Implanted reuptake-deficient or wild-type dopaminergic neurons improve ON L-dopa dyskinesias without OFF-dyskinesias in a rat model of Parkinson's disease.
OFF-L-dopa dyskinesias have been a surprising side-effect of intrastriatal foetal ventral mesencephalic transplantation in patients with Parkinson's disease. It has been proposed that excessive and unregulated dopaminergic stimulation of host post-synaptic striatal neurons by the grafts could be responsible for these dyskinesias. To address this issue we transplanted foetal dopaminergic neurons from mice lacking the dopamine transporter (DATKO) or from wild-type mice, into a rat model of Parkinson's disease and L-dopa-induced dyskinesias. Both wild-type and DATKO grafts reinnervated the host striatum to a similar extent, but DATKO grafts produced a greater and more diffuse increase in extra-cellular striatal dopamine levels. Interestingly, grafts containing wild-type dopaminergic neurons improved parkinsonian signs to a similar extent as DATKO grafts, but provided a more complete reduction of L-dopa induced dyskinesias. Neither DATKO nor wild-type grafts induced OFF-L-dopa dyskinesias. Behavioural and receptor autoradiography analyses demonstrated that DATKO grafts induced a greater normalization of striatal dopaminergic receptor supersensitivity than wild-type grafts. Both graft types induced a similar downregulation and normalization of PEnk and fosb/Deltafosb in striatal neurons. In summary, DATKO grafts causing high and diffuse extra-cellular dompamine levels do not per se alter graft-induced recovery or produce OFF-L-dopa dyskinesias. Wild-type dopaminergic neurons appear to be the most effective neuronal type to restore function and reduce L-dopa-induced dyskinesias.
Vinuela
A
A
Udall Parkinson Disease Research Center of Excellence,Center for Neuroregeneration Research, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
Hallett
P J
PJ
Reske-Nielsen
C
C
Patterson
M
M
Sotnikova
T D
TD
Caron
M G
MG
Gainetdinov
R R
RR
Isacson
O
O
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use; D016380:Brain Tissue Transplantation; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000502:physiology; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000628:therapy; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D016332:Fetal Tissue Transplantation; D005786:Gene Expression Regulation; D006085:Graft Survival; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008636:Mesencephalon / Q000637:transplantation; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000637:transplantation; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D000978:Antiparkinson Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; C033660:preproenkephalin; D004298:Dopamine