The mechanism of the releasing action of amphetamine. Uptake, superfusion,and electrophysiological studies on transporter-transfected cells

Amphetamine analogues are able to induce signs of neurotoxicity in the brai n. In order to understand this type of neurotoxicity, the interaction of am phetamine with its molecular targets must be elucidated. These molecular ta rgets are plasmalemmal and vesicular monoamine transporters. We investigate d the interaction of amphetamine with these transporters in cells transfect ed with the respective cDNA. Superfusion and whole-cell, patch-clamp experi ments were performed, and the toxicity of substrates of the transporters wa s studied. Amphetamine was taken up by dopamine transporter-expressing cell s in a sodium-dependent and cocaine-blockable manner. Furthermore, it elici ted inward currents in these cells concentration-dependently. Correlation o f uptake, release, and patch-clamp experiments suggest that ion fluxes indu ced by substrate-gating on transporters may significantly contribute to the releasing action of amphetamine and of other transporter substrates. Dopam ine accumulation into serotoninergic terminals depleted of serotonin by 3,4 -methylenedioxymethamphetamine was discussed as a mechanism of Ecstasy-toxi city. This is in agreement with a toxic effect of intracellular dopamine wh ich could be demonstrated on our transporter-overexpressing cells. These re sults, apart from their relevance for the toxicity by amphetamine analogues , may also have bearings on the mechanisms in neurodegenerative diseases af fecting monoamine transmitters.