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Vol. 59, Issue 1, 83-95, January 2001
Vollum Institute (P.P., M.S.S., S.G.A.) and Howard Hughes Medical
Institute (S.G.A.), Oregon Health Sciences University, Portland,
Oregon; and Department of Biology, University of Virginia,
Charlottesville, Virginia (S.K.P., J.H.)
Extracellular concentrations of monoamine neurotransmitters are
regulated by a family of high-affinity transporters that are the
molecular targets for such psychoactive drugs as cocaine, amphetamines,
and therapeutic antidepressants. In Drosophila
melanogaster, cocaine-induced behaviors show striking
similarities to those induced in vertebrate animal models. Although a
cocaine-sensitive serotonin carrier exists in flies, there has been no
pharmacological or molecular evidence to support the presence of
distinct carrier subtypes for other bioactive monoamines. Here we
report the cloning and characterization of a cocaine-sensitive fly
dopamine transporter (dDAT). In situ hybridization demonstrates that
dDAT mRNA expression is restricted to dopaminergic cells in the fly
nervous system. The substrate selectivity of dDAT parallels that of the
mammalian DATs in that dopamine and tyramine are the preferred
substrates, whereas octopamine is transported less efficiently, and
serotonin not at all. In contrast, dDAT inhibitors display a rank order of potency most closely resembling that of mammalian norepinephrine transporters. Cocaine has a moderately high affinity to the cloned dDAT
(IC50 = 2.6 µM). Voltage-clamp analysis of dDAT
expressed in Xenopus laevis oocytes indicates
that dDAT-mediated uptake is electrogenic; however, dDAT seems to lack
the constitutive leak conductance that is characteristic of the
mammalian catecholamine transporters. The combination of a DAT-like
substrate selectivity and norepinephrine transporter-like inhibitor
pharmacology within a single carrier, and results from phylogenetic
analyses, suggest that dDAT represents an ancestral catecholamine
transporter gene. The identification of a cocaine-sensitive target
linked to dopaminergic neurotransmission in D.
melanogaster will serve as a basis for further dissection of
the genetic components of psychostimulant-mediated behavior.
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