Amphetamine and methamphetamine differentially regulate biophysical properties of dopamine transporter

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Dopamine transporter (DAT) substrates, amphetamine (AMPH) & methamphetamine (METH), compete with dopamine (DA) uptake & induce DA reverse transport via DAT albeit by poorly understood mechanism. Whole‐cell recordings of cells overexpressing DAT indicate that small differences in chemical structure or chirality of substrates influence the nature of DAT‐mediated currents. D‐AMPH elicits a DAT‐mediated persistent depolarizing current larger than that of the racemic mixture of METH (S(+), R(‐) isomers) or R(‐)‐METH alone. Extracellular S(+)‐METH elicits larger DAT currents than R(‐)‐METH or the racemic mixture. Thus, R(‐)‐METH may be a DAT partial agonist which decrease DAT current elicited by S(+)‐METH, the more effective stereoisomer (or full agonist). Ongoing experiments examine whether drug access to the internal DAT binding site is required to elicit a response or whether simultaneous or stepwise drug access to the internally accessible binding site, in addition to an externally accessible DAT binding site, is required for maximum response. Via recording pipette, mouse DA neurons will be directly dialyzed with these compounds or their stereoisomers while measuring DAT current & firing activity. Funding was provided by DA026947/DA/NIDA and NS071122/NS/NINDS