Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia.
Dyskinesia (abnormal involuntary movements) is a common complication of l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. Dopamine (DA) denervated mice can exhibit behavioral and cellular signs of dyskinesia when they are treated with l-DOPA, but the clinical relevance of this animal model remains to be established. In this study, we have examined the pharmacological profile of l-DOPA-induced abnormal involuntary movements (AIMs) in the mouse. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) in the striatum. The animals were treated chronically with daily doses of l-DOPA that were sufficient to ameliorate akinetic features without inducing overt signs of dyskinesia upon their first administration. In parallel, other groups of mice were treated with antiparkinsonian agents that do not induce dyskinesia when administered de novo, that is, the D2/D3 agonist ropinirole, and the adenosine A2a antagonist KW-6002. During 3 weeks of treatment, l-DOPA-treated mice developed AIMs affecting the head, trunk and forelimb on the side contralateral to the lesion. These movements were not expressed by animals treated with ropinirole or KW-6002 at doses that improved forelimb akinesia. The severity of l-DOPA-induced rodent AIMs was significantly reduced by the acute administration of compounds that have been shown to alleviate l-DOPA-induced dyskinesia both in parkinsonian patients and in rat and monkey models of Parkinson's disease (amantadine, -47%; buspirone, -46%; riluzole, -33%). The present data indicate that the mouse AIMs are indeed a functional equivalent of l-DOPA-induced dyskinesia.
Lundblad
M
M
Wallenberg Neuroscience Centre, Section of Basal Ganglia Pathophysiology, BMC A11, S-221 84 Lund, Sweden.
Usiello
A
A
Carta
M
M
Håkansson
K
K
Fisone
G
G
Cenci
M A
MA
D058908:Adenosine A2 Receptor Agonists; D018663:Adrenergic Agents / Q000009:adverse effects; D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D002065:Buspirone / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D018491:Dopamine Agonists / Q000494:pharmacology; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D015203:Reproducibility of Results; D019782:Riluzole / Q000494:pharmacology; D016896:Treatment Outcome
D058908:Adenosine A2 Receptor Agonists; D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D007211:Indoles; D011687:Purines; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; C046649:ropinirole; C111599:istradefylline; D007980:Levodopa; D019782:Riluzole; D016627:Oxidopamine; D000547:Amantadine; D002065:Buspirone