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Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving

Molecular Psychiatry (2025)Cite this article

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Abstract

Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca2+-permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca2+ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naïve rats rapidly upregulates CP-AMPARs. This is observed only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, we observe CP-AMPAR upregulation in D1 MSN (but not D2 MSN) and the effect of exogenous RA application is occluded in these D1 MSN. Instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of ‘incubated rats’ normalizes elevated cue-induced cocaine seeking back to non-incubated levels. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.

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Fig. 1: Retinoic acid (RA) induces upregulation of synaptic CP-AMPARs in nucleus accumbens core (NAcc) medium spiny neurons (MSN).
Fig. 2: Retinoic acid (RA) causes postsynaptic alterations in nucleus accumbens core (NAcc) medium spiny neurons (MSN) without affecting presynaptic functions or intrinsic membrane properties.
Fig. 3: Pretreatment with the retinoic acid (RA) synthesis inhibitor DEAB blocks RA- or cocaine-mediated upregulation of synaptic CP-AMPARs in nucleus accumbens core (NAcc) medium spiny neurons (MSN).
Fig. 4: Acute inhibition of retinoic acid (RA) synthesis in the nucleus accumbens core (NAcc) with DEAB reduces the expression of incubation of cocaine craving.
Fig. 5: CP-AMPAR upregulation via retinoic acid (RA) signaling occurs preferentially in D1+ medium spiny neurons (MSN) in the nucleus accumbens core (NAcc).

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Data availability

All data needed to evaluate the conclusions in the paper are provided in the main article and supplementary information. The data can be requested from the corresponding author (wolfmar@ohsu.edu) and are available upon reasonable request.

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Acknowledgements

We thank Alana L Moutier, Jonathan R Funke and Madelyn M Beutler for assistance with drug self-administration, Dr. Daniel T Christian for assistance with pilot experiments and Dr. Alex B Kawa for assistance with the RNAscope experiment. We thank Drs. Deena M Walker, Arthur Godino, Molly S Estill, Aarthi Ramakrishnan, and Eric J Nestler for assistance with analysis of raw data on RARA expression from a previous publication [22].

Funding

This work was supported by USPHS grants R01 DA049930 (MEW) and F32 DA046141 (AMW). We also acknowledge the Rat Resource & Research Center P40OD011062.

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  1. Amanda M. Wunsch

    Present address: National Center for Wellness and Recovery, Oklahoma State University Center for Health Sciences, Tulsa, OK, 74107, USA

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  1. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA

    Eun-Kyung Hwang, Amanda M. Wunsch & Marina E. Wolf

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Conception and Design of Study: EKH, AMW, MEW Acquisition of Data: EKH, AMW Analysis and/or Interpretation: EKH, AMW, MEW Drafting the Manuscript: EKH, MEW.

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Correspondence to Marina E. Wolf.

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Competing interests

Dr. Wolf and OHSU have a financial interest in Eleutheria Pharmaceuticals LLC, a company that may have a commercial interest in results related to the research described herein. This potential conflict of interest has been reviewed and managed by Oregon Health & Science University. The other authors declare no competing interests.

Ethics approval

Studies were performed in accordance with the relevant guidelines and regulations. All animal experiments and procedures were approved by the Institutional Animal Care and Use Committee of Oregon Health & Science University (protocol number TR03_IP00001792).

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Hwang, EK., Wunsch, A.M. & Wolf, M.E. Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03026-9

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