The dopamine transporter: a vigilant border control for psychostimulant action

Neurotransmission within the mesocorticolimbic dopamine system has remained the central focus of investigation into the molecular, cellular and behavioral properties of psychostimulants for nearly three decades. The primary means by which dopamine transmission in the synapse is terminated is via the dopamine transporter (DAT), the presynaptic plasmalemmal protein that is responsible for the reuptake of released dopamine. Numerous abused as well as clinically important drugs have important pharmacological interactions with DAT. In general, these compounds fall into two categories: those that block dopamine transport (e.g., cocaine, methylphenidate) and those that serve as substrates for transport [e.g., dopamine, amphetamine and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy")]. Recent data from in vitro and in vivo studies have suggested that DAT, like other biogenic amine transporters, share several characteristics with classical ligand-gated ion channels. In addition, substrates for transport promote redistribution of DAT away from the plasma membrane, while transport inhibitors such as cocaine disrupt this process. In addition, presynaptic autoreceptors for dopamine have been implicated in the modulation of DAT surface expression and function. The present chapter summarizes some of the recent discoveries pertaining to the electrogenic properties of DAT and their potential relevance to the effects of amphetamine-like stimulants on DAT function. Although there are a number of intracellular and extracellular modulatory influences on dopamine clearance that may play particular roles in psychostimulant action, we specifically focus on the differential direct modulation of DAT function by transport substrates and inhibitors, and we also discusses the role of presynaptic D2 receptors in transport regulation.