Levodopa-induced Dyskinesia Research Articles

Chapter 11 - Plasticity, genetics, and epigenetics in l-dopa-induced dyskinesias

l-Dopa-induced dyskinesias (LIDs) are a frequent complication in l-dopa-treated patients affected by Parkinson's disease (PD). In the last years, several progresses in the knowledge of LIDs mechanisms have led to the identification of several molecular and electrophysiologic events. A complex cascade of intracellular events underlies the pathophysiology of LIDs, and, among these, aberrant plasticity in the cortico-basal ganglia system, at striatal and cortical level, plays a key role. Furthermore, several recent studies have investigated genetic susceptibility and epigenetic modifications in LIDs pathophysiology that might have future relevance in clinical practice and pharmacologic research. These progresses might lead to the development of specific strategies not only to treat, but also to prevent or delay the development of LIDs in PD.

Clinical phenomenology and pathophysiology of daytime and nighttime imperative movements

Imperative movements have an intermediate position between voluntary and involuntary movements and are also referred to as semi-voluntary, or induced. Their common characteristic is the urge, forcing the patient to perform an action that can have a different duration and degree of complexity - from a short twitch (with tics) to prolonged episodes of general motor restlessness (for example, akathisia or stereotypes). The ability to slow down this movement for a short or longer period of time by volitional effort is associated with the urge to make a movement, which predetermines the patient's perception of the degree of its imperativeness and arbitrariness. All motor syndromes based on an imperative need to make movements (akathisia, tics, restless legs syndrome, some levodopa-induced dyskinesias, tardive dyskinesia, compulsive disorders, stereotypes), despite their differences, can be conditionally combined by the term «akathisia spectrum disorders». In some cases, violent imperative movements are paradoxically combined with hypokinetic disorders, primarily with parkinsonism, which makes the discomfort experienced by patients particularly severe.

Cigarette Smoking, nicotine and Parkinson’s disease: Controversies in clinical trials data and medical practice.

It’s well known that smoking cigarettes is causally linked to a number of serious mortal diseases. These include laryngeal, lung, bladder, and digestive tract cancers, chronic obstructive pulmonary disease and a number of cardiovascular diseases, such as aortic aneurysm, stroke, and ischemic heart disease. In 2014, U.S. Surgeon General Report states that smoking is causally associated with inflammation and impaired immune function, and that regular smokers are at higher risk of developing pneumonia, tuberculosis, and other airway infections. So the best way to avoid harm from smoking is to never start, and for smokers to quit. However, evidence from epidemiological studies suggests a relationship between cigarette smoking and low risk of Parkinson’s disease. As a major component of tobacco smoke, nicotine has been proposed to be a substance for preventing against Parkinson’s disease risk, with a key role in regulating striatal activity and behaviors mediated through the dopaminergic system. Another data suggests quick deterioration and disease exacerbation after smoking cessation. Animal studies also showed that nicotine could modulate dopamine transmission and reduce levodopa-induced dyskinesias. Smoking cessation, proposed because of the health issues as certainly reducing the risk of cardiovascular events and cancer, must be definitely accepted as major health paramount procedure, but in the case of Parkinson’s disease nicotine-substitute supplements must be provided. As a small amount of nicotine can saturate a substantial portion of nicotine receptors in the brain, nicotine from other sources, such as less harmful smoking advanced devices as well as diet, could be a promising therapeutic substance for motility support and protection against Parkinson’s disease.

The pathomechanisms of levodopa-induced dyskinesia in Parkinson's disease.

The pathomechanisms of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa-induced dyskinesias in Parkinson's disease increase cerebrospinal fluid nitric oxide metabolites' levels.

