The Dopamine Transporter: Molecular Biology, Pharmacology and Genetics

Abstract

More than 30 years ago, accumulation of dopamine by brain tissue was demonstrated after intraventricular injection of [³H]dopamine (Glowinski and Iversen 1966). The highest concentration was found in the striatum, the brain region with the highest innervation by dopaminergic neurons. From neuronal noradrenaline uptake, which had been discovered several years earlier (Axelrod et al. 1959; Hertting et al. 1961) dopamine uptake was shown to be pharmacologically different: tricyclic antidepressants such as desipramine inhibited dopamine uptake with low potency in vivo (Glowinski et al. 1966; Carlsson et al. 1966; Fuxe and Ungerstedt 1968) and in vitro (Ross and Renyi 1967; Hamberger 1967; Jonason and Rutledge 1968) and, in contrast to the uptake system in noradrenaline neurons, (+)- and (-)-noradrenaline were equipotent as inhibitors of [³H]dopamine uptake by striatal synaptosomes (Coyle and Snyder 1969). The potent inhibitors of dopamine uptake, nomifensine, mazindol and cocaine were radiolabeled and used as ligands to specifically label what was called the dopamine transporter (DAT) complex (Javitch et al. 1983; Kennedy and Hanbauer 1983; Pimoule et al. 1983; Dubocovich and Zahniser 1985). Photoaffinity probes based on dopamine uptake blocking diphenylpiperazine derivatives were shown to incorporate into a glycoprotein of approximately 60 kDa apparent molecular mass (Grigoriadis et al. 1989; Sallee et al. 1989), and molecular cloning finally established the DAT as a molecular entity distinct from other plasmalemmal neurotransmitter transporters (Giros et al. 1991; Kilty et al. 1991; Shimada et al. 1991; Usdin et al. 1991).