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 Previous Article
The Journal of Neuroscience, February 15, 2001, 21(4):1413-1419
Methamphetamine-Induced Rapid and Reversible Changes in Dopamine
Transporter Function: An In Vitro Model
Verónica
Sandoval,
Evan L.
Riddle,
Yvette V.
Ugarte,
Glen
R.
Hanson, and
Annette E.
Fleckenstein
Department of Pharmacology and Toxicology, University of Utah, Salt
Lake City, Utah 84112
This laboratory has demonstrated that a single methamphetamine
(METH) injection rapidly and reversibly decreases the activity of the
dopamine transporter (DAT), as assessed ex vivo in
synaptosomes prepared from treated rats. This decrease does not occur
because of residual drug introduced by the original injection or nor is it associated with a change in binding of the DAT ligand WIN35428. The
purpose of this study was to elucidate the mechanism or mechanisms of
this METH effect by determining whether direct application of this
stimulant to synaptosomes causes changes in DAT similar to those
observed ex vivo. Similar to the ex vivo
effect, incubation of striatal synaptosomes with METH decreased DAT
activity, but not WIN35428 binding: the effect on activity was not
eliminated by repeated washing of synaptosomes. Also, as observed
ex vivo, incubation with
3,4-methylenedioxymethamphetamine, but not cocaine or methylphenidate,
caused a METH-like reduction in DAT function. The rapid and reversible
METH-induced diminution in DAT activity did not occur because of a
change in membrane potential, as assessed in vitro and
ex vivo by
[3H]tetraphenylphosphonium accumulation. However,
the METH-related decline in DAT function may be attributed to
phosphorylation because NPC15437, a protein kinase C inhibitor,
attenuated the METH-induced decline in DAT function. Similarities
between previously reported effects ex vivo of a single
METH injection on serotonin and norepinephrine transporter function and
effects of direct METH application in vitro were also
found. Together, these data demonstrate that the in
vitro incubation model mimics the rapid and reversible effects observed after a single METH injection.
Key words:
in vitro; rapid and reversible; serotonin; norepinephrine; transport; phosphorylation
Copyright © 2001 Society for Neuroscience 0270-6474/01/2141413-07$05.00/0
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