Insights in How Amphetamine ROCKs (Rho-Associated Containing Kinase) Membrane Protein Trafficking

Amphetamine (AMPH) is a psychostimulant that induces efflux of dopamine (DA) within dopaminergic nodes, a phenomenon that has been recognized since the late 1950s (1). However, the ability of AMPH to alter DA transporter (DAT) cell surface expression did not emerge from the literature until the late 1990s (2). DAT, a key target of AMPH actions, is an important regulator of synaptic DA levels. Fleckenstein et al. (3) first hypothesized that AMPH not only induces transporter efflux but also may regulate transporter surface expression levels. This hypothesis was based on their observation that in rats, a single, high-dose injection of AMPH results in a decrease of DAT function 1 h later (3). Since then, initiated by the work of Saunders et al. (2), AMPH-induced regulation of DAT trafficking has been demonstrated in numerous studies, and the investigation into the mechanisms underlying this phenomenon has become an area of intense research (4⇓–6). In PNAS, Wheeler et al. (7) shed light on the mechanism by which AMPH causes trafficking of DAT as well as on the behavioral impact of this mechanism. The first demonstration of AMPH-induced trafficking of DAT in heterologous systems surfaced a few years after Fleckenstein’s original proposal (3). In that study, acute treatment with the DAT substrates AMPH and DA not only reduced [3H]DA uptake and AMPH-induced currents but also clearly decreased DAT cell surface expression (1). By using a dominant-negative mutant of dynamin I (K44A) to prevent substrate-induced trafficking, the authors also provided preliminary evidence to suggest that AMPH-stimulated DAT endocytosis occurs via a dynamin-dependent pathway. … [↵][1]1To whom correspondence may be addressed. Email: aurelio.galli{at}vanderbilt.edu or christine.saunders{at}vanderbilt.edu. [1]: #xref-corresp-1-1