Mechanisms by which amphetamine redistributes dopamine out of vesicles: a computational study.

Computer simulations of dopamine (DA) and amphetamine interactions associated with dopaminergic storage vesicles were developed in order to better explain how amphetamine causes redistribution of DA out of the vesicles. In the model, DA can be transported into vesicles via the vesicular monoamine transporter. Amphetamine competitively inhibits DA uptake either as a substrate for the transporter or by interference with DA binding to the transporter. Both of the amines can passively diffuse across the membrane in both directions, but only the neutral species can cross the membrane in this manner. The abundance of neutral and positive moieties of the amines is governed by the Henderson-Hasselbalch equation. The model reproduces experimentally observed steady-state DA levels in vesicles, vesicles emptying faster after a change of pH inside the vesicle than after a change in access of DA for the vesicular monoamine transporter, and the impact of amphetamine on DA uptake and efflux in a variety of experimental paradigms. The simulations indicate that a small percentage of DA is constantly diffusing out of vesicles and is replaced by DA entering the vesicle by the vesicular monoamine transporter. Low doses of amphetamine cause DA redistribution out of vesicles primarily by inhibiting DA storage while an enhancement of efflux rates as a result of a change in vesicle pH is added at higher concentrations of amphetamine.