# Retinoic acid signaling and incubation of cocaine craving

> **NIH NIH F32** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $67,806

## Abstract

Project Summary
A major problem in treating drug abuse is persistent vulnerability to relapse, even after long periods of
abstinence. In the incubation of cocaine craving model of relapse, rats undergo extended access to cocaine self-
administration. During withdrawal, rats exhibit a progressive intensification (incubation) of cue-induced cocaine
craving. We have shown that calcium (Ca2+)-permeable AMPA receptors (CP-AMPAR), comprised exclusively
of the GluA1 subunit, accumulate in the nucleus accumbens (NAc) during late withdrawal and thereafter are
required for the expression of incubated cue-induced craving. Therefore, understanding mechanisms regulating
CP-AMPAR accumulation and maintenance may yield novel therapeutic targets for reducing craving and
prolonging abstinence. Work from our lab and others have shown that cocaine withdrawal is associated with
multiple adaptations that predict reduced Ca2+ levels in NAc medium spiny neurons (MSN). However, little is
known about mechanisms that may link this reduced activity during withdrawal to the subsequent insertion of
CP-AMPARs. One promising candidate involves the retinoic acid (RA) signaling cascade. Studies in
hippocampal neurons have demonstrated that Ca2+ levels associated with basal synaptic transmission are
sufficient to suppress RA synthesis. However, following a period of inactivity, RA synthesis is disinhibited, leading
to increased translation of GluA1 and synaptic insertion of homomeric GluA1 CP-AMPARs. CP-AMPAR
accumulation in the NAc during incubation may likewise involve reduced activity and has been demonstrated in
our unpublished studies to be associated with increased translation of GluA1. Based on these similarities to RA-
induced synaptic scaling, my central hypothesis is that cocaine incubation leads to a decrease in activity in NAc
neurons at baseline, increased RA synthesis, and scaling up of CP-AMPARs. Aim 1 will determine if Ca2+
levels are altered in the NAc core during incubation of cocaine craving. I will use fiber photometry to
measure changes in intracellular Ca2+, a correlate of neural activity, in early and late withdrawal from extended
access to cocaine (or saline) self-administration. I will measure Ca2+ at baseline and during exposure to a
cocaine-associated cue. Aim 2 will determine whether RA contributes to CP-AMPAR accumulation in NAc
core MSN of cocaine incubated rats. Whole-cell patch clamp recordings in brain slices from cocaine incubated
or saline rats will be used to determine if pharmacological manipulation of RA signaling alters AMPAR-mediated
synaptic transmission in NAc medium spiny neurons. Aim 3 will determine if RA mediates synaptic scaling
in cultured NAc MSN. I will use a RA reporter system to confirm that RA expression in MSN is activity-
dependent, and pharmacological methods to determine whether RA-dependent scaling of CP-AMPAR occurs in
NAc neurons. While these studies are underway, I will participate in a multi-faceted training plan to de...

## Key facts

- **NIH application ID:** 9881276
- **Project number:** 5F32DA046141-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Amanda Marilyn Wunsch
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,806
- **Award type:** 5
- **Project period:** 2018-02-18 → 2022-02-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881276

## Citation

> US National Institutes of Health, RePORTER application 9881276, Retinoic acid signaling and incubation of cocaine craving (5F32DA046141-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9881276. Licensed CC0.

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