l-DOPA-Induced Dyskinesia in the Intrastriatal 6-Hydroxydopamine Model of Parkinson's Disease: Relation to Motor and Cellular Parameters of Nigrostriatal Function

doi:10.1006/nbdi.2002.0499

Neurobiology of Disease

Volume 10, Issue 2, July 2002, Pages 165-186

https://doi.org/10.1006/nbdi.2002.0499 Get rights and content

Abstract

In order to assess the role of striatal dopamine (DA) afferents in l-DOPA-induced dyskinesia, we have studied a large series of rats sustaining 2, 3, or 4 unilateral injections of 6-hydroxydopamine (6-OHDA) in the lateral striatum. This type of lesion produced a dose-dependent depletion of DA fibers in the caudate-putamen, which was most pronounced in the lateral aspects of this structure. An additional group of rats was injected with 6-OHDA in the medial forebrain bundle to obtain complete DA denervation on one side of the brain. During a course of chronic l-DOPA treatment, rats with intrastriatal 6-OHDA lesions developed abnormal involuntary movements (AIMs), which mapped onto striatal domains exhibiting at least ∼90% denervation, as judged by DA transporter autoradiography. The denervated areas showed local upregulation of preproenkephalin and prodynorphin mRNA, and FosB-like immunoreactivity, which were highly correlated with the rats' AIM scores. When compared to completely DA-denervated animals, the rats with intrastriatal 6-OHDA lesions showed an overall lower incidence, lower severity and different topographic distribution of AIMs. The involvement of proximal limb and axial muscles in the abnormal movements was proportional to the spreading of the lesion from lateral towards medial aspects of the caudate-putamen. Locomotive AIMs were only seen in rats with complete lesions, but not in any of the animals with intrastriatal 6-OHDA (which showed > 5% DA fiber sparing in the medial striatum). Intrastriatally 6-OHDA-lesioned rats had a larger therapeutic window for l-DOPA than did rats with complete bundle lesions, since they exhibited an overall lower predisposition to dyskinesia but a similar degree of drug-induced motor improvement in a test of forelimb stepping. Our results are the first to demonstrate that selective and partial DA denervation in the sensorimotor part of the striatum can confer cellular and behavioral supersensitivity to l-DOPA, and that the phenomenology of l-DOPA-induced rat AIMs can be accounted for by the topography of DA denervation within the caudate-putamen.

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Background: Levodopa-induced dyskinesia (LID) is a common motor complication of levodopa (L-DOPA) treatment for Parkinson's disease (PD). In recent years, the role of astrocytes in LID has increasingly attracted attention. Objective: To explore the effect of an astrocyte regulator (ONO-2506) on LID in a rat model and the potential underlying physiological mechanism. Methods: Unilateral LID rat models, established by administering 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle through stereotactic injection, were injected with ONO-2506 or saline into the striatum through brain catheterization and were administered L-DOPA to induce LID. Through a series of behavioral experiments, LID performance was observed. Relevant indicators were assessed through biochemical experiments. Results: In the LID model of 6-OHDA rats, ONO-2506 significantly delayed the development and reduced the degree of abnormal involuntary movement in the early stage of L-DOPA treatment and increased glial fibrillary acidic protein and glutamate transporter 1 (GLT-1) expression in the striatum compared to saline. However, there was no significant difference in the improvement in motor function between the ONO-2506 and saline groups. Conclusions: ONO-2506 delays the emergence of L-DOPA-induced abnormal involuntary movements in the early stage of L-DOPA administration, without affecting the anti-PD effect of L-DOPA. The delaying effect of ONO-2506 on LID may be linked to the increased expression of GLT-1 in the rat striatum. Interventions targeting astrocytes and glutamate transporters are potential therapeutic strategies to delay the development of LID.
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Regular Articlel-DOPA-Induced Dyskinesia in the Intrastriatal 6-Hydroxydopamine Model of Parkinson's Disease: Relation to Motor and Cellular Parameters of Nigrostriatal Function

Abstract

Neurobiol. Dis.

Neuroscience

Neuroscience

Neuroscience

Neuroscience

Exp. Neurol.

Neuroscience

Brain Res.

Exp. Neurol.

Neuroscience

J. Neurosci. Methods.

Neuroscience

Pharmacol. Biochem. Behav.

Neuroscience

Trends Neurosci.

Exp. Neurol.

Prog. Brain Res.

Trends Neurosci.

Estimation of nuclear population from microtome sections

Anat. Rec.

cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum

J. Neurosci.

Evaluation of simple and complex sensorimotor behaviours in rats with a partial lesion of the dopaminergic nigrostriatal system

Eur. J. Neurosci.

Dopamine-receptor stimulation: Biobehavioral and biochemical consequences

Trends Neurosci.

Regular Article
l-DOPA-Induced Dyskinesia in the Intrastriatal 6-Hydroxydopamine Model of Parkinson's Disease: Relation to Motor and Cellular Parameters of Nigrostriatal Function