Abstract
L-DOPA is the most effective treatment for Parkinson's disease (PD), but prolonged use leads to disabling motor complications including dyskinesia. Strong evidence supports a role of the subthalamic nucleus (STN) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy. Here, we investigated the involvement of STN in dyskinesia, using single-unit extracellular recording, behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic L-DOPA administration. Our results show that chronic L-DOPA treatment does not modify the abnormal STN activity induced by the 6-hydroxydopamine lesion of the nigrostriatal pathway in this model. Likewise, we observed a loss of STN responsiveness to a single L-DOPA dose both in lesioned and sham animals that received daily L-DOPA treatment. We did not find any correlation between the abnormal involuntary movement (AIM) scores and the electrophysiological parameters of STN neurons recorded 24 h or 20–120 min after the last L-DOPA injection, except for the axial subscores. Nonetheless, unilateral chemical ablation of the STN with ibotenic acid resulted in a reduction in global AIM scores and peak-severity of dyskinesia. In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner. Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB, phosphoDARPP-32, dopamine receptor (DR) D3 and DRD2/DRD1 ratio. The STN lesion attenuated the striatal molecular changes and normalized the DRD2/DRD1 ratio. Taken together, our results show that the STN plays a role, if modest, in the physiopathology of dyskinesias.
Highlights
Parkinson disease (PD) involves the degeneration of dopamine (DA) neurons in the substantia nigra (SN) and a subsequent DA depletion in the striatum [1]
We did not observe abnormal involuntary movement (AIM) in any of the control groups, including sham animals treated with saline or L-DOPA, and 6-OHDA lesioned rats treated with saline
Electrophysiological characterization of the subthalamic nucleus in hemiparkinsonian rats with L-DOPA induced dyskinesia To investigate the effect of L-DOPA chronic treatment on the STN activity, neurons from sham and 6-OHDA lesioned rats treated with saline or L-DOPA were recorded 24 h after the last saline or L-DOPA dose
Summary
Parkinson disease (PD) involves the degeneration of dopamine (DA) neurons in the substantia nigra (SN) and a subsequent DA depletion in the striatum [1]. Long-term administration of L-DOPA induces abnormal involuntary movements known as L-DOPAinduced dyskinesia (LID) in the majority of PD patients. These motor complications are potentially disabling, and affect up to 40% of PD patients within 5 years of treatment [2]. The specific mechanisms underlying LID are poorly understood there is vast consensus that it results from dysregulated DA neurotransmission depending on both presynaptic alterations and postsynaptic dopamine receptor (DR) supersensitivity [3]. Altered glutamatergic transmission within the basal ganglia may be involved since changes in NMDA and metabotropic glutamate receptors (mGluR) have been reported
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