title: SKF-83566, a D1-dopamine receptor antagonist, inhibits the dopamine transporter.
abstract: Dopamine (DA) is an important transmitter in both motor and limbic pathways. We sought to investigate the role of D(1)-receptor activation in axonal DA release regulation in dorsal striatum using a D(1)-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, with a maximum increase of ∼ 65% in 5 μM SKF-83566. This was accompanied by a concentration-dependent increase in extracellular DA concentration 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 [(3)H]DA uptake into LLc-PK cells expressing rat DAT, and confirmed that SKF-83566 is a competitive DAT inhibitor with an IC(50) of 5.7 μM. Binding studies with [(3)H]CFT, a cocaine analog, showed even more potent action of SKF-83566 at the DAT cocaine binding site (IC(50) = 0.51 μM). Thus, data obtained using SKF-83566 as a D(1) 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 this drug at the cocaine versus DA binding site of the DAT.
authors.affiliation: Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Stouffer
authors.forename: Solav
authors.initials: S
authors.lastname: Ali
authors.forename: Maarten E A
authors.initials: ME
authors.lastname: Reith
authors.forename: Jyoti C
authors.initials: JC
authors.lastname: Patel
authors.forename: Federica
authors.initials: F
authors.lastname: Sarti
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Carr
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Rice
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000378:metabolism* / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D009627:Nomifensine / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium / Q000493:pharmacokinetics; D014326:Tropanes / Q000493:pharmacokinetics
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D004298:Dopamine; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D009627:Nomifensine; D014316:Tritium; D014326:Tropanes; C406245:2-carbomethoxy-3-(4-fluoromethylphenyl)tropane; C044846:SKF83566