# Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $13,948

## Abstract

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Project Summary:
Cocaine abuse is a major public health problem in the United States with high rates of relapse and a lack to
pharmacological treatment options. We have recently demonstrated that zeta-inhibitory peptide (ZIP) infused
into the nucleus accumbens blocks cocaine reinstatement, an animal model of relapse. Further, ZIP's effects
persist up to 1 week after the peptide is cleared from the brain and ZIP does not alter food reinstatement.
Recent evidence has called the mechanism of action of ZIP into question. Therefore, the goal of this proposal
is to examine mechanisms by which ZIP affects cocaine-induced behavioral, synaptic and structural plasticity.
We, and others, have shown that cocaine self-administration leads to impaired NMDA-dependent long-term
depression (LTD) within the accumbens. Future learning, such as the extinction of drug-associated cues, could
be occluded without the ability to rescale these synapses. As LTD is dependent upon the removal of GluA2-
containing AMPARs, we hypothesize that ZIP may restore the capacity for LTD following cocaine by preventing
PKC-mediated removal of GluA2-containing AMPARs. Changes in AMPAR trafficking are dynamic and
alterations in structural plasticity, such as changes in spine density, provide a mechanism for persistent
changes at the receptor level. In fact, chronic cocaine has been shown to lead to structural plasticity within the
nucleus accumbens and manipulations that disrupt this structural plasticity decrease cocaine reward
behaviors, including reinstatement behavior. As structural plasticity is dependent upon actin polymerization and
cocaine has been shown to alter this process, we propose that ZIP may reverse cocaine-induced structural
plasticity via disruption of actin dynamics. As the ability of ZIP to eliminate cocaine reinstatement could provide
an avenue to designing potential therapeutics, understanding the mechanism by which these effects occur is
critical. Aim 1 focuses on determining how ZIP administration in the nucleus accumbens affects synaptic
plasticity and AMPAR trafficking. Additionally, this aim will determine whether the effects of ZIP on cocaine
reinstatement are dependent upon the ability to blunt LTD the necessity of the ability of ZIP to reverse this
plasticity in its behavioral effects. Aim 2 will focus on the potential affects of ZIP on cocaine-induced structural
plasticity. Aim 3 focuses on determining whether the effects of ZIP are dependent upon another atypical PKC,
PKCι/λ. Thus, the overall goal of the proposed experiments is to elucidate the mechanisms by which ZIP may
disrupt cocaine-induced plasticity at the level of the receptor and the dendrite.

## Key facts

- **NIH application ID:** 10399321
- **Project number:** 3R01DA047265-03S1
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** LISA A BRIAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $13,948
- **Award type:** 3
- **Project period:** 2019-04-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399321

## Citation

> US National Institutes of Health, RePORTER application 10399321, Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide (3R01DA047265-03S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10399321. Licensed CC0.

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