Levodopa-induced dyskinesia (LID) is a common complication of Parkinson's disease (PD) therapy. Nitric oxide in the central nervous system may have a role in its pathophysiology. The present work investigates plasma and CSF levels of nitric oxide metabolites nitrite and nitrate in patients with PD, LID, and healthy control. We measured plasma and CSF nitrite and nitrate levels in patients with PD with and without LID and in healthy controls. The levels of plasma and CSF nitrite and nitrate were measured by ozone-based chemiluminescence. Sixty-seven participants were enrolled. CSF nitrite levels in patients with PD and LID were higher than in patients with PD without LID and healthy controls. CSF/plasma ratio of nitrite was higher in patients with PD and LID than in patients with PD without LID. The CSF/plasma ratio of nitrite in patients with PD and LID was higher than 1, indicating an intrathecal production of NO in patients with this motor complication. There was an increase in nitrate levels of CSF and CSF/plasma ratio of nitrate in patients with PD and LID compared to the healthy controls. Sex, age at evaluation, disease duration, and levodopa equivalent daily doses, as well as processing and storage time, did not critically influence these results. The present study demonstrated an increase in nitrite and nitrate levels in the central nervous system of patients with PD and LID. This finding strengthens the role of NO on LID pathophysiology.

Deep Brain Stimulation and Treatment Outcomes of Young- and Late-Onset (≤55 Years) Parkinson's Disease: A Population-Based Study.

Background: No studies have reported the rate of motor complications (MC) and response to medical and surgical treatment in a population-based cohort of young-onset Parkinson's Disease (YOPD) patients and a cohort of sex-matched late-onset Parkinson's Disease (LOPD).Objective: To assess the outcomes of dopaminergic treatment in YOPD and LOPD, explore treatment-induced MC, medical adjustment, and rate of deep brain stimulation (DBS).Methods: We used the expanded Rochester Epidemiology Project (eREP) to investigate a population-based cohort of YOPD between 2010 and 2015 in 7 counties in Minnesota. Cases with onset ≤55 years of age were included as YOPD. An additional sex-matched cohort of LOPD (onset at ≥56 years of age) was included for comparison. All medical records were reviewed to confirm the diagnoses.Results: In the seven counties 2010–15, there were 28 YOPD patients, which were matched with a LOPD cohort. Sixteen (57%) YOPD had MC, as compared to 9 (32%) LOPD. In YOPD, 9 had motor fluctuations (MF) and Levodopa-induced dyskinesia (LID) together, whereas 3 had LID only and 4 MF only. In LOPD, 3 had MF and LID, 3 MF only, and 3 LID only. Following medical treatment for MC, 6/16 YOPD (38%) and 3/9 (33%) LOPD had symptoms resolution. In YOPD, 11/16 (69%) were considered for DBS implantation, in LOPD they were 2/9 (22%), but only 7 (6 YOPD and 1 LOPD) underwent the procedure. YOPD had significantly higher rates in both DBS candidacy and DBS surgery (respectively, p = 0.03 and p = 0.04). Among DBS-YOPD, 5/6 (83%) had positive motor response to the surgery; the LOPD case had a poor response. We report the population-based incidence of both YOPD with motor complications and YOPD undergoing DBS, which were 1.17 and 0.44 cases per 100,000 person-years, respectively.Conclusion: Fifty-seven percent of our YOPD patients and 32% of the LOPD had motor complications. Roughly half of both YOPD and LOPD were treatment resistant. YOPD had higher rates of DBS candidacy and surgery. Six YOPD and 1 LOPD underwent DBS implantation and most of them had a positive motor response after the surgery.

Metabolic Profile in Plasma AND CSF of LEVODOPA-induced Dyskinesia in Parkinson's Disease: Focus on Neuroinflammation.

The existence of few biomarkers and the lack of a better understanding of the pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) require new approaches, as the metabolomic analysis, for discoveries. We aimed to identify a metabolic profile associated with LID in patients with PD in an original cohort and to confirm the results in an external cohort (BioFIND). In the original cohort, plasma and CSF were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. LC-MS/MS and metabolomics data analysis were used to perform untargeted metabolomics. Untargeted metabolomics data from the BioFIND cohort were analyzed. We identified a metabolic profile associated with LID in PD, composed of multiple metabolic pathways. In particular, the dysregulation of the glycosphingolipid metabolic pathway was more related to LID and was strongly associated with the severity of dyskinetic movements. Furthermore, bile acid biosynthesis metabolites simultaneously found in plasma and CSF have distinguished patients with LID from other participants. Data from the BioFIND cohort confirmed dysregulation in plasma metabolites from the bile acid biosynthesis pathway. There is a distinct metabolic profile associated with LID in PD, both in plasma and CSF, which may be associated with the dysregulation of lipid metabolism and neuroinflammation.

