# Retinoic acid, homeostatic plasticity and cocaine craving

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $437,201

## Abstract

Project Summary
We will use the `incubation of craving' model to study a major challenge in treating cocaine addiction, that is, the
persistence of vulnerability to cue-induced relapse even after long periods of abstinence. In this model, rats
exhibit progressive intensification (incubation) of cue-induced craving after withdrawal from extended-access
cocaine self-administration. Incubation of craving also occurs in humans. Previously, we showed that Ca2+-
permeable AMPARs (CP-AMPARs; homomeric GluA1) accumulate in synapses on medium spiny neurons
(MSN) of the nucleus accumbens (NAc) core after ~30 days of withdrawal. Thereafter, their activation is required
for expression of incubated cocaine craving. Thus, understanding CP-AMPAR plasticity may provide clues about
how the intensity of craving is regulated. Work from our lab and others has shown that cocaine withdrawal is
associated with multiple adaptations that predict reduced activity or Ca2+ signaling in NAc MSN. However, little
is known about how this might be linked to CP-AMPAR insertion. A promising candidate is a form of homeostatic
plasticity involving retinoic acid (RA) signaling. Work in hippocampal neurons has shown that Ca2+ levels
associated with ongoing synaptic transmission are sufficient to suppress RA synthesis. However, after a period
of inactivity, RA synthesis is disinhibited. This increases GluA1 translation, enabling a homeostatic increase in
synaptic strength via insertion of homomeric GluA1 CP-AMPARs. CP-AMPAR accumulation in the NAc core
during incubation of craving may likewise involve reduced Ca2+ (see above) and we recently showed that it is
associated with increased GluA1 translation. Based on these similarities to RA-mediated homeostatic plasticity
in hippocampus and on other data, we hypothesize that cocaine withdrawal is associated with decreased Ca2+
signaling in MSN, leading to disinhibition of RA synthesis, increased GluA1 translation and increased synaptic
levels of homomeric GluA1 CP-AMPARs. Aim 1 will test the relationship between excitatory transmission, RA
synthesis, and GluA1 translation in cultured NAc MSN (co-cultured with cortical cells to restore glutamate inputs).
Aim 2 will use fiber photometry to test the hypothesis that baseline Ca2+ in NAc core MSN is reduced during
cocaine withdrawal, although it may transiently increase during cue-induced seeking tests and this increase may
be augmented as incubation of craving occurs. Transgenic rats expressing Cre recombinase in D1 or A2a
receptor-positive MSN (A2a is a marker for D2 MSN) will enable both MSN populations to be studied. In Aim 3,
whole-cell patch clamp recordings in identified D1 or A2a NAc core MSN will determine if acute manipulation of
RA signaling alters CP-AMPAR levels and if protein translation is involved. Then, we will determine if knocking
down a critical RA synthetic enzyme in NAc core during cocaine withdrawal attenuates CP-AMPAR accumulation
and maintenance of incubated craving aft...

## Key facts

- **NIH application ID:** 9866009
- **Project number:** 1R01DA049930-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Marina Elizabeth Wolf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,201
- **Award type:** 1
- **Project period:** 2020-03-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866009

## Citation

> US National Institutes of Health, RePORTER application 9866009, Retinoic acid, homeostatic plasticity and cocaine craving (1R01DA049930-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9866009. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*