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Dynamic Regulation of Signaling Pathways in Dopamine Neurons: The Intracellular Actions of Amphetamines, Susan Amara, PhD
October 5, 2016 @ 8:40 am - 9:05 am
Susan Amara, PhD, Scientific Director, Division of Intramural Research Program and Chief, Laboratory of Molecular and Cellular Neurobiology, National Institute of Mental Health, National Institutes of Health —
Neurotransmitter transporters present at the plasma membrane are 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 children. In recent studies we have observed that once amphetamine-like drugs enter dopamine neurons they 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 the neuronal glutamate transporter (EAAT3) by a RhoA- and dynamin-dependent pathway. These events depend upon the activation of a G-protein coupled trace amine receptor, TAAR1, within the cell. This work implies that amphetamine-like drugs not only block monoamine transport and potentiate neurotransmitter action, but also act on specific cytoplasmic targets that regulate protein trafficking and many other cellular activities. Â This intracellular mode of amphetamine action has important implications for the mechanisms of neuroplasticity and neurotoxicity associated with psychostimulant use and suggests novel drug targets for modulating the actions of amphetamines.