Long-term changes in short-interval intracortical facilitation modulate motor cortex plasticity and L-dopa-induced dyskinesia in Parkinson's disease

BackgroundAbnormal glutamatergic neurotransmission in the primary motor cortex (M1) contributes to Parkinson's disease (PD) pathophysiology and is related to l-dopa-induced dyskinesia (LID). We previously showed that short-term treatment with safinamide, a monoamine oxidase type-B inhibitor with anti-glutamatergic properties, improves abnormally enhanced short-interval intracortical facilitation (SICF) in PD patients. ObjectiveTo examine whether a long-term SICF modulation has beneficial effects on clinical measures, including LID severity, and whether these changes parallel improvement in cortical plasticity mechanisms in PD. MethodsWe tested SICF in patients with and without LID before (S0) and after short- (14 days - S1) and long-term (12 months - S2) treatment with safinamide 100 mg/day. Possible changes in M1 plasticity were assessed using intermittent theta-burst stimulation (iTBS). Finally, we correlated safinamide-related neurophysiological changes with modifications in clinical scores. ResultsSICF was enhanced at S0, and prominently in patients with LID. Safinamide normalized SICF at S1, and this effect persisted at S2. Impaired iTBS-induced plasticity was present at S0 and safinamide restored this alteration at S2. There was a significant correlation between the degree of SICF and the amount of iTBS-induced plasticity at S0 and S2. In patients with LID, the degree of SICF at S0 and S2 correlated with long-term changes in LID severity. ConclusionsAltered SICF contributes to M1 plasticity impairment in PD. Both SICF and M1 plasticity improve after long-term treatment with safinamide. The abnormality in SICF-related glutamatergic circuits plays a role in LID pathophysiology, and its long-term modulation may prevent LID worsening over time.

Morphological and functional changes of striatal neurons with L‐dopa‐induced dyskinesia

AbstractPriming and expression of L‐dopa‐induced dyskinesia (LID) is associated with maladaptive plasticity of striatal spiny projection neurons (SPNs) in the direct pathway of the basal ganglia. The L‐dopa dosage threshold for dyskinesia decreases immediately after dopaminergic denervation, then gradually after repeated L‐dopa treatment. Dopaminergic denervation induces D1 receptor hypersensitivity in the soma and axon terminals and diminishes negative feedback from GABAB receptors in the direct pathway SPNs, resulting in neuronal hypersensitivity. After dopaminergic denervation, serotonergic neurons metabolize L‐dopa. Serotonergic neurons do not have D2 receptors or dopamine transporters, resulting in a non‐regulated release of dopamine, with subsequent pulsatile dopamine receptor stimulation. L‐dopa treatment post‐dopaminergic denervation induces LID in rat models. Dyskinetic rats show a lack of depotentiation at their corticostriatal synapses and enlargement of their dendritic spines within direct pathway SPNs, both of which account for strengthened corticostriatal synaptic transmission in LID models. Intra‐SPN signal transduction is activated, resulting in the hypersynthesis of GABA. The volume of the internal segment of the globus pallidus (GPi) increases alongside the enlargement of axon terminals with many synaptic vesicles containing GABA from direct pathway SPNs. When the model expresses LID, excessive GABA is released into the GPi. LID priming involves excessive GABA storage in GPi axon terminals, with LID triggered by enhanced GABA release into the GPi.

White matter connectivity networks predict levodopa-induced dyskinesia in Parkinson's disease.

Although levodopa-induced dyskinesia-relevant white matter change has been evaluated, it is uncertain whether these changes may reflect the underlying predisposing conditions leading to the development of levodopa-induced dyskinesia. To elucidate the role of white matter connectivity networks in the development of levodopa-induced dyskinesia in drug-naïve Parkinson's disease. We recruited 30patients who developed levodopa-induced dyskinesia within 5years from MRI acquisition (vulnerable-group), 47 patients who had not developed levodopa-induced dyskinesia within 5years (resistant-group), and 28 controls. We performed comparative analyses of whole-brain white matter integrity and connectivity using tract-based spatial and network- and degree-based statistics. We evaluated the predictability of levodopa-induced dyskinesia development and relationship with its latency, using the average connectivity strength as a predictor in Cox- and linear-regression, respectively. Mean-diffusivity was lower mainly at the left frontal region in the vulnerable-group compared to the resistant-group. Network-based statistics identified a subnetwork consisting of the bilateral fronto-striato-pallido-thalamic and lateral parietal regions (subnetwork A) and degree-based statistics identified four subnetworks (hub-subnetwork) consisting of edges centered on the left superior frontal gyrus, left putamen, left insular, or left precentral gyrus, where the vulnerable-group had stronger connectivity compared to the resistant-group. Stronger connectivity within the subnetwork A and hub-subnetwork centered on the left superior frontal gyrus was a predictor of levodopa-induced dyskinesia development independent of known risk factors and had an inverse relationship with its latency. Our data suggest that white matter connectivity subnetworks within corticostriatal regions play a pivotal role in the development of levodopa-induced dyskinesia.

