Amphetamine reverses or blocks the operation of the human noradrenaline transporter depending on its concentration: superfusion studies on transfected cells

Whether amphetamine enhances noradrenergic activity by uptake blockade or a releasing action is still a matter of debate. In order to gain insight int o the interaction of amphetamine with the noradrenaline transporter its cDN A was transfected into COS-7 cells (NAT-cells) or cotransfected with the cD NA of the vesicular monoamine transporter (NAT/VMAT-cells); cells were load ed with [H-3]noradrenaline, superfused and the efflux analysed for total tr itium and [H-3]noradrenarine. In NAT-celis amphetamine stimulated [H-3]nora drenaline efflux concentration-dependently when added to the superfusion bu ffer at 0.01, 0.1 and 1 mu M. By contrast, 10 or 100 mu M amphetamine stimu lated efflux to a smaller extent or not at all; however, on switching back to amphetamine-free buffer a prompt increase of efflux was observed. Cocain e did not increase efflux per se and blocked the amphetamine-induced efflux . In NAT/VMAT-cells amphetamine stimulated efflux in a concentration-depend ent manner. The effect showed saturation at 1 mu M and was not suppressed a t higher concentrations. Cocaine also elicited efflux from NAT/VMAT-cells c oncentration-dependently; the maximum was reached at approximately 1 mu M a nd amounted to only about half of the amphetamine-induced efflux. It is con cluded that amphetamine can induce noradrenaline transporter mediated relea se only at high nanomolar to low micromolar concentrations. At higher conce ntrations it blocks the noradrenaline transporter; in this case, the releas ing action of amphetamine, like that of cocaine, is dependent on a vesicula r pool of noradrenaline. (C) 1999 Elsevier Science Ltd. All rights reserved .