The mechanism of the releasing action of amphetamine. Uptake, superfusion,
and electrophysiological studies on transporter-transfected cells*
C. Pifl1**, H. H Sitte1,
H. Reither1, and E. A. Singer2
1Institute of Biochemical
2Pharmacological Institute, University of Vienna, A-1090 Vienna,
Abstract: Amphetamine analogues are able to induce signs of
neurotoxicity in the brain. In order to understand this type of neurotoxicity,
the interaction of amphetamine with its molecular targets must be elucidated.
These molecular targets are plasmalemmal and vesicular monoamine transporters.
We investigated the interaction of amphetamine with these transporters
in cells transfected with the respective cDNA. Superfusion and whole-cell,
patch-clamp experiments were performed, and the toxicity of substrates
of the transporters was studied. Amphetamine was taken up by dopamine
transporter-expressing cells in a sodium-dependent and cocaine-blockable
manner. Furthermore, it elicited inward currents in these cells concentration-dependently.
Correlation of uptake, release, and patch-clamp experiments suggest
that ion fluxes induced by substrate-gating on transporters may significantly
contribute to the releasing action of amphetamine and of other transporter
substrates. Dopamine accumulation into serotoninergic terminals depleted
of serotonin by 3,4-methylenedioxymethamphetamine was discussed as a
mechanism of Ecstasy-toxicity. This is in agreement with a toxic effect
of intracellular dopamine which could be demonstrated on our transporter-overexpressing
cells. These results, apart from their relevance for the toxicity by
amphetamine analogues, may also have bearings on the mechanisms in neurodegenerative
diseases affecting monoamine transmitters.
at the 4th Congress of Toxicology in Developing Countries (4th CTOX-DC),
Antalya, Turkey, 6-10 November 1999
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