Transcranial Magnetic Stimulation Alleviates Levodopa-Induced Dyskinesia in Parkinson's Disease and the Related Mechanisms: A Mini-Review.

After long-term use of levodopa, Parkinson's patients almost inevitably develop dyskinesia, a kind of drug side effect manifesting as uncontrollable choreic movements and dystonia, which could be crippling yet have limited therapeutic options. Transcranial magnetic stimulation is the most widely studied non-invasive neuromodulation technology to treat levodopa-induced dyskinesia. Many studies have shown that transcranial magnetic stimulation has beneficial effects on levodopa-induced dyskinesia and is patient-tolerable, barely with reported adverse effects. Changes in brain connectivity, neuroplasticity, neurotransmitter, neurorestoration, and blood flow modulation could play crucial roles in the efficacy of transcranial magnetic stimulation for levodopa-induced dyskinesia. The appearance of new modes and application for emerging targets are possible solutions for transcranial magnetic stimulation to achieve sustained efficacy. Since the sample size in all available studies is small, more randomized double-blind controlled studies are needed to elucidate the specific treatment mechanisms and optimize treatment parameters.

Dopamine D3 receptor ligand suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of parkinson's disease

Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.

Histological Correlates of Neuroanatomical Changes in a Rat Model of Levodopa-Induced Dyskinesia Based on Voxel-Based Morphometry.

Long-term therapy with levodopa (L-DOPA) in patients with Parkinson’s disease (PD) often triggers motor complications termed as L-DOPA-induced dyskinesia (LID). However, few studies have explored the pathogenesis of LID from the perspective of neuroanatomy. This study aimed to investigate macroscopic structural changes in a rat model of LID and the underlying histological mechanisms. First, we established the hemiparkinsonism rat model through stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, followed by administration of saline (PD) or L-DOPA to induce LID. Magnetic resonance imaging (MRI) and behavioral evaluations were performed at different time points. Histological analysis was conducted to assess the correlations between MRI signal changes and cellular contributors. Voxel-based morphometry (VBM) analysis revealed progressive bilateral volume reduction in the cortical and subcortical areas in PD rats compared with the sham rats. These changes were partially reversed by chronic L-DOPA administration; moreover, there was a significant volume increase mainly in the dorsolateral striatum, substantia nigra, and piriform cortex of the lesioned side compared with that of PD rats. At the striatal cellular level, glial fibrillary acidic protein-positive (GFAP+) astrocytes were significantly increased in the lesioned dorsolateral striatum of PD rats compared with the intact side and the sham group. Prolonged L-DOPA treatment further increased GFAP levels. Neither 6-OHDA damage nor L-DOPA treatment influenced the striatal expression of vascular endothelial growth factor (VEGF). Additionally, there was a considerable increase in synapse-associated proteins (SYP, PSD95, and SAP97) in the lesioned striatum of LID rats relative to the PD rats. Golgi-Cox staining analysis of the dendritic spine morphology revealed an increased density of dendritic spines after chronic L-DOPA treatment. Taken together, our findings suggest that striatal volume changes in LID rats involve astrocyte activation, enrichment of synaptic ultrastructure and signaling proteins in the ipsilateral striatum. Meanwhile, the data highlight the enormous potential of structural MRI, especially VBM analysis, in determining the morphological phenotype of rodent models of LID.

Amantadine: an old drug reborn

In my opinion, amantadine is the most under-appreciated, under-utilised, and under prescribed oral medication in the treatment of patients with Parkinson's disease. I applaud Olivier Rascol and colleagues 1 Rascol O Fabbri M Poewe W Amantadine in the treatment of Parkinson disease and other movement disorders. Lancet Neurol. 2021; (published online Oct 19)https://doi.org/10.1016/S1474-4422(21)00249-0 Google Scholar for providing a timely update on the uses of amantadine in the treatment of Parkinson's disease and other movement disorders. Their Personal View also provides insight into the reasons why amantadine is not so widely used and emphasises the fact that, even though this drug has been available for 50 years, its complex pharmacology is still not fully understood nor are the mechanisms behind its beneficial effects. Amantadine in the treatment of Parkinson's disease and other movement disordersThe efficacy of amantadine in the symptomatic treatment of patients with Parkinson's disease, discovered serendipitously more than 50 years ago, has stood the test of time and the drug is still commonly used by neurologists today. Its pharmacological actions are unique in combining dopaminergic and glutamatergic properties, which account for its dual effect on parkinsonian signs and symptoms and levodopa-induced dyskinesias. Furthermore, amantadine has additional and less well-defined pharmacological effects, including on anticholinergic and serotonergic activity. Full-Text PDF

Induction and Assessment of Levodopa-induced Dyskinesias in a Rat Model of Parkinson's Disease.

Levodopa (L-DOPA) remains the gold-standard therapy used to treat Parkinson's disease (PD) motor symptoms. However, unwanted involuntary movements known as L-DOPA-induced dyskinesias (LIDs) develop with prolonged use of this dopamine precursor.It is estimated that the incidence of LIDs escalates to approximately 90% of individuals with PD within 10-15 years of treatment. Understanding the mechanisms of this malady and developing both novel and effective anti-dyskinesia treatments requires consistent and accurate modeling for pre-clinical testing of therapeutic interventions. A detailed method for reliable induction and comprehensive rating of LIDs following 6-OHDA-induced nigral lesioning in a rat model of PD is presented here. Dependable LID assessment in rats provides a powerful tool that can be readily utilized across laboratories to test emerging therapies focused on reducing or eliminating this common treatment-induced burden for individuals with PD.

Induction and Assessment of Levodopa-induced Dyskinesias in a Rat Model of Parkinson's Disease

Induction and Assessment of Levodopa-induced Dyskinesias in a Rat Model of Parkinson's Disease

Lack of Association Between GBA Mutations and Motor Complications in European and American Parkinson's Disease Cohorts.

Background:Motor complications are a consequence of the chronic dopaminergic treatment of Parkinson’s disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA-associated PD differ in their risk of developing motor complications compared to the general PD population.Objective:To evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD.Methods:Motor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models.Results: In 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p = 0.43).Conclusion:This study does not provide evidence that GBA-carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA-associated PD.

Neuropsychiatric Burden Is a Predictor of Early Freezing and Motor Progression in Drug-Naïve Parkinson's Disease.

Neuropsychiatric symptoms (NPS) are the most common non-motor symptom in Parkinson's disease (PD). To investigate the association between the burden of NPS and motor prognosis in patients with PD. We enrolled 329 drug-naïve patients with PD, who was non-demented and followed-up≥2 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging and neuropsychiatric inventory (NPI) scores. We performed a survival analysis and a linear mixed model analysis to assess longitudinal motor outcomes according to the NPI total score. The Kaplan-Meier analysis showed no difference in the development of levodopa-induced dyskinesia and wearing-off according to the NPI total score. However, higher burden of NPI total score was associated with earlier freezing of gait (FOG) development in the time-dependent Cox regression models after adjusting for age at symptom onset, sex, disease duration, Unified PD Rating Scale motor score, baseline Mini-Mental State Examination score, DAT activity in the posterior putamen and levodopa-equivalent daily dose (LEDD) (Hazard ratio 1.047, p = 0.002). A linear mixed model analysis revealed that patients with a higher NPI total score had a more rapid LEDD increment (NPI×time, p = 0.003). Among 52 patients with PD who eventually developed FOG during the follow-up period, there was a significant correlation between the NPI total score and time with FOG development (γ= -0.472; p = 0.001) after adjusting for confounding factors. The present study demonstrated that the severity of NPS is a predictor of early freezing and motor progression in patients with PD.

Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.

Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease.

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.