# Mechanisms of Extinction Memory Enhancement for Cocaine Addiction Treatment

> **NIH NIH R01** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2020 · $517,440

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of this project is to investigate strategies that augment the acquisition and retrieval of extinction
memory as a means to compete with and subsequently inhibit the reemergence of drug memory during periods
of cocaine reexposure. We previously developed a novel animal model of cue exposure therapy for cocaine
addiction treatment that incorporates drug memory retrieval methods with extinction training as a means to
inhibit cocaine relapse. We found that adding a glycine transporter-1 (GlyT-1) inhibitor significantly enhanced
the effectiveness with which cocaine-cue extinction training subsequently reduces reacquisition of cocaine self-
administration in adult male rats and monkeys. In this project, we propose to extend our treatment model to
include environmental enrichment (EE), a documented behavioral procedure that improves learning and
memory in rat and man. Our work will focus on the introduction of limited (4hr) periods of EE scheduled in
conjunction with weekly sessions of cocaine-cue extinction training, an approach that augmented the rate of
extinction learning and reduced reacquisition of cocaine self-administration in preliminary studies. To
implement a multi-modal approach for which sex as a biological variable will be monitored, we will examine the
combined effects of EE and GlyT-1 inhibition with cocaine-cue extinction training in adult male and female rats
(Aim 1). Synergy between these combined treatments for augmenting acquisition and retrieval of extinction
memory to reduce cocaine relapse is hypothesized. To broaden the scope of our investigation, we will examine
molecular changes in key brain regions that underlie the effects of EE and a GlyT-1 inhibitor. We will focus on
receptors for glutamate (NMDAR; AMPAR) and brain derived neurotrophic factor (TrkB) as well as on two
novel targets Nedd4 and USP46, as these influence the primary cellular means by which learning, memory and
synaptic plasticity unfold. Our preliminary studies support an investigation of these targets, particularly in
basolateral amygdala and ventromedial prefrontal cortex. We plan a dual approach in which expression,
trafficking and ubiquination of relevant protein targets (Aim 2) as well as viral-mediated knockdown and
overexpression of those targets (Aim 3) will be studied in male and female rats treated with EE and a GlyT-1
inhibitor combined with extinction training. An investigation into how these two strategies (EE and GlyT-1
inhibition) synergize in combination in rats could have considerable scientific and clinical significance. Results
from these studies will help identify mechanisms that mediate behavioral improvements attained through our
multi-modal treatment intervention. Identifying critical changes in these targets as a result of extinction training
combined with EE and GlyT-1 inhibition may aid in the development of pharmacotherapies with novel
mechanisms of action and in the discovery of unique behavioral the...

## Key facts

- **NIH application ID:** 9955227
- **Project number:** 5R01DA043454-04
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** Kathleen M. Kantak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $517,440
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955227

## Citation

> US National Institutes of Health, RePORTER application 9955227, Mechanisms of Extinction Memory Enhancement for Cocaine Addiction Treatment (5R01DA043454-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9955227. Licensed CC0.

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