SKF-83566, a D1 dopamine receptor antagonist, inhibits the dopamine transporter

Dopamine (DA) is an important transmitter in both motor and limbic pathways. We sought to investigate the role of D1-receptor activation in axonal DA release regulation in dorsal striatum using a D1-receptor antagonist, SKF-83566. Evoked DA release was monitored in rat striatal slices using fast-scan cyclic voltammetry. SKF-83566 caused a concentration-dependent increase in peak single-pulse evoked extracellular DA concentration ([DA]o), with a maximum increase of ~65% in 5 μM SKF-83566. This was accompanied by a concentration-dependent increase in [DA]o clearance time. Both effects were occluded by nomifensine (1 μM), a dopamine transporter (DAT) inhibitor, suggesting that SKF-83566 acted via the DAT. We tested this by examining [3H]DA uptake into LLc-PK cells expressing rat DAT, and confirmed that SKF-83566 is a competitive DAT inhibitor with an IC50 of 5.7 μM. Binding studies with [3H]CFT, a cocaine analog, showed even more potent action at the DAT cocaine binding site (IC50 = 0.51 μM SKF-83566). Thus, data obtained using SKF-83566 as a D1 DA-receptor antagonist may be confounded by concurrent DAT inhibition. More positively, however, SKF-83566 might be a candidate to attenuate cocaine effects in vivo because of the greater potency of SKF-83566 at the cocaine versus DA binding site of the DAT.