Neurotransmitter transporters present at the plasma membrane contribute to the clearance and recycling of neurotransmitters and have a profound impact on the extent of receptor activation during neuronal signaling.In addition to their role in neurotransmitter clearance, these carriers are the primary targets for psychostimulant drugs of abuse, therapeutic antidepressants and other drugs used to treat brain disorders.In recent studies we have observed that once amphetamine-like drugs enter dopamine neurons, they activate multiple intracellular signaling pathways (including cAMP-and Rho-dependent pathways) to trigger changes in the cellular trafficking of the dopamine transporter and other neuronal membrane proteins.Interestingly, these actions of amphetamine are completely blocked by co-application of cocaine.This implies that in addition to their ability to block monoamine transport and potentiate neurotransmitter action, amphetamine-like drugs also act on specific cytoplasmic targets that regulate protein trafficking and many other cellular activities.Although many steps in the process are yet to be defined, this novel intracellular mode of amphetamine action has major implications for the mechanisms of neuroplasticity and neurotoxicity associated with psychostimulant use and suggests novel drug targets for modulating the actions of amphetamines.