# Organic cation transporter 3: a novel molecular target to treat amphetamine abuse

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $192,500

## 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 an OCT3 inhibitor, decynium-22 (D22),
inhibits amphetamine-evoked hyperlocomotion and DA release in vivo, effects that were lost in constitutive OCT3
knockout (KO, -/-) mice. Furthermore, amphetamine-induced substrate efflux could be inhibited by D22 in a manner
independent of cocaine-sensitive transporters. These data raise the exciting possibility that OCT3 is a critical
player in the actions of amphetamine, which may help to explain why DAT-based therapeutics have not been
successful in treating amphetamine abuse. Our intention is to submit an R01 to build on these exciting findings,
but before doing so, additional preliminary data are needed. First, we need to determine if potential compensation
in constitutive OCT3-/- mice accounts for the lack of difference in their locomotor and DA releasing responses to
amphetamine compared with wild-type (OCT3+/+) mice. To do this, OCT3 floxed mice have recently been
generated at the University of Texas Health Science Center at San Antonio (UTHSCSA). We will cross these mice
with a commercially available Cre line to generate a tamoxifen inducible global OCT3 KO. In this way, we can
temporally control OCT3 KO, and in future studies, use different Cre lines to create brain region specific inducible
KOs. We will use these mice to test the hypothesis that amphetamine-induced DA release, locomotion, and
stereotypy will be attenuated in inducible OCT3 KO mice compared with control mice. Moreover, if OCT3 is to be
a useful target in the treatment of amphetamine abuse, we need to demonstrate that OCT3 is important in mediating
the rewarding and reinforcing effects of amphetamine. To this end, we will use conditioned place preference (CPP),
and self-administration in mice to test the hypotheses that the rewarding and reinforcing effects of amphetamine
are less in inducible OCT3 KO mice than control mice, and that D22 will attenuate development of CPP...

## Key facts

- **NIH application ID:** 9968219
- **Project number:** 5R21DA049044-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** LYNETTE C DAWS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968219

## Citation

> US National Institutes of Health, RePORTER application 9968219, Organic cation transporter 3: a novel molecular target to treat amphetamine abuse (5R21DA049044-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9968219. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*