Validation of an improved scale for rating l-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists.
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 (3-6mg/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.
Basal Ganglia Pathophysiology Unit, Dept. Exp. Medical Science, Lund University, BMC, 221 84 Lund, Sweden. Electronic address: irene.sebastianutto@med.lu.se.
Irene
I
Sebastianutto
Basal Ganglia Pathophysiology Unit, Dept. Exp. Medical Science, Lund University, BMC, 221 84 Lund, Sweden.
Natallia
N
Maslava
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA.
Corey R
CR
Hopkins
Basal Ganglia Pathophysiology Unit, Dept. Exp. Medical Science, Lund University, BMC, 221 84 Lund, Sweden. Electronic address: angela.cenci_nilsson@med.lu.se.
M Angela
MA
Cenci
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000009:adverse effects*; D018492:Dopamine Antagonists / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology*; D005106:Exploratory Behavior / Q000187:drug effects; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009068:Movement / Q000187:drug effects; D017063:Outcome Assessment, Health Care; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D015203:Reproducibility of Results; D013997:Time Factors
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D007980:Levodopa; D016627:Oxidopamine
Dystonia; Experimental therapeutics; Movement disorders; Parkinson's disease; Rodent models