Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

Abstract

L-DOPA is the criterion standard of treatment for Parkinson disease. Although it alleviates some of the Parkinsonian symptoms, long-term treatment induces L-DOPA–induced dyskinesia (LID). Several theoretical models including the firing rate model, the firing pattern model, and the ensemble model are proposed to explain the mechanisms of LID. The “firing rate model” proposes that decreasing the mean firing rates of the output nuclei of basal ganglia (BG) including the globus pallidus internal segment and substantia nigra reticulata, along the BG pathways, induces dyskinesia. The “firing pattern model” claimed that abnormal firing pattern of a single unit activity and local field potentials may disturb the information processing in the BG, resulting in dyskinesia. The “ensemble model” described that dyskinesia symptoms might represent a distributed impairment involving many brain regions, but the number of activated neurons in the striatum correlated most strongly with dyskinesia severity. Extensive evidence for circuit mechanisms in driving LID symptoms has also been presented. LID is a multisystem disease that affects wide areas of the brain. Brain regions including the striatum, the pallidal–subthalamic network, the motor cortex, the thalamus, and the cerebellum are all involved in the pathophysiology of LID. In addition, although both amantadine and deep brain stimulation help reduce LID, these approaches have complications that limit their wide use, and a novel antidyskinetic drug is strongly needed; these require us to understand the circuit mechanism of LID more deeply.

Fisetin Ameliorates Levodopa-Induced Dyskinesia in Experimental Model Parkinson's Disease: Role of Mitochondrial Activities and Monoamines Turnover

“…Multiple lines of evidence indicated that cFos and FosB are vital transcription factors from the Fos family involved in the mechanisms of dyskinesia. 28,29 During post DA denervation, the levels of FosB explicitly increased in the striatal region of chronic L-DOPA-treated rats 28 and PD patients. 30 In line with observations of the previous investigators, our study also reported that mRNA expression of cFos and FosB were effectively upregulated in the ipsilateral region of the striatum of LID rats.…”

Levodopa-Induced Ocular Dyskinesia in an Early-Onset Parkinson Disease Patient With GBA Mutation

“…The ocular dyskinesia symptoms of our case were relieved with amantadine, suggesting that the N-methyl-D-aspartic acid-type glutamate receptors may regulate related pathways. 31 Further positron emission tomography scanning with the of N-methyl-D-aspartic acid receptors could be helpful in supporting this hypothesis.…”

Altered functional connectivity of cerebellar dentate nucleus in peak-dose dyskinesia in Parkinson’s disease

“…Such observations were in good agreement with our results that dyskinetic PD patients exhibited enhanced connectivity between left DN and right putamen during ON medication state with the presence of clinical dyskinesias, which heralded that peak-dose dyskinesia might result from a pathological interaction in the DN-putamen loop. As we know, the putamen was the most affected region by dopaminergic denervation with the progress of PD ( Kish et al, 1988 ), which was concurrently considered the central target in the pathogenesis of LID ( Yang et al, 2021 ). Herz et al (2014) observed that dyskinetic PD patients displayed significant overactivation of bilateral putamen after levodopa intake.…”

“…As we know, the putamen was the most affected region by dopaminergic denervation with the progress of PD (Kish et al, 1988), which was concurrently considered the central The significance of post-hoc t-tests was set at voxel-level p < 0.001, cluster-level p < 0.01, corrected by Gaussian random field; Positive t-value indicates the regions in which the former group had higher functional connectivity than the latter group. target in the pathogenesis of LID (Yang et al, 2021). Herz et al (2014) observed that dyskinetic PD patients displayed significant overactivation of bilateral putamen after levodopa intake.…”