Abstract
Decision-making impairments are a core symptom of several psychiatric disorders, including gambling and substance use disorders (SUD). These disorders frequently co-occur, suggesting shared neurobiological mechanisms underlying dysfunctional decision-making. We previously demonstrated that chronic cocaine exposure increases risk preference in a rat gambling task (rGT). Given that the prelimbic cortex (PrL) to the nucleus accumbens (NAc) core pathway plays a crucial role in regulating risk-based decision-making, we further explored how chemogenetic modulation of this pathway alters cocaine-induced increase in risky decision-making in the rGT. Notably, activation of Gi, but not Gq, designer receptors exclusively activated by designer drugs (DREADD) in the PrL attenuated the cocaine-induced increase of risk preference in risk-averse rats, while simultaneously reducing cocaine-induced attentional deficits measured by task omissions. Subsequent molecular analyses revealed that cocaine significantly induced changes in the expression levels of calcium channel alpha 1 C subunit (CaV1.2) and in the ratio of phosphorylation at serine 97 of total dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32) in the PrL region of these rats, which returned to basal levels with concurrent Gi-DREADD activation. No significant behavioral or molecular changes were observed in risk-seeking rats. These results suggest that modulating the PrL-NAc core pathway can selectively control risk-based decision-making behavior and attentional processes affected by cocaine exposure, offering therapeutic potential for addressing decision-making impairments in dual diagnoses of gambling and SUD.
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Data availability
The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation. Correspondence and requests for materials should be addressed to Wha Young Kim or Jeong-Hoon Kim.
Code availability
The code used for analysis is available from the corresponding author on reasonable request.
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Acknowledgements
This work was supported by the National Research Foundation of Korea funded by the Ministry of Science and ICT (2022R1A4A5033852, RS-2025-00563430, RS-2025-24873007).
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Joonyeup Han: Writing – original draft, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Myung Ji Kwak: Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Wha Young Kim: Writing – original draft, Validation, Supervision, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization, Jeong-Hoon Kim: Writing – original draft, Validation, Supervision, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.
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All animal experiments and methods were performed in accordance with the relevant guidelines and regulations. The experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of Yonsei University College of Medicine (Approval No. A-2023-0176). As this study involved only animal subjects, requirements for informed consent from human participants and consent for publication of identifiable human images are not applicable.
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Han, J., Kwak, M.J., Kim, W.Y. et al. Chemogenetic modulation of the prelimbic cortex to the nucleus accumbens core pathway reduces cocaine-induced increase of risk preference. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-04015-4
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DOI: https://doi.org/10.1038/s41398-026-04015-4
