Literature reports suggest that polychlorinated biphenyls (PCBs) may alter dopaminergic neurotransmission in mammalian forebrain. In vitro, PCBs can decrease dopamine levels in PC 12 cells and studies of the structure-activity relationship (SAR) indicate that ortho-substituted (non-coplanar) PCB congeners are more active than para-substituted (coplanar) congeners. This report tested the hypothesis that ortho-substituted PCBs can selectively (vs para-substituted congeners) decrease dopamine synthesis in mammalian forebrain by inhibiting the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis. In vitro effects of individual PCB congeners on activity of striatal tyrosine hydroxylase from two different rat strains were assessed. It was found that certain ortho-substituted PCB congeners (e.g., 2,2′-DCB) can inhibit tyrosine hydroxylase activity and dopamine synthesis by nearly 40% in minces of corpus striatum prepared from Sprague-Dawley and Long-Evans hooded rats. Comparatively, the ortho, meta-substituted PCB congener 2,2′,5,5′-TeCB inhibited tyrosine hydroxylase activity only in striatal minces obtained from Sprague-Dawley rats, suggesting that genetic factors may influence the susceptibility of mammals to effects of PCBs that compromise brain dopamine synthesis. The PCB-induced inhibition of tyrosine hydroxylase activity in mammalian forebrain observed here appears to occur through indirect and as yet unknown mechanisms.