Validation of an improved scale for rating l-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists

Sebastianutto, Irene; Maslava, Natallia; Hopkins, Corey R.; Cenci, M. Angela

doi:10.1016/j.nbd.2016.09.001

Cited by 60 publications

(53 citation statements)

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“…Evaluation of 6-OHDA lesion in mice and rats. Three weeks after 6-OHDA lesion, forelimb use asymmetry was evaluated in rats and mice using the cylinder test, revealing a significant reduction in the spontaneous use of the forelimb contralateral to the lesion (69)(70)(71)(72). Briefly, mice and rats were placed individually in a glass cylinder (10 cm diameter and 14 cm height for mice; 21 cm diameter and 34 cm height for rats) and were videotaped for 5 minutes.…”

Section: Discussionmentioning

confidence: 99%

D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

Sebastianutto¹,

Goyet²,

Andreoli³

et al. 2020

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

Sebastianutto¹,

Goyet²,

Andreoli³

et al. 2020

Journal of Clinical Investigation

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“…With regard to phenomenology, dyskinetic movements are more rapid and variable in mice than rats, which may diminish the accuracy of on‐line AIM ratings, particularly if the rater has not yet acquired sufficient experience with the model. Nevertheless, we have recently proven that it is possible to accurately rate mouse AIMs on‐line using both the standard time‐based scale and an amplitude scale similar to that developed in the rat . Merging time‐based scores with amplitude scores yields a measure of dyskinesia (“global AIMs”) having high sensitivity and wide dynamic range .…”

Section: Models In Rodentsmentioning

confidence: 99%

“…Nevertheless, we have recently proven that it is possible to accurately rate mouse AIMs on‐line using both the standard time‐based scale and an amplitude scale similar to that developed in the rat . Merging time‐based scores with amplitude scores yields a measure of dyskinesia (“global AIMs”) having high sensitivity and wide dynamic range . Moreover, it is possible to combine on‐line ratings with mobile videorecordings to allow for additional verifications …”

Section: Models In Rodentsmentioning

confidence: 99%

“…66 Merging time-based scores with amplitude scores yields a measure of dyskinesia ("global AIMs") having high sensitivity and wide dynamic range. 66 Moreover, it is possible to combine on-line ratings with mobile videorecordings to allow for additional verifications. 67 Mouse AIMs respond to compounds having antidyskinetic efficacy in both PD patients and NHP models (see Table 1).…”

Section: Models In Rodentsmentioning

confidence: 99%

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Animal models of l‐dopa‐induced dyskinesia in Parkinson's disease

Cenci

Crossman

2018

Movement Disorders

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Understanding the biological mechanisms of l-dopa-induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing-off fluctuations and abnormal involuntary movements appearing when plasma levels of l-dopa are high, commonly referred to as peak-dose l-dopa-induced dyskinesia. Parkinsonian models exhibiting these features have been well-characterized in both rodent and nonhuman primate species. The first animal models of peak-dose l-dopa-induced dyskinesia were produced in monkeys lesioned with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated chronically with l-dopa to elicit choreic movements and dystonic postures. Seminal studies were performed in these models using both metabolic mapping and electrophysiological techniques, providing fundamental pathophysiological insights that have stood the test of time. A decade later, it was shown possible to reproduce peak-dose l-dopa-induced dyskinesia in rats and mice rendered parkinsonian with nigrostriatal 6-hydroxydopamine lesions. When treated with l-dopa, these animals exhibit abnormal involuntary movements having both hyperkinetic and dystonic components. These models have enabled molecular- and cellular-level investigations into the mechanisms of l-dopa-induced dyskinesia. A flourishing literature using genetically engineered mice is now unraveling the role of specific genes and neural circuits in the development of l-dopa-induced motor complications. Both non-human primate and rodent models of peak-dose l-dopa-induced dyskinesia have excellent construct validity and provide valuable tools for discovering therapeutic targets and evaluating potential treatments. © 2018 International Parkinson and Movement Disorder Society.

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“…LID is quantified by a subjective measure called the abnormal involuntary movement (AIM) scale [33]. Related behavioral tests with predictive validity have been developed in rodent and non-human primate models based on genetic-or neurotoxin-induced degeneration of DAN [9,34]. In the 6-OHDA model, the unilateral striatal injections of the dopaminergic toxin 6-OHDA results in dopaminergic denervation of the ipsilateral striatum and rotational bias (extended data Fig.…”

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confidence: 99%

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Abnormal Involuntary Movements

Malave¹,

Zuelke²,

Starikov³

et al. 2020

Preprint

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Our limited understanding of neuronal co-transmission complicates predicting the effects of pharmacological interventions from neuronal wiring diagrams [1, 2]. For example, dopamine neurons (DAN), whose degeneration causes the motor and cognitive deficits of Parkinson's Disease (PD) [3], communicate with all their targets by dopamine (DA) and in addition use the neurotransmitters GABA, Glutamate and secreted peptides including the morphogen Sonic Hedgehog (Shh) to signal to select subsets of neurons [4][5][6][7][8]. It is unknown whether Levodopa (L-Dopa) induced dyskinesia (LID), a debilitating side effect of DA supplementation therapy in PD [9], might appear because DAN targets become exposed to high levels of DA but diminished levels of other DAN produced signaling factors. Here we show that restoring the balance of DA and Shh signaling by agonists of the Shh signaling effector G-protein coupled receptor Smoothened (Smo [10, 11]) attenuates LID in mouse-and macaque-models of PD. Using conditional genetic loss of function approaches of pre-and post-synaptic Shh signaling we found that reducing the activity of Smo selectively in cholinergic neurons facilitates LID. Conversely, the expression of a constitutive active form of Smo (SmoM2 [12]) in cholinergic neurons is sufficient to render the sensitized aphakia model of PD resistant to LID. Furthermore, the acute diminishment of Shh emanating from DAN by optogenetic means in the otherwise intact brain and in the absence of L-Dopa results in LID-like abnormal involuntary movements. We reveal that Shh co-transmission counteracts DA action in a DAN target-and striatal domain-specific manner. Our results suggest an un-anticipated mechanism -reduced Shh signaling -by which DAN degeneration sensitizes PD patients to LID. We anticipate that our models provide a starting point for assessing the contributions of Shh to the "teaching" signal that emanates from DAN and testing the hypothesis that LID are caused by aberrant learning [13][14][15]. Main:Previous work has implicated aberrant cholinergic activity in LID in PD models but mechanistic details remain ill-defined since both boosting as well as inhibiting cholinergic signaling were found to attenuate LID [16][17][18][19][20][21][22]. These divergent results are likely a reflection of the post synaptic complexity of cholinergic signaling in the striatum [23]. Hence, normalizing cholinergic activity at the level of CIN themselves might prevent the formation of LID and preserve the contribution of regulated CIN activity to striatal function. In the healthy brain, DAN engage CIN as a relay hub to control striatal circuits by patterning cholinergic activity [24,25]: DA inhibits CIN through binding to D2 receptor (D2R) resulting in the pause of the "burst-pause-burst" firing pattern of CIN in response to reward-related cues or outcomes [26,27] [28,29]. Unfortunately, how DAN degeneration results in aberrant CIN activity is also not well understood [30]. For example, as DA levels fall in the PD brain, cholinergic signaling s...

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Validation of an improved scale for rating l-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists

Cited by 60 publications

References 70 publications

D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

Animal models of l‐dopa‐induced dyskinesia in Parkinson's disease

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Abnormal Involuntary Movements

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