Effects of oligonucleotide antisense to dopamine D(1A) receptor messenger RNA in a rodent model of levodopa-induced dyskinesia.
Dyskinesias are abnormal involuntary movements which develop as a side-effect of long-term treatment with levodopa in patients with Parkinson's disease. The pathophysiology underlying these dyskinesias remains unclear, although, it has been suggested that heightened activity of dopamine D(1) receptor-bearing striatonigral neurons may play a key role. Chronic pulsatile levodopa administration to hemiparkinsonian rats results in sensitization of rotational responses to apomorphine. This sensitization is thought to be analogous to levodopa-induced dyskinesias in humans. In these studies, we further clarify the role of the dopamine D(1A) receptor in this rodent model of levodopa-induced dyskinesias using an in vivo oligonucleotide antisense approach. Hemiparkinsonian rats received twice daily injections of levodopa for three weeks followed by intrastriatal infusion of dopamine D(1A) receptor antisense (7nmol/day, three days), a scrambled missense control sequence, or saline. Those animals treated with antisense displayed significantly fewer apomorphine-induced rotations than saline- or missense-treated controls.By reducing dopamine D(1A) receptor expression, we were able to attenuate sensitization of the response to apomorphine resulting from chronic pulsatile levodopa treatment. Thus, the dopamine D(1A) receptor appears to play a significant role in levodopa-induced dyskinesias and warrants further examination. These findings may have important implications for the development of selective treatment strategies designed to alleviate parkinsonian symptoms, while minimizing motor complications.
Van Kampen
J M
JM
Neurodegenerative Disorders Centre, Faculty of Medicine, University of British Columbia, 2221 Wesbrook Mall, B.C., V6T 2B5, Vancouver, Canada.
Stoessl
A J
AJ
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001058:Apomorphine / Q000494:pharmacology; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D003714:Denervation; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000235:genetics / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016627:Oxidopamine; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020891:Raclopride / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000378:metabolism; D012399:Rotation; D013378:Substantia Nigra / Q000737:chemistry / Q000503:physiopathology; D013565:Sympatholytics; D014316:Tritium
D000978:Antiparkinson Agents; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; C098593:dopamine D1A receptor; D014316:Tritium; D020891:Raclopride; D007980:Levodopa; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D016627:Oxidopamine; D003042:Cocaine; D001058:Apomorphine