Abstract
Humans with drug addiction exhibit compulsive drug-seeking associated with impairment of prefrontal cortex cognitive function. Whether prefrontal cortex dysfunction is a consequence of chronic drug exposure, or mediates the transition from drug use to drug dependence, is unknown. The current study investigates whether a history of escalated vs controlled cocaine intake is associated with specific working memory impairments, and long-lasting alterations of the dorsomedial prefrontal cortex and orbitofrontal cortex in rats. Working memory was assessed in rats with a history of extended (6 h per session) or limited (1 h per session) access to cocaine (0.5 mg/kg per injection), 3–17 days after the last self-administration session, using a delayed nonmatching-to-sample task. The density of neurons, oligodendrocytes, and astrocytes was quantified in the dorsomedial prefrontal cortex and orbitofrontal prefrontal cortex 2 months after the last self-administration session. Working memory impairments were observed after a history of chronic and escalated cocaine intake, but not after repeated limited access to cocaine. Moreover, working memory impairments were correlated with a decreased density of neurons and oligodendrocytes but not astrocytes in the dorsomedial prefrontal cortex, and with a decreased density of oligodendrocytes in the orbitofrontal cortex. Considering the role of the prefrontal cortex in goal-directed behavior, the prefrontal cortex dysfunctions observed here may exacerbate the loss of control associated with increased drug use and facilitate the progression to drug addiction.
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Acknowledgements
This is publication number 18690 from The Scripps Research Institute. This work was supported by National Institutes of Health grant DA04398 from the National Institute on Drug Abuse, the Pearson Center for Alcoholism and Addiction Research, and IES Brain Research Foundation. We thank Dr Frederique Ambroggi and Dr Heather Richardson for helpful comments on the manuscript, and the reviewers for their constructive critiques. We also thank Katy Rahmani, Hanan Jammal, Youn Kyung Lee, Stephanie HoChan, and Robert Lintz for their technical assistance and Michael Arends for his editorial assistance.
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The authors declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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George, O., Mandyam, C., Wee, S. et al. Extended Access to Cocaine Self-Administration Produces Long-Lasting Prefrontal Cortex-Dependent Working Memory Impairments. Neuropsychopharmacol 33, 2474–2482 (2008). https://doi.org/10.1038/sj.npp.1301626
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DOI: https://doi.org/10.1038/sj.npp.1301626
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