# Targeting organic cation transporter 3 in treatment of substance use disorders

> **NIH NIH U18** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $296,485

## Abstract

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 l...

## Key facts

- **NIH application ID:** 10107447
- **Project number:** 1U18DA052527-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** LYNETTE C DAWS
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $296,485
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107447

## Citation

> US National Institutes of Health, RePORTER application 10107447, Targeting organic cation transporter 3 in treatment of substance use disorders (1U18DA052527-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107447. Licensed CC0.

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