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Prefrontal cortex excitatory neurons show distinct response to heroin-associated cue and social stimulus after prolonged heroin abstinence in mice

Neuropsychopharmacology volume 50, pages 1284–1297 (2025)Cite this article

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Abstract

Substance use disorder (SUD) has been linked with social impairments. The social cognitive dysfunctions can further increase the risk of the development of SUD or relapse. Therefore, understanding the neural mechanism of substance exposure-associated social impairments is beneficial for the development of novel prevention or treatment strategies for SUD. The prefrontal cortex (PFC) is a key brain region involved in both social cognition and drug addiction. Specifically, the prelimbic part of PFC (PrL) regulates social interaction and heroin-seeking behavior. Therefore, in this study, we explored how PFC excitatory neurons respond to social stimuli after prolonged abstinence from heroin self-administration (SA). Using fiber photometry calcium imaging, we monitored calcium-dependent fluorescent signals in PrL CaMKII-expressing neurons during drug seeking and social interaction tests following 14 days of abstinence from heroin SA. We found that GCaMP6f signals in PrL CaMKII-expressing neurons were increased when heroin-associated cues were presented during drug-seeking tests in both male and female mice after prolonged heroin abstinence, although the baseline neuronal activity in home cage is lower in the heroin group. Conversely, the calcium signals in PrL CaMKII-expressing neurons during social investigation were decreased after heroin abstinence in both sexes, along with reduced total social interaction time. In addition, drug-seeking behavior is partially negatively correlated with social investigation time. These findings provide direct evidence showing that opioid exposure impairs the PFC functional response to social stimuli, which may potentially increase the risk for opioid relapse.

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Fig. 1: Drug-seeking behavior and altered social interaction in male and female mice underwent saline or heroin self-administration followed by abstinence.
Fig. 2: Disrupted neuronal activity and excitatory input in PrL excitatory neurons after heroin abstinence in male and female mice.
Fig. 3: The activation of PrL excitatory neurons by heroin-associated cues during drug-seeking test in male and female mice.
Fig. 4: The attenuated activation of PrL excitatory neurons by social stimuli after heroin abstinence in male and female mice.
Fig. 5: The correlation between social interaction and drug-seeking behavior and the correlation between neuronal activity during baseline and drug seeking.

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The data supporting the findings of this study are available in the article and in its online supplementary material.

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Acknowledgements

We would like to thank the NIDA drug supply program for providing controlled substances. We would like to thank Magnus Marciniak, Christian Brenden Young and Dr. Jai Subramanian for helping with the data analysis.

Funding

ZJW is supported by NIH grants DA050908 and DA056804. YW, SY, and LC are supported by the Sobek-Zhang Foundation. ESC is supported by NIH grant DA048931.

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Author notes

  1. These authors contributed equally: Yunwanbin Wang, Junting Liu.

Authors and Affiliations

  1. Department of Pharmacology & Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA

    Yunwanbin Wang, Junting Liu, Shuwen Yue, Lu Chen, Archana Singh, Tianshi Yu & Zi-Jun Wang

  2. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Erin S. Calipari

  3. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA

    Erin S. Calipari

  4. Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA

    Erin S. Calipari

  5. Cofrin Logan Center for Addiction Research and Treatment, University of Kansas, Lawrence, KS, USA

    Zi-Jun Wang

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  1. Yunwanbin Wang
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Contributions

YW and JL: performed experiments, analyzed data, and drafted the manuscript. SY, LC and AS: performed experiments and analyzed data. TY: analyzed data. ESC: experiment design advising and manuscript preparation. ZJW: designed experiments, supervised the project, and wrote the manuscript.

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Correspondence to Zi-Jun Wang.

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Wang, Y., Liu, J., Yue, S. et al. Prefrontal cortex excitatory neurons show distinct response to heroin-associated cue and social stimulus after prolonged heroin abstinence in mice. Neuropsychopharmacol. 50, 1284–1297 (2025). https://doi.org/10.1038/s41386-025-02102-6

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