# Cocaine-induced adaptation in NMDA receptors

> **NIH NIH R37** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $416,614

## Abstract

Abstract
During drug abstinence, re-exposure to cues previously associated with cocaine often trigger drug relapse. In
rodent models of cocaine seeking and relapse, animals that self-administer cocaine in the presence of
contingent cues often establish a strong association between cues and cocaine, such that after drug
withdrawal, the presence of cues induces strong cocaine seeking. Cue-induced cocaine seeking is extremely
long-lasting and intensifies progressively after withdrawal. The goal of this application is to develop new
concepts and approaches through which the cue-cocaine association can be disrupted to reduce cocaine
relapse. The cue-cocaine association that drives cocaine seeking shares general features of cue-conditioned
memories. Similar to classic conditioning memories, cue-conditioned drug memories also undergo a
destabilization and reconsolidation process after retrieval. During the brief destabilization time window,
amnesic treatments are often more effective in reducing subsequent cue-induced cocaine seeking. However,
the neural substrates that mediate cue-drug memory retrieval and reconsolidation remain elusive. Targeting
this knowledge gap, this application focuses on cocaine-generated silent synapses and their dynamic changes
within the basolateral amygdala (BLA) to nucleus accumbens (NAc) projection. We recently showed that
cocaine self-administration generates silent synapses in the BLA-to-NAc projection. Silent synapses are
excitatory synapses that contain NMDA receptors without stable AMPA receptors (AMPARs). Our additional
results suggest that cocaine-generated silent synapses may serve as the initial hubs to establish a potentially
new set of circuits. After cocaine withdrawal, BLA-to-NAc silent synapses become `un-silenced' by recruiting
calcium-permeable AMPARs (CP-AMPARs), resulting in consolidation of the silent synapse-imbedded circuits.
Reversing the un-silencing of BLA-to-NAc silent synapses decreases cue-induced cocaine seeking. These
results suggest that the newly formed, silent synapse-embedded BLA-to-NAc projections contribute to the
establishment and subsequent consolidation of cue-cocaine association. Based on extensive preliminary
results, we hypothesize that after cocaine withdrawal, a brief re-exposure to cocaine-associated cues instantly
induces CP-AMPAR internalization and re-silences the same set of BLA-to-NAc silent synapses that are
generated by cocaine self-administration, contributing to the destabilization of cue-cocaine association. These
re-silenced synapses are un-silenced again by re-recruiting CP-AMPARs hours after cue re-exposure,
contributing to reconsolidation of cue-cocaine association. We will use electrophysiology, optogenetics, in vivo
calcium imaging, viral-mediated gene transfer, and operant behavioral assays to test this hypothesis. By
accomplishing the proposed work, we may identify a cellular and circuit basis underlying destabilization and
reconsolidation of cue-cocaine associa...

## Key facts

- **NIH application ID:** 9828647
- **Project number:** 5R37DA023206-14
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yan Dong
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,614
- **Award type:** 5
- **Project period:** 2008-03-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828647

## Citation

> US National Institutes of Health, RePORTER application 9828647, Cocaine-induced adaptation in NMDA receptors (5R37DA023206-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9828647. Licensed CC0.

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