Near total striatal dopamine denervation results in a decrease in substance P and an increase in enkephalin messenger RNA expression in the striatum. It is unknown whether partial depletions of striatal dopamine content produce similar changes in these peptide messenger RNAs. To test whether compensations in dopamine synthesis and release following partial dopamine denervation prevent the lesion-induced alterations in substance P and enkephalin messenger RNAs, varying concentrations of 6-hydroxydopamine were injected unilaterally into the substantia nigra. Seven days after injection of 6-hydroxydopamine (2-16 micrograms) or vehicle, in situ hybridization histochemistry was used to examine tyrosine hydroxylase messenger RNA in the substantia nigra and substance P and enkephalin messenger RNAs in the striatum. The extent of the dopamine depletion was determined by measuring striatal dopamine tissue content. The decrease in tyrosine hydroxylase messenger RNA paralleled the change in striatal tissue dopamine content. Substance P messenger RNA was decreased in all lesioned rats. In contrast, a significant increase in enkephalin messenger RNA was not detected until striatal dopamine was reduced to 10% of control levels. These results suggest that compensations within the residual dopamine system are not sufficient to maintain normal striatal substance P messenger RNA levels in partially denervated animals, but are sufficient to maintain normal striatal enkephalin messenger RNA expression.