging, flailing movements, often associated with damage to the subthalamic nucleus.

CHOREOATHETOSIS

A movement disorder that is characterized by constant writhing and jerking motions.

MYOCLONUS

Brief, involuntary twitching of a muscle or a group of muscles. Familiar examples of normal myoclonus include hiccups and jerks experienced when drifting off to sleep.

AKATHISIA

Motor restlessness associated with increased nervousness, jittery feeling and insomnia. It is often seen as a side effect of long-term antipsychotic treatment.

6-HYDROXYDOPAMINE MODEL

Unilateral administration of 6-OHDA to the substantia nigra of rodents leads to degeneration of the nigrostriatal dopamine pathway. The extent of dopamine depletion can then be assessed by examining circling behaviour in response to amphetamine and apomorphine.

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY

A method in which images are generated by using radionuclides that emit single photons of a given energy. Images are captured at multiple positions by rotating the sensor around the subject; the three-dimensional distribution of radionuclides is then used to reconstruct the images. SPECT can be used to observe biochemical and physiological processes, as well as the size and volume of structures. Unlike positron emission tomography, SPECT requires the physical alignment of the photons for their detection, resulting in the loss of many available photons and the degradation of the image.

DIPRENORPHINE

A marker of μ-, κ- and δ-opioid receptors that is sensitive to the levels of endogenous opioids.

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Bezard, E., Brotchie, J. & Gross, C. Pathophysiology of levodopa-induced dyskinesia: Potential for new therapies. Nat Rev Neurosci 2, 577–588 (2001). https://doi.org/10.1038/35086062

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