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Cocaine-induced ischemia in prefrontal cortex is associated with escalation of cocaine intake in rodents

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Abstract

Cocaine-induced vasoconstriction reduces blood flow, which can jeopardize neuronal function and in the prefrontal cortex (PFC) it may contribute to compulsive cocaine intake. Here, we used integrated optical imaging in a rat self-administration and a mouse noncontingent model, to investigate whether changes in the cerebrovascular system in the PFC contribute to cocaine self-administration, and whether they recover with detoxification. In both animal models, cocaine induced severe vasoconstriction and marked reductions in cerebral blood flow (CBF) in the PFC, which were exacerbated with chronic exposure and with escalation of cocaine intake. Though there was a significant proliferation of blood vessels in areas of vasoconstriction (angiogenesis), CBF remained reduced even after 1 month of detoxification. Treatment with Nifedipine (Ca2+ antagonist and vasodilator) prevented cocaine-induced CBF decreases and neuronal Ca2+ changes in the PFC, and decreased cocaine intake and blocked reinstatement of drug seeking. These findings provide support for the hypothesis that cocaine-induced CBF reductions lead to neuronal deficits that contribute to hypofrontality and to compulsive-like cocaine intake in addiction, and document that these deficits persist at least one month after detoxification. Our preliminary data showed that nifedipine might be beneficial in preventing cocaine-induced vascular toxicity and in reducing cocaine intake and preventing relapse.

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Acknowledgments

We specially thank to Sunmee Wee for conducting the initial self-administration experiment and analyzing that behavior data. Also to J. Li for partially assisting with figure illustration (Fig. 5) and Q.J. Zhang for assisting with noncontingent cocaine administration of rats and their VEGF studies on PFC and the somatosensory cortex. This work was supported in part by National Institutes of Health (NIH) grants 1R01DA029718 (C.D. and Y.P.), R21DA042597 (Y.P. and C.D.), R01DA04398 (G.F.K. when he was at The Scripps Research Institute), and NIH’s Intramural Program of NIAAA (NDV). The authors would also like to thank the NIDA drug supply program for providing the cocaine used in the calcium antagonist and mouse model experiments.

Author contributions

C.D. and Y.P. designed and built the optical setups. N.D.V., C.D., and Y.P. designed the experiments. G.F.K. designed the self-administration model and provided self-administering animals and helped with analysis and interpretation of the results. C.P.A. conducted self-administration animals for Ca2+ antagonist studies. C.P.A., J.Y., and K.P. carried out the imaging experiments and data analysis. All authors proofread the manuscript.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, USA

    Congwu Du, Jiang You, Kicheon Park, Craig P. Allen & Yingtian Pan

  2. National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20857, USA

    Nora D. Volkow

  3. National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, 20892, USA

    George F. Koob

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  1. Congwu Du
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Correspondence to Congwu Du, Nora D. Volkow or Yingtian Pan.

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Du, C., Volkow, N.D., You, J. et al. Cocaine-induced ischemia in prefrontal cortex is associated with escalation of cocaine intake in rodents. Mol Psychiatry 25, 1759–1776 (2020). https://doi.org/10.1038/s41380-018-0261-8

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