Plastic effects of L-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia

doi:10.1016/S1353-8020(09)70782-5

Parkinsonism & Related Disorders

Volume 15, Supplement 3, December 2009, Pages S59-S63

https://doi.org/10.1016/S1353-8020(09)70782-5 Get rights and content

Summary

The development of L-DOPA-induced dyskinesia (LID) is attributed to plastic responses triggered by dopamine (DA) receptor stimulation in the parkinsonian brain. This article reviews studies that have uncovered different levels of maladaptive plasticity in animal models of LID. Rats developing dyskinesia on chronic L-DOPA treatment show abnormal patterns of signaling pathway activation and synaptic plasticity in striatal neurons. In addition, these animals show a gene expression profile indicative of structural cellular plasticity, including pronounced upregulation of genes involved in extracellular matrix remodeling, neurite extension, synaptic vesicle trafficking, and endothelial and cellular proliferation. Structural changes of neurons and microvessels within the basal ganglia are currently being unraveled by detailed morphological analyses. The structural and functional adaptations induced by L-DOPA in the brain can be viewed as an attempt to meet increased metabolic demands and to boost cellular defense mechanisms. These homeostatic responses, however, also predispose to the appearance of dyskinesia and other complications during the course of the treatment.

Introduction

L-DOPA remains the most efficacious drug to treat the signs and symptoms of Parkinson's disease, but it causes dyskinesia (abnormal involuntary movements) in the majority of the patients. L-DOPA-induced dyskinesia (LID) has been reported to occur in about 10% of patients per year in the first seven years of treatment [1], but the reported incidence of LID varies greatly between studies and patient groups [2]. Some people exhibit severe dyskinesias very rapidly, whereas others do not develop this complication despite many years of L-DOPA treatment. A generally accepted view holds that the susceptibility to LID is determined by the brain's “plasticity potential” [3]. According to this view, LID is an aberrant form of neuroplasticity that is triggered by the combined effects of DA denervation and pharmacological DA replacement. The gradual development and persistence of LID suggest that a disorder of brain plasticity is implicated in its pathophysiology. Once developed, LID is very difficult to reduce or reverse, it is promptly elicited by L-DOPA even after long periods of treatment discontinuation, it is induced also by non dyskinesiogenic drugs (e.g. long-acting DA agonists), and it can be precipitated by stress (partly reviewed in [4]). The brain's “plasticity potential” varies among individuals depending on age and genetics, and this has been proposed as an explanation to the varying susceptibility to dyskinesia in PD [3]. The group at highest risk of developing LID are young-onset PD patients (see [2] for review), who are supposedly endowed with the greatest potential for neuroplasticity within the parkinsonian patient population. The time to onset of LID in PD is influenced by a functional polymorphism in the gene coding for brain-derived neurotrophic factor (BDNF) [5], which is a prime mediator of neuroplasticity in health and disease (see below). Furthermore, using a paired associative stimulation protocol, abnormal plastic responses of the motor cortex have been evidenced in PD patients affected by LID [6]. Because corticostriatal synapses play a pivotal role in movement selection, many authors have attributed LID to an aberrant plasticity of corticostriatal synapses (reviewed in [4, 7]). Studies in acute brain slices from L-DOPA-treated rats have indeed revealed an abnormal form of corticostriatal synaptic plasticity in dyskinetic animals, consisting in a failure to reverse long-term potentiation (LTP) upon low-frequency stimulation of the cortical afferent pathway [8]. Despite all these strong indicia, questions on the “why, where, and what” of abnormal plasticity mechanisms in LID are still wide-open. The studies of corticostriatal synaptic plasticity thus far performed are neither exhaustive nor conclusive (in particular, a causal link between the observed abnormality and the occurrence of dyskinesia has not yet been demonstrated). Moreover, in addition to corticostriatal synapses, many types of cells and circuits within the basal ganglia show plastic changes in animal models of LID. By reviewing different levels of plastic alterations in LID, this article will provide a brief survey on a presently scattered, but rapidly growing area of investigation.

Section snippets

Presynaptic plasticity

Large intermittent fluctuations in brain levels of DA have been classically attributed a prime causal role in LID [9]. These fluctuations would be due to the loss of nigrostriatal DA neurons, which inevitably causes L-DOPA to be taken up and decarboxylated by brain cells that lack DA storage capacity (reviewed in [4]). Recent studies in animal models of LID and human PD patients suggest that the extent of nigrostriatal DA lesion is not the only determinant of the large DA fluctuations induced

Denervation-induced postsynaptic plasticity in the striatum

Presynaptic abnormalities in the handling of exogenous L-DOPA cannot alone account for LID. Indeed, dyskinesias indistinguishable from those induced by L-DOPA are evoked by direct DA receptor agonists in both animal models [17] and PD patients [18]. Like LID, DA agonist-induced dyskinesias only occur when the nigrostriatal DA pathway is severely damaged. This argues for a critical role of postsynaptic mechanisms in the predisposition to LID caused by DA denervation. In this context, two types

Plasticity of the serotonin system and involvement of BDNF

Serotonin (5-hydroxytryptamine, 5-HT) is produced by neurons in the brainstem raphe nuclei, which send widespread projections to cortical and subcortical brain regions, modulating a wide array of functions, including sensorimotor control, cognition and mood. A closer look at this neuronal system is highly warranted given its crucial role in the generation of LID (at least in animal models), and its potential implication in the cognitive and psychiatric problems afflicting PD patients.

Serotonin

Structural plasticity

Activation of intracellular signaling pathways, gene and protein induction are rapid responses that cannot account for the virtually permanent predisposition to dyskinesia established by chronic L-DOPA treatment. This truly long-lasting form of behavioural plasticity is likely to rely on structural modifications of cells and circuits in the brain (Fig. 1). The first indications that chronic L-DOPA treatment promotes structural plasticity in the brain came from gene array studies using

Microvascular plasticity

An emerging literature is revealing that functional and structural alterations of the brain microvessels accompany both the progression of PD and the development of LID. Post-mortem investigations on human parkinsonian brains have revealed morphological alterations of capillaries and increased numbers of endothelial cells in the substantia nigra [38, 39]. The observed changes were regarded as a response to the neurodegenerative process in PD and a possible effect of DA replacement therapy was

Concluding remarks

The term neuroplasticity refers to the brain's ability to reorganize itself in response to inner or outer challenges. On a cellular level, brain plasticity involves functional and structural modifications of synapses, neurons, and non-neuronal cells. The brain's “plasticity potential” conditions the capacity for functional recovery after brain damage and the response to neuropsychiatric treatment interventions. This has been clearly demonstrated to be the case for antidepressant

Conflict of interests

The authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Acknowledgements

The authors' ongoing projects in this area are supported by grants from the Swedish Research Council, the Michael J. Fox Foundation for Parkinson's Research, the Swedish Parkinson Foundation, and from the EU grant contract number 222918 (REPLACES) FP7 (Thematic priority HEALTH).

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The gold standard pharmacological treatment over the past 40 years for PD is represented by oral administration of the DA precursor levodopa (L-DOPA). However, long-term L-DOPA treatment often leads to uncontrollable abnormal involuntary movements (AIMs) termed L-DOPA induced dyskinesias (LID), which affects approximately 90% of its users after a decade [2]. Increasing evidence points to the serotonergic system as a key player in the induction and expression of LID in both parkinsonian patients and animal models [3,4].
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Plastic effects of L-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia

Summary

Introduction

Section snippets

Presynaptic plasticity

Denervation-induced postsynaptic plasticity in the striatum

Plasticity of the serotonin system and involvement of BDNF

Structural plasticity

Microvascular plasticity

Concluding remarks

Conflict of interests

Acknowledgements

Trends Pharmacol Sci

Curr Opin Neurobiol

Parkinsonism Relat Disord

Biol Psychiatry

Brain Res

Biol Psychiatry

Trends Neurosci

Biol Psychiatry

Neurobiol Dis

Lancet

Neuroscience

Risk factors for levodopa-induced dyskinesias in Parkinson's disease

J Neurol

Levodopa-induced dyskinesias, the clinical problem: clinical features, incidence, risk factors, management and impact on quality of life

Postversus presynaptic plasticity in L-DOPA-induced dyskinesia

J Neurochem

BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson's disease

J Neurol Neurosurg Psychiatry

Motor cortex plasticity in Parkinson's disease and levodopa-induced dyskinesias

Brain

Molecular mechanisms of L-DOPA-induced dyskinesia

Nat Rev Neurosci

Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia

Nat Neurosci

Levodopa therapy: consequences of the nonphysiologic replacement of dopamine

Neurology

Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia

Brain

PET demonstrates reduced dopamine transporter expression in PD with dyskinesias

Neurology