Effects of oligonucleotide antisense to dopamine D3 receptor mRNA in a rodent model of behavioural sensitization to levodopa.
Levodopa-induced dyskinesias are abnormal involuntary movements that develop as a side-effect of long-term treatment with levodopa for Parkinson's disease. The mechanisms underlying such effects are unclear but may include abnormal stimulation of dopamine D(3) receptors. Elevations in dopamine D(3) receptor mRNA and binding are seen in the denervated striatum of hemiparkinsonian rats treated chronically with levodopa, and these changes correlate well with behavioural sensitization in this model. Further investigation of dopamine D(3) receptor involvement in levodopa-induced dyskinesias is hampered by the lack of appropriately selective ligands for this receptor. Here, in vivo administration of an antisense oligonucleotide designed to reduce striatal dopamine D(3) receptor expression provides a level of specificity not available through traditional pharmacological approaches. Following chronic treatment with levodopa, hemiparkinsonian rats received intrastriatal infusion of oligonucleotide antisense to dopamine D(3) receptor mRNA for 5 days. Antisense treatment effectively and selectively reduced striatal dopamine D(3) receptor binding and blocked behavioural sensitization to the effects of repeated levodopa. These findings confirm the importance of the D3 receptor in the expression of behavioural sensitization to levodopa in animals with dopaminergic denervation and contribute to our limited understanding of the functional significance of this receptor. In that sensitization to the effects of repeated levodopa in this setting may be analogous to medication-induced dyskinesias in humans, our findings furthermore suggest that drugs which block D(3) function may be helpful in the treatment of dyskinesias, without necessarily exacerbating Parkinsonism.
van Kampen
J M
JM
Pacific Parkinson's Research Centre, 2221 Wesbrook Mall Rm M36, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Stoessl
A Jon
AJ
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage / Q000009:adverse effects; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism*; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3
D015259:Dopamine Agents; C493595:Drd3 protein, rat; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D007980:Levodopa