Amphetamine-induced dyskinesia in the transplanted hemi-Parkinsonian mouse.
The transplantation of dopamine-rich tissue into the putamen of patients with Parkinson's disease shows much potential for use as a therapeutic strategy. However, a number of grafted individuals subsequently developed a set of abnormal involuntary movements (AIMs), unrelated to the dyskinesia caused by L-DOPA treatment, which have been termed graft-induced dyskinesia. Given the small number of patients, pre-clinical modeling of graft-induced dyskinesia in animal models will be critical to determine the underlying mechanisms and amelioration potential of this technique. Here we show that abnormal involuntary movements of the limbs, trunk and face can be observed in transplanted hemi-parkinsonian mice following amphetamine administration, similar to those previously described to model graft-induced dyskinesias in rats. C57Bl6 and CD1 mice were first rendered hemi-parkinsonian with 6-hydroxydopamine, treated with L-DOPA for 21 days until dyskinetic, and then transplanted with a single cell suspension of embryonic ventral mesencephalon (VM E12.5) tissue from corresponding strains into the denervated striatum. At 16 weeks post-transplantation, a single injection of amphetamine-elicited dyskinesia in a subgroup of mice of both strains, behavioural pattern not observed pre-transplantation. The number of surviving dopaminergic cells in the graft did not differ between those that developed AIMs and those that did not. The movements were phenotypically comparable to those seen in the rat model and parallels can be drawn to the human form of the movements, although the mouse model maybe less reproducible than the rat equivalent. This mouse model will facilitate assessment of graft-induced dyskinesia with mouse-derived stem cell lines and exploration of mechanisms using transgenic mice in future studies.
Neuroregeneration Laboratories, McLean Hospital/Harvard Medical school, Belmont, MA 02478, USA. gsmith@mclean.harvard.edu
Gaynor A
GA
Smith
Andreas
A
Heuer
Alexander
A
Klein
Ngoc-Nga
NN
Vinh
Stephen B
SB
Dunnett
Emma L
EL
Lane
D018663:Adrenergic Agents / Q000633:toxicity; D000661:Amphetamine / Q000009:adverse effects*; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D017690:Cell Transplantation / Q000379:methods*; D003342:Corpus Striatum / Q000502:physiology / Q000601:surgery; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000601:surgery*; D004622:Embryo, Mammalian; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology*; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology / Q000637:transplantation*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D013239:Stereotyped Behavior / Q000187:drug effects
D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D018765:Dopamine Uptake Inhibitors; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine