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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

Sebastianutto, Irene LU ; Maslava, Natallia LU ; Hopkins, Corey R. and Cenci Nilsson, Angela LU (2016) In Neurobiology of Disease 96. p.156-170
Abstract

Rodent models of L-DOPA-induced dyskinesia (LID) are essential to investigate pathophysiological mechanisms and treatment options. Ratings of abnormal involuntary movements (AIMs) are used to capture both qualitative and quantitative features of dyskinetic behaviors. Thus far, validated rating scales for the mouse have anchored the definition of severity to the time during which AIMs are present. Here we have asked whether the severity of axial, limb, and orolingual AIMs can be objectively assessed with scores based on movement amplitude. Mice sustained 6-OHDA lesions in the medial forebrain bundle and were treated with L-DOPA (3–6 mg/kg/day) until they developed stable AIMs scores. Two independent investigators rated AIM severity using... (More)

Rodent models of L-DOPA-induced dyskinesia (LID) are essential to investigate pathophysiological mechanisms and treatment options. Ratings of abnormal involuntary movements (AIMs) are used to capture both qualitative and quantitative features of dyskinetic behaviors. Thus far, validated rating scales for the mouse have anchored the definition of severity to the time during which AIMs are present. Here we have asked whether the severity of axial, limb, and orolingual AIMs can be objectively assessed with scores based on movement amplitude. Mice sustained 6-OHDA lesions in the medial forebrain bundle and were treated with L-DOPA (3–6 mg/kg/day) until they developed stable AIMs scores. Two independent investigators rated AIM severity using both the validated time-based scale and a novel amplitude scale, evaluating the degree of deviation of dyskinetic body parts relative to their resting position. The amplitude scale yielded a high degree of consistency both within- and between raters. Thus, time-based scores, amplitude scores, and a combination of the two (‘global AIM scores’) were applied to compare antidyskinetic effects produced by amantadine and by the following subtype-specific DA receptor antagonists: SCH23390 (D1/D5), Raclopride (D2/D3), PG01037 (D3), L-745,870 (D4), and VU6004461 (D4). SCH23390 and Raclopride produced similarly robust reductions in both time-based scores and amplitude scores, while PG01037 and L-745,870 had more partial effects. Interestingly, a novel and highly brain penetrable D4 receptor antagonist (VU6004461) markedly attenuated both time-based and amplitude scores without diminishing the general motor stimulant effect of L-DOPA. In summary, our results show that a dyskinesia scale combining a time dimension with an amplitude dimension (‘global AIMs’) is more sensitive than unidimensional scales. Moreover, the antidyskinetic effects produced by two chemically distinct D4 antagonists identify the D4 receptor as a potential future target for the treatment of LID.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Dystonia, Experimental therapeutics, Movement disorders, Parkinson's disease, Rodent models
in
Neurobiology of Disease
volume
96
pages
15 pages
publisher
Elsevier
external identifiers
  • Scopus:84987956578
ISSN
0969-9961
DOI
10.1016/j.nbd.2016.09.001
language
English
LU publication?
yes
id
25fffa75-f63f-4e42-b32e-5ece0c0a61b4
date added to LUP
2016-10-12 12:57:01
date last changed
2016-10-13 03:00:02
@misc{25fffa75-f63f-4e42-b32e-5ece0c0a61b4,
  abstract     = {<p>Rodent models of L-DOPA-induced dyskinesia (LID) are essential to investigate pathophysiological mechanisms and treatment options. Ratings of abnormal involuntary movements (AIMs) are used to capture both qualitative and quantitative features of dyskinetic behaviors. Thus far, validated rating scales for the mouse have anchored the definition of severity to the time during which AIMs are present. Here we have asked whether the severity of axial, limb, and orolingual AIMs can be objectively assessed with scores based on movement amplitude. Mice sustained 6-OHDA lesions in the medial forebrain bundle and were treated with L-DOPA (3–6 mg/kg/day) until they developed stable AIMs scores. Two independent investigators rated AIM severity using both the validated time-based scale and a novel amplitude scale, evaluating the degree of deviation of dyskinetic body parts relative to their resting position. The amplitude scale yielded a high degree of consistency both within- and between raters. Thus, time-based scores, amplitude scores, and a combination of the two (‘global AIM scores’) were applied to compare antidyskinetic effects produced by amantadine and by the following subtype-specific DA receptor antagonists: SCH23390 (D1/D5), Raclopride (D2/D3), PG01037 (D3), L-745,870 (D4), and VU6004461 (D4). SCH23390 and Raclopride produced similarly robust reductions in both time-based scores and amplitude scores, while PG01037 and L-745,870 had more partial effects. Interestingly, a novel and highly brain penetrable D4 receptor antagonist (VU6004461) markedly attenuated both time-based and amplitude scores without diminishing the general motor stimulant effect of L-DOPA. In summary, our results show that a dyskinesia scale combining a time dimension with an amplitude dimension (‘global AIMs’) is more sensitive than unidimensional scales. Moreover, the antidyskinetic effects produced by two chemically distinct D4 antagonists identify the D4 receptor as a potential future target for the treatment of LID.</p>},
  author       = {Sebastianutto, Irene and Maslava, Natallia and Hopkins, Corey R. and Cenci Nilsson, Angela},
  issn         = {0969-9961},
  keyword      = {Dystonia,Experimental therapeutics,Movement disorders,Parkinson's disease,Rodent models},
  language     = {eng},
  month        = {12},
  pages        = {156--170},
  publisher    = {ARRAY(0x87919d8)},
  series       = {Neurobiology of Disease},
  title        = {Validation of an improved scale for rating L-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists},
  url          = {http://dx.doi.org/10.1016/j.nbd.2016.09.001},
  volume       = {96},
  year         = {2016},
}