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 do paminergic systems with low affinity for dopamine D, receptors and potent n ormalizing 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 prima te brain by in situ hybridization histochemistry. Common marmoset monkeys s ustaining unilateral g-hydroxydopamine lesions of the nigrostriatal pathway received L-DOPA/carbidopa, L-DOPA/carbidopa plus (-)-OSU6162, or vehicle o ver 14 days. In vehicle-treated animals, PPE mRNA levels were markedly incr eased 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 i n PPE mRNA expression in a number of sensorinotor and associative subregion s of the denervated striatum, Coadministration of (-)-OSU6162 with L-DOPA p artially reversed the lesion- and L-DOPA-induced elevation of PPE expressio n and, by affecting PPE mRNA expression differentially on the intact and le sioned striatum, markedly reduced the side-to-side difference in PPE mRNA e xpression. The effects on PPE mRNA expression were apparent throughout the rostrocaudal extent of the putamen and the dorsal portions of the caudate n ucleus. L-DOPA treatment resulted in an enhancement in PDyn mRNA expression in all functional compartments of the striatum, Coadministration of (-)-OS U6162 had no apparent influence on these L-DOPA-induced changes in PDyn mRN A expression. The present results suggest that (-)-OSU6162 acts primarily b y modifying striatal output via the indirect pathway, a zool Academic Press .