# Retinoic acid signaling: a novel factor for addiction-related behavior

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $440,782

## Abstract

ABSTRACT
The development of pharmacotherapeutics for cocaine use disorder has lagged behind treatments for other
neuropsychiatric conditions, emphasizing the need for new targets. Preliminary data suggest that rats with a
protective phenotype for cocaine taking/seeking produced by environmental enrichment have less retinoic acid
signaling in the nucleus accumbens, a brain region highly implicated in addiction. Additional preliminary data
show that increasing retinoic acid signaling increases neuronal firing and EPSCs in the nucleus accumbens
(NAc) shell and increases cocaine taking/seeking in rats. Inversely, decreasing one aspect of retinoic acid
signaling in the NAc in vivo decreases neuronal firing and cocaine taking. The current proposal will generate
specific mechanistic evidence regarding how retinoic acid signaling confers susceptibility to cocaine self-
administration. Accordingly, the overall hypothesis of this proposal is that specific components of the retinoic
acid signaling pathway in the NAc shell control susceptibility/resilience to cocaine self-administration and will
represent valuable novel targets for the future treatment of cocaine dependence. Thus, the successful
completion of this project will prioritize high-quality “druggable” targets in the retinoic acid pathway for
subsequent pharmacotherapeutic development that can be developed and translated into clinical practice. The
first aim will determine if decreasing retinoic acid synthesis in the NAc shell alone confers a protective
phenotype for cocaine self-administration. Expression of the retinoic acid synthesis enzyme Aldh1a1 will be
knocked down in vivo using a novel adeno-associated viral vector (AAV) prior to behavioral phenotyping and
electrophysiological analysis. Next, the acute effects of Aldh1a1 inhibition on behavior, firing, and synaptic
transmission will be tested using a small-molecule inhibitor. The second aim will determine the relative
influence of retinoic acid receptor (RAR) vs. peroxisome proliferative receptor (PPARbeta/delta) signaling
mechanisms. AAV vectors will be used to either knock down PPARbeta/delta or overexpress RARbeta to
create a protective behavioral and electrophysiological phenotype in susceptible rats. The results will
determine which of the competing mechanisms contains the most promising therapeutic target. The third aim
will determine the relative genomic vs. non-genomic influence of retinoic acid signaling in rat NAc. Chromatin
immunoprecipitation will be employed with DNA sequencing to assess the genomic aspect. The non-genomic
side of the equation will focus on rapid RA-dependent homeostatic synaptic plasticity from neuronal RNA
granules. The final result of this project will be a much-needed novel candidate target for therapeutic
development for cocaine addiction.

## Key facts

- **NIH application ID:** 10177986
- **Project number:** 5R01DA047102-04
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Thomas Arthur Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,782
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177986

## Citation

> US National Institutes of Health, RePORTER application 10177986, Retinoic acid signaling: a novel factor for addiction-related behavior (5R01DA047102-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10177986. Licensed CC0.

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