The dopamine (DA) uptake inhibitor, GBR 12909 (GBR) and a neonatal dopaminergic denervated rat model were used as tools to study the influence of DA on the serotonin (5HT) system in the striatum. The striatal levels of the amines and their acid metabolites (dihydroxyphenylacetic acid, DOPAC; 5-hydroxyindoleacetic acid, 5HIAA) were determined by HPLC. The administration of a single dose (20 mg/kg) of GBR failed to affect the steady-state levels of the amines or metabolites. Repeated administration of GBR (20 mg/kg/day) for 2 or 4 days decreased DA and DOPAC; only the 4-day regimen decreased 5HT and increased 5HIAA levels. The neonatal dopaminergic lesion with 6-hydroxydopamine (6OHDA) depleted (> 95%) DA and DOPAC and increased 5HT and 5HIAA levels in the striatum. Administration of GBR (20 mg/kg/day for 4 days) to lesioned animals failed to influence the lesion-induced increases in 5HT and 5HIAA levels. The results suggest GBR decreases the steady-state levels of DA, resulting in a compensatory increase in the turnover of 5HT that is dependent on the presence of intact dopaminergic terminals. Thus, the effect of GBR on 5HT turnover is indirect. The studies provide further support for a prominent dopaminergic influence on striatal 5HT metabolism.