Effects of amphetamine on subcellular distribution of dopamine and DOPAC

Amphetamine effects on distribution of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and amphetamine in vesicular, cytosolic, and extracellular compartments associated with a striatal varicosity were estimated through use of a computer simulation model. In addition, contribution to overall effects of amphetamine by each of five actions--transport by dopamine transporter (DAT), transport by vesicular monoamine transporter, stimulation of reverse transport, inhibition of monoamine oxidase (MAO), and slowing of dopamine cell firing rate--were evaluated. Amphetamine enters a varicosity almost entirely by DAT and accumulates to very high levels within the varicosity. Both reverse transport by DAT and passive diffusion contribute to continual amphetamine egress across the plasma membrane. Amphetamine enters storage vesicles by both transport and diffusion. The transport portion competes with dopamine storage, resulting in redistribution of approximately half of dopamine from vesicles to cytosol. The high concentration of amphetamine in the cytosol inhibits MAO, protecting cytosolic dopamine. A very small fraction of cytosolic dopamine is moved to extracellular compartment via reverse transport by DAT. The amount of dopamine moved by reverse transport is limited because of competition by very high cytosolic levels of amphetamine. In the presence of amphetamine, rate of dopamine transfer to extracellular compartment is less than control; however, high levels of extracellular dopamine are maintained because amphetamine occupies the DAT, thus limiting dopamine reuptake. Simulation output from a model using exchange-diffusion mechanism of reverse transport does not match all published data that were simulated, suggesting that inward transport of a substrate is not required to initiate reverse transport.