ABSTRACT Medications to help treat addiction exist for many major drugs of abuse, but not for psychostimulants, such as amphetamine, and its congeners. They are also lacking for increasingly used synthetic drugs designed to mimic the actions of known psychostimulants. Both known and new psychoactive substances continue to pose a major and increasing public health threat. To develop effective treatments, the mechanisms by which these stimulants produce their abuse-related effects need to be fully understood. Many stimulants interact with the dopamine (DA) transporter (DAT), which is thought to mediate their abuse-related effects. However, strategies targeting DAT have yielded little to no benefit in the treatment of psychostimulant addiction, raising the possibility that these stimulants have significant actions elsewhere to modulate dopaminergic neurotransmission. Consistent with this, a rapidly growing literature supports a prominent role for organic cation transporter 3 (OCT3) in regulating dopaminergic neurotransmission. Our preliminary data support this idea, showing that decynium-22 (D22) (an inhibitor of OCT1, OCT2, OCT3 and the plasma membrane monoamine transporter [PMAT]), inhibits amphetamine-evoked hyperlocomotion and DA release in vivo, effects that were lost in constitutive OCT3 knockout mice. Furthermore, amphetamine-induced substrate efflux could be inhibited by D22 in a manner independent of cocaine-sensitive transporters (the DA, serotonin and norepinephrine transporters). These data raise the exciting possibility that OCT3 is a critical player in the actions of amphetamine and its congeners, which may help to explain why DAT-based therapeutics have not been successful in treating amphetamine abuse. However, a major obstacle in realizing OCT3 as a target for amphetamine-type substance use disorder (SUD) is the lack of selective drugs for this transporter. In this regard, RFA-DA-20-025, “Step up for SUD: A drug target initiative for scientists engaged in fundamental research”, is especially timely given the objective of our proposed studies to screen existing transporter-focused drug libraries to yield OCT3-selective hits and leads. Selectivity of lead hits will be determined using in vitro cell based assays, and in vivo using OCT3 wildtype and knockout mice. These screens will advance the development and validation of OCT3 inhibitors as a target for SUD treatment by (1) identifying selective scaffolds for development; and (2) providing OCT3 inhibitor structure activity relationships that will enable us to refine scaffolds and build OCT3 computational models. Moreover, we will (3) assess a wide range of drugs of abuse for activity at OCT3 to determine the range of drugs for which OCT3 may be a potential therapeutic target. Together, the successful accomplishment of these aims will provide information crucial to the strategic synthesis of OCT3-selective compounds, which lack off-target effects, in future, larger scale studies. Our long-term goal is to provide the research community with a much-needed selective pharmacological tool to study OCT3, but importantly, to validate OCT3 as a novel therapeutic target for the treatment of SUDs.

Medications to treat addiction exist for many drugs of abuse, but not for amphetamine-type stimulants, which include amphetamine, methamphetamine and the increasingly popular new psychoactive substances such as synthetic cathinones, also knowns as “bath salts” and “legal highs”. Preliminary data point to organic cation transporter 3 (OCT3) as a promising target for the treatment of amphetamine-type substance use disorder (SUD), however lacking are drugs selective for this transporter. Proposed studies will screen existing transporter-focused drug libraries to yield OCT3-selective hits and leads, a critical first step to the development and validation of OCT3 inhibitors as a treatment for SUDs.