Abstract
One behavioral feature of drug addiction is continued drug use despite awareness that this causes negative consequences. Attempts to model this feature in animals typically involve punishing drug self-administration with electrical footshock to identify individuals whose drug use is differently suppressed by punishment. Here we sought to further study individual responsiveness of drug use to punishment in rats self-administering intravenous cocaine. Rats were first trained during several weeks to self-administer cocaine under a fixed-ratio 3 schedule of reinforcement. Then, their self-administration behavior was punished with increasing intensity of footshock (i.e., from 0.1 mA to 0.9 mA, every 30 min). With increasing intensity of punishment, rats first continued to self-administer cocaine before eventually stopping near completely. When retested, however, drug use became more responsive to punishment and was suppressed by a low and initially ineffective footshock intensity (i.e., 0.1 mA). This increase in responsiveness to punishment was seen in all individuals tested, albeit with varying degrees, and was acquired after one single experience with an intensity of punishment that near completely suppressed drug self-administration. Mere passive, non-contingent exposure to the same intensity, however, had no such effect. Once acquired, increased responsiveness to punishment persisted during at least one month when rats were tested every week, but not every day. Finally, increased responsiveness to punishment was not observed after exposure to a non-painful form of punishment (i.e., histamine). Overall, this study reveals that initial responsiveness of drug use to punishment can change rapidly and persistently with experience. We discuss several possible mechanisms that may account for this change in punishment responsiveness and also draw some of the implications and future perspectives for research on animal models of compulsion-like behavior.
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Acknowledgements
We thank Christophe Bernard, Mathieu Louvet and Eric Wattelet for administrative assistance. We also thank Drs. Karine Guillem and Magalie Lenoir for their helpful comments on a previous version of the manuscript. We also thank Pr. Gavan McNally for bringing our attention to the old literature on punishment. We also thank the reviewers for their insightful and constructive criticisms.
Funding
This work was supported by the French Research Council (CNRS), the Université de Bordeaux, the Conseil Régional d’Aquitaine (CRA20101301022; CRA11004375/11004699) and the French National Agency (ANR2010-BLAN-1404-01, ANR-10-EQX-008-1, LabEx BRAIN). LF was supported by the CAPES–Brazilian Federal Agency for Support and Evaluation of Graduate Education within the Ministry of Education of Brazil.
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SHA conceived the project. AD, SHA designed the experiments. AD carried out the experiments with the participation of PG and LF. AD collected the experimental data. AD, SHA analyzed the data. AD, SHA wrote the paper. All authors reviewed content and approved the final version of the manuscript.
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Durand, A., Girardeau, P., Freese, L. et al. Increased responsiveness to punishment of cocaine self-administration after experience with high punishment. Neuropsychopharmacol. 47, 444–453 (2022). https://doi.org/10.1038/s41386-021-01159-3
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DOI: https://doi.org/10.1038/s41386-021-01159-3
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