Abstract
Individuals with cocaine addiction can experience many craving episodes and subsequent relapses, which represents the main obstacle to recovery. Craving is often favored when abstinent individuals ingest a small dose of cocaine, encounter cues associated with drug use or are exposed to stressors. Using a cocaine-primed reinstatement model in rat, we recently showed that cocaine-conditioned interoceptive cues can be extinguished with repeated cocaine priming in the absence of drug reinforcement, a phenomenon we called extinction of cocaine priming. Here, we applied a large-scale c-Fos brain mapping approach following extinction of cocaine priming in male rats to identify brain regions implicated in processing the conditioned interoceptive stimuli of cocaine priming. We found that cocaine-primed reinstatement is associated with increased c-Fos expression in key brain regions (e.g., dorsal and ventral striatum, several prefrontal areas and insular cortex), while its extinction mostly disengages them. Moreover, while reinstatement behavior was correlated with insular and accumbal activation, extinction of cocaine priming implicated parts of the ventral pallidum, the mediodorsal thalamus and the median raphe. These brain patterns of activation and inhibition suggest that after repeated priming, interoceptive signals lose their conditioned discriminative properties and that action-outcome associations systems are mobilized in search for new contingencies, a brain state that may predispose to rapid relapse.
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Data availability
All raw c-Fos data are available in the Supplementary files. Other data is available upon reasonable request to the corresponding authors.
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Acknowledgements
We thank Eric Wattelet for administrative assistance. We also thank Sandra Dovero, Evelyne Doudnikoff, and Matthieu Bastide for technical advice, and Etienne Gontier from the Bordeaux Imaging Center (BIC) for giving us access to his laboratory facility for brain perfusion.
Funding
This research was supported by funding from the Centre National de la Recherche Scientifique (CNRS), the Agence Nationale de la Recherche (ANR- 2010-BLAN-1404-01), the Université de Bordeaux and the Conseil Regional d’Aquitaine (CRA11004375/11004699).
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SHA conceived the project. SN, PG and SHA designed the experiments. SN, PG performed the experiments and collected the experimental data. ML, ME analyzed the data. ML and ME wrote the first draft of the paper. ML, ME and SHA revised and edited the paper. All authors reviewed content and approved the final version of the manuscript.
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Lenoir, M., Engeln, M., Navailles, S. et al. A large-scale c-Fos brain mapping study on extinction of cocaine-primed reinstatement. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01867-6
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DOI: https://doi.org/10.1038/s41386-024-01867-6