Abstract
Neurotransmitter transporters present at the cell surface are well-established asthe primary targets for psychostimulant drugs of abuse and for drugs such asmethylphenidate and amphetamines, which are used to treat attention deficitdisorders. In recent studies, we have observed that once amphetamines enterneurons they can activate multiple intracellular signaling pathways. Within thecell, amphetamines activate the small GTPases, Rho and Rac1, and triggerendocytosis of the dopamine transporter (DAT) and a neuronal glutamatetransporter (EAAT3) by a RhoA-dependent internalization pathway. These eventsdepend upon the expression of an intracellular G-protein coupled trace aminereceptor (TAAR1) that signals through at least two types of G-proteinalpha-subunit within the cell. Using a series of subcellularly-targeted geneticfluorescence resonance energy transfer (FRET) sensors to detect RhoA or PKAactivation, we have been able to characterize the subcellular membranecompartments where TAAR1 signaling events initiate. These results imply thatamphetamine-like drugs not only inhibit monoamine transport and potentiateneurotransmitter action, but they also activate signaling pathways through theirdirect action on an intracellular GPCR target. This lecture will highlight therole of TAAR1- and other GPCR-mediated signaling events in amphetamine actionand will consider how they are linked to the action of a variety of drugs thatmodulate monoamine signaling.
