# Memory Destabilization and Cocaine-Cue Induced Reinstatement in Rat

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $330,750

## Abstract

Drug-associated conditioned stimuli (CS), or cues, contribute to both the progression and persistence
of addiction. We hypothesize, as have others, that blocking reconsolidation of cocaine-cue memories could
prevent cue-induced relapse. Reconsolidation is a process whereby reactivation of a memory renders it labile
and vulnerable to disruption. Our published data, and that of others, confirm that limbic-striatal dopamine (DA)-
dependent and several plasticity-regulated signaling mechanisms are involved in cocaine-cue reconsolidation
processes. In this new proposal we hypothesize that violation of cocaine-cue expectancy renders a memory
labile by triggering memory destabilization, thereby making cocaine-cue memories more sensitive to
subsequent disruption by amnestic agents. The ability to induce the destabilization of cocaine-cue memories
may be a key factor in enabling the use of targeted pharmacotherapies to block cocaine-cue memory
reconsolidation and treat maladaptive memories. We propose to investigate directly the role of expectancy in
reconsolidation of cocaine-cue memories and their impact on subsequent relapse-like behaviors by varying the
difference between what is expected and experienced during reactivation and by photo stimulation of midbrain
DA-containing VTA neurons to neutralize or induce prediction error (PE)-like signals.
 In Aim 1 we will reactivate cocaine memories by violating expectations of a) US (i.e., cocaine)
magnitude and b) CS-US temporal contiguity. These manipulations should generate PE-like signals at the time
of memory retrieval. According to our hypothesis and preliminary data, both positive and negative PE-like
signals should induce destabilization and make the cue memory susceptible to blockade (i.e., reconsolidation)
by an amnestic agent to reduce subsequent relapse to drug-seeking behavior. Relapse-like behaviors will
include cue-induced and drug-primed reinstatement, and other measures, in male and female rats subjected to
weeks of long-access cocaine self-administration. Select agents that potently and selectively alter memory
reconsolidation processes – the protein-synthesis inhibitor anisomycin (ANI) and the histone acetyltransferase
(HAT) inhibitor garcinol – will be used to render the destabilized memory subject to amnestic blockade.
 In Aim 2 we will optogenetic-based photostimulation of midbrain VTA DA neurons (TH-Cre+ rats)
during cocaine-cue memory reactivation a) to artificially produce a dip or b) a spike in DA signaling, to
artificially act as a negative or positive PE-like signal, respectively, to destabilize the cue memory and render it
susceptible to amnestic blockade, ultimately reducing measures of cocaine relapse-like behaviors.
 Together these studies will define novel behavioral conditions whereby destabilization mechanisms can
be used to make memories more susceptible to amnestic agents, to block reconsolidation of cocaine-cue
memories, to reduce relapse-like behaviors, and to inspire the...

## Key facts

- **NIH application ID:** 10599998
- **Project number:** 5R01DA052385-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jane R Taylor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $330,750
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599998

## Citation

> US National Institutes of Health, RePORTER application 10599998, Memory Destabilization and Cocaine-Cue Induced Reinstatement in Rat (5R01DA052385-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10599998. Licensed CC0.

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