Action potentials (APs) release dopamine (DA) via voltage gated ion channels that de-polarize the presynaptic membrane, open Ca++ channels, and increase the probability of vesicle fusion and DA release. The dopamine transporter (DAT) transports DA back into the presynaptic membrane where it is repackaged into synaptic vesicles. Presynaptic membrane depolarization is thus the trigger for neurotransmitter release. We will argue that abused drugs (such as amphetamine, AMPH, methamphetamine, METH, and certain structurally related cathinones present in bath salts) bypass the normal AP-generated DA release mechanism. Present theories to explain drug-induced DA release rely on DAT reverse transport and include AMPH-DA exchange, phosphorylation-induced efflux, channel-mode efflux, or AMPH-induced vesicular depletion. An alternative mechanism for drug-induced DA release requires a departure from the traditional model of Na-coupled transport (the fixed stoichiometry alternating access model) and proposes another model of co-transport (the flux coupled channel model). We have recorded electrical currents mediated by hDAT expressed in Xenopus laevis oocytes and HEK cells exposed to DA, METH, a known hDAT stimulant and DA releaser, mephedrone (MEPH), methylenedioxypyrovalerone (MDPV), MEPH + MDPV, or cocaine, a known hDAT inhibitor (1). DA, METH, and MEPH induce an inward depolarizing current when cells are held near rest (-60 mV), therefore acting as excitatory hDAT substrates. Structurally analogous MDPV induces an outward hyperpolarizing current under the same conditions, similar to cocaine, and therefore acts as an inhibitory non-substrate blocker. Two common components of bath salts, MEPH and MDPV, thus produce opposite effects at hDAT that are comparable to METH and cocaine, respectively. In our assay MEPH is nearly as potent as METH; however, MDPV is 35X more potent than cocaine and its effect as a blocker lasts much longer. When applied in combination, MEPH exhibits faster kinetics than MDPV; namely, the MEPH depolarizing current occurs seconds before the slower MDPV hyperpolarizing current. Bath salts are not a defined combination of drugs; however, those that contain MEPH (or a similar drug) and MDPV might be expected initially to release DA and subsequently to prevent its reuptake via hDAT. The channel mode of dopamine transporters is thus crucial to understand how AMPH-like drugs including synthetic cathinones can affect the integration of inputs to dopaminergic neurons to modify excitability, activate voltage-gated channels, and regulate synaptic signaling. Our central hypothesis states that AMPH-like drugs (including certain synthetic cathinones present in bath salts) induce depolarizing currents in excitable cells that increase the probability of Ca++ entry, vesicular fusion, and DA release from the presynaptic terminal. In addition, wherever hDAT is located (for example on the cell body), drug-induced depolarization via the channel mode of transporters may increase excitability (2). The powerful positive feedback mechanism of AMPH-like drugs on dopaminergic neurons may generalize to drugs that interact with serotonin or norepinephrine transporters. Conversely, transporter blockers such as cocaine, MDPV, or fluoxetine may have a negative feedback on endogenous or induced currents mediated via transporters, thus lowering the probability of transmitter release. The contribution of transporters to the electrical profile of neurons depends on a more complete picture of synapses than we have at present. In particular, the setting of transporters in the context of voltage-gated ion channels would be essential to understand fully the contribution of transporter channels to neurotransmitter release. However, evidence is growing that AMPH, and by inference AMPH-like drugs, may release DA via vesicle fusion mechanisms (3, 4). In summary, bath salts that contain both DA releasers (mephedrone, methylone, etc.) and a reuptake inhibitor (MDPV) act synergistically on hDAT, which may explain the powerful effect of this drug combination on bath salts abusers. We will discuss how drug interactions with transporters modify electrical signaling for nerve cell communication that is important for brain physiology and pathology.