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Cocaine-Mediated Autophagy in Astrocytes Involves Sigma 1 Receptor, PI3K, mTOR, Atg5/7, Beclin-1 and Induces Type II Programed Cell Death

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Abstract

Cocaine, a commonly used drug of abuse, has been shown to cause neuropathological dysfunction and damage in the human brain. However, the role of autophagy in this process is not defined. Autophagy, generally protective in nature, can also be destructive leading to autophagic cell death. This study was designed to investigate whether cocaine induces autophagy in the cells of CNS origin. We employed astrocyte, the most abundant cell in the CNS, to define the effects of cocaine on autophagy. We measured levels of the autophagic marker protein LC3II in SVGA astrocytes after exposure with cocaine. The results showed that cocaine caused an increase in LC3II level in a dose- and time-dependent manner, with the peak observed at 1 mM cocaine after 6-h exposure. This result was also confirmed by detecting LC3II in SVGA astrocytes using confocal microscopy and transmission electron microscopy. Next, we sought to explore the mechanism by which cocaine induces the autophagic response. We found that cocaine-induced autophagy was mediated by sigma 1 receptor, and autophagy signaling proteins p-mTOR, Atg5, Atg7, and p-Bcl-2/Beclin-1 were also involved, and this was confirmed by using selective inhibitors and small interfering RNAs (siRNAs). In addition, we found that chronic treatment with cocaine resulted in cell death, which is caspase-3 independent and can be ameliorated by autophagy inhibitor. Therefore, this study demonstrated that cocaine induces autophagy in astrocytes and is associated with autophagic cell death.

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Acknowledgments

The work was supported by grants from National Institute on Drug Abuse (DA025528 and DA025011). We also acknowledge the use of the confocal microscope in the University Missouri, Kansas City School of Dentistry Confocal Microscopy Core. This facility is supported by the UMKC Office of Research Services, UMKC Center of Excellence in Dental and Musculoskeletal Tissues, and NIH grant S10RR027668.

Author Contributions

LC, MW, SK, MF, and AK conceptualized and designed the project. LC did all the experiments and analyzed the data. LC wrote the first draft of the manuscript, and AK finalized the manuscript for submission.

Conflict of Interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO, 64108, USA

    Lu Cao & Anil Kumar

  2. Department of Oral and Craniofacial Sciences, School of Dentistry Center of Excellence in Musculoskeletal and Dental Tissues, University of Missouri—Kansas City, Kansas City, MO, 64108, USA

    Mary P. Walker

  3. Department of Mathematics and Statistics, University of Missouri, Kansas City, MO, 64110, USA

    Naveen K. Vaidya

  4. Department of Basic Medical Science, School of Medicine, School of Medicine, University of Missouri—Kansas City, Kansas City, MO, 64108, USA

    Mingui Fu

  5. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Santosh Kumar

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  1. Lu Cao
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Correspondence to Anil Kumar.

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Cao, L., Walker, M.P., Vaidya, N.K. et al. Cocaine-Mediated Autophagy in Astrocytes Involves Sigma 1 Receptor, PI3K, mTOR, Atg5/7, Beclin-1 and Induces Type II Programed Cell Death. Mol Neurobiol 53, 4417–4430 (2016). https://doi.org/10.1007/s12035-015-9377-x

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