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Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter

Molecular Psychiatry volume 26, pages 370–382 (2021)Cite this article

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Abstract

Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine. We previously showed that toxic levels of cocaine induce autophagic neuronal cell death. Here, we show that subnanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Autophagy inhibitors reduce the locomotor stimulant effect of cocaine in mice. Cocaine-induced autophagy degrades transporters for dopamine but not serotonin in the nucleus accumbens. Autophagy inhibition impairs cocaine conditioned place preference in mice. Our findings indicate that autophagic degradation of DAT modulates behavioral actions of cocaine.

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Fig. 1: Cocaine potently induces autophagy in neurons.
Fig. 2: Autophagy regulates the locomotor stimulant effect of cocaine.
Fig. 3: Cocaine induces autophagic degradation of the dopamine transporter (DAT).
Fig. 4: The autophagy inhibitor hydroxychloroquine impairs cocaine conditioned place preference.

Data availability

All data generated or analyzed during this study are included in this published article (and its Supplementary Data files).

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Acknowledgements

We thank L. Hester, R. Barrow, A. Snowman, S. McTeer, and L. Albacarys from the SHS laboratory for their assistance. We thank B. Smith and the Microscope Core Facility at the Institute for Basic Biomedical Sciences, Johns Hopkins School of Medicine, for helping in preparation of the TEM samples. We are also grateful for fruitful discussions with members of the SHS Laboratory.

Funding

This work was supported by U.S. Public Health Service Grants DA00266 and DA044123 to SHS and a NARSAD Young Investigator Grant (# 25360) from the Brain & Behavior Foundation to MMH. Support for this research was provided in part by the National Institute on Drug Abuse—Intramural Research