Coadministration of (-)-OSU6162 with l-DOPA normalizes preproenkephalin mRNA expression in the sensorimotor striatum of primates with unilateral 6-OHDA lesions.
The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D(2) receptors and potent normalizing effects on l-DOPA-induced dyskinesias. We studied the effects of coadministration of (-)-OSU6162 with l-DOPA on the regulation of striatal preproenkephalin (PPE) and prodynorphin (PDyn) mRNA expression in the primate brain by in situ hybridization histochemistry. Common marmoset monkeys sustaining unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received l-DOPA/carbidopa, l-DOPA/carbidopa plus (-)-OSU6162, or vehicle over 14 days. In vehicle-treated animals, PPE mRNA levels were markedly increased in the sensorimotor territory of the lesioned striatum. By contrast, a rather uniform lesion-induced reduction of PDyn mRNA levels was found in the vehicle group. Subchronic l-DOPA treatment induced a further increase in PPE mRNA expression in a number of sensorimotor and associative subregions of the denervated striatum. Coadministration of (-)-OSU6162 with l-DOPA partially reversed the lesion- and l-DOPA-induced elevation of PPE expression and, by affecting PPE mRNA expression differentially on the intact and lesioned striatum, markedly reduced the side-to-side difference in PPE mRNA expression. The effects on PPE mRNA expression were apparent throughout the rostrocaudal extent of the putamen and the dorsal portions of the caudate nucleus. l-DOPA treatment resulted in an enhancement in PDyn mRNA expression in all functional compartments of the striatum. Coadministration of (-)-OSU6162 had no apparent influence on these l-DOPA-induced changes in PDyn mRNA expression. The present results suggest that (-)-OSU6162 acts primarily by modifying striatal output via the indirect pathway.
Pirker
W
W
Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, S-17176, Sweden.
Tedroff
J
J
Pontén
H
H
Gunne
L
L
Andrén
P E
PE
Hurd
Y L
YL
D000818:Animals; D001345:Autoradiography; D002144:Callithrix; D002421:Caudate Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017403:In Situ Hybridization; D007279:Injections, Subcutaneous; D007980:Levodopa / Q000008:administration & dosage*; D008024:Ligands; D008297:Male; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D011699:Putamen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014316:Tritium
D015259:Dopamine Agents; D004745:Enkephalins; D008024:Ligands; D010880:Piperidines; D011498:Protein Precursors; D012333:RNA, Messenger; C109513:OSU 6162; D014316:Tritium; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin