Neurotransmitter transporters present at the cell surface are well-established as the primary targets for psychostimulant drugs of abuse and for drugs such as methylphenidate and amphetamines, which are used to treat attention deficit disorders. In recent studies, we have observed that once amphetamines enter neurons they can activate multiple intracellular signaling pathways. Within the cell, amphetamines activate the small GTPases, Rho and Rac1, and trigger endocytosis of the dopamine transporter (DAT) and a neuronal glutamate transporter (EAAT3) by a RhoA-dependent internalization pathway. These events depend upon the expression of an intracellular G-protein coupled trace amine receptor (TAAR1) that signals through at least two types of G-protein alpha-subunit within the cell. Using a series of subcellularly-targeted genetic fluorescence resonance energy transfer (FRET) sensors to detect RhoA or PKA activation, we have been able to characterize the subcellular membrane compartments where TAAR1 signaling events initiate. These results imply that amphetamine-like drugs not only inhibit monoamine transport and potentiate neurotransmitter action, but they also activate signaling pathways through their direct action on an intracellular GPCR target. This lecture will highlight the role of TAAR1- and other GPCR-mediated signaling events in amphetamine action and will consider how they are linked to the action of a variety of drugs that modulate monoamine signaling.

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