Coadministration of (-)-OSU6162 with L-DOPA normalizes preproenkephalin mRNA expression in the sensorimotor striatum of primates with unilateral 6-OHDA lesions

Walter Pirker, Joakim Tedroff, Henrik Pontén, Lars Gunne, Per E. Andrén, Yasmin L. Hurd

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D2 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.

Original languageEnglish
Pages (from-to)122-134
Number of pages13
JournalExperimental Neurology
Volume169
Issue number1
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Basal ganglia
  • In situ hybridization
  • Monkey
  • Opioid neuropeptide
  • Parkinson's disease
  • Prodynorphin

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