The present investigation examined the effects of neonatal and adult 6-hydroxydopamine (6-OHDA)-induced lesions of dopaminergic neurons on opioid and tachykinin peptides and their gene expression in the rat basal ganglia. This work was undertaken to determine if changes in these neuropeptide systems were contributing to the differing behavioral responses observed between neonatally and adult-lesioned rats after dopamine agonist administration. [Met5]Enkephalin (ME) content was increased in striatal tissue from both 6-OHDA-lesioned groups when compared with unlesioned controls. Dynorphin-A (1-8) content was not altered by the 6-OHDA lesions. The tachykinin peptides substance P and neurokinin A were significantly decreased in level in the striatum and substantia nigra of neonatally lesioned rats, but not in the adult-lesioned rats, when compared with unlesioned controls. Proenkephalin mRNA abundance (quantified by an RNA-cDNA hybridization technique) and precursor level (as reflected by cryptic ME content) were increased in the striatum of both neonatally and adult-lesioned rats. The abundance of preprotachykinin mRNA coding for the tachykinin peptides was markedly decreased in the neonatally lesioned rats, whereas only a small reduction was observed in the adult-lesioned rats. These results suggest that destruction of dopamine-containing terminals with 6-OHDA elevates the level of ME by accelerating transcriptional and/or translational processes; conversely, the reduced content of tachykinins in neonatally lesioned rats may be due to a reduction in such processes. Thus, preproenkephalin-A and preprotachykinin gene expression are differentially regulated after lesioning of catecholamine-containing neurons, an observation suggesting a close functional relationship among these neurotransmitter systems. Furthermore, of the peptides studied, only levels of the tachykinin peptides were differentially altered in the striatum and substantia nigra of the neonatally lesioned rats compared with adult-lesioned rats; therefore, these peptides may be associated with the distinctive behavioral differences between neonatally and adult 6-OHDA-lesioned rats given dopamine agonists.