Focal striatal dopamine may potentiate dyskinesias in parkinsonian monkeys.
Striatal neurons convert L-dopa to dopamine (DA) following gene transfer of aromatic L-amino acid decarboxylase (AADC) via adeno-associated virus (AAV) in parkinsonian monkeys. We investigated whether AAV-AADC could reduce or eliminate L-dopa-induced dyskinesias (LIDs) and side effects in MPTP-treated monkeys. Five monkeys were made parkinsonian by bilateral MPTP lesions. The optimal therapeutic dose of L-dopa was determined using an acute dose response regimen. After 3 weeks of chronic L-dopa treatment, AAV-AADC or control vector was bilaterally injected into the striatum. Animals were assessed for 6 months with the same L-dopa dosing as presurgery as well as chronic oral L-dopa treatment. Presurgery LID was observed at doses greater than 5 mg/kg. The AAV-AADC-treated animals displayed an average 7.3-fold decrease in the therapeutic dose of L-dopa throughout the 6-month follow-up period. Only AAV-AADC-treated monkeys were susceptible to dyskinesias even at sub-clinical doses. Immunohistochemical analysis revealed well-delineated foci of AADC within the striatum. These results suggest that high levels of focal DA were generated in response to L-dopa administration and may be responsible for the exacerbation of dyskinesias. This may be similar to focal dopaminergic activity in PD patients that developed off-drug or "runaway" dyskinesias following fetal mesencephalic grafts.
Bankiewicz
Krystof S
KS
Department of Neurological Surgery, University of California San Francisco, Mission Center Building 0555, 1855 Folsom Street, Room 230, 94103, USA. kbank@itsa.ucsf.edu
Daadi
Marcel
M
Pivirotto
Philip
P
Bringas
John
J
Sanftner
Laura
L
Cunningham
Janet
J
Forsayeth
John R
JR
Eberling
Jamie L
JL
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D000229:Dependovirus / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000009:adverse effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry / Q000379:methods; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects*; D020267:MPTP Poisoning / Q000150:complications / Q000188:drug therapy; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging / Q000379:methods; D009474:Neurons / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods; D013997:Time Factors
D000978:Antiparkinson Agents; D007980:Levodopa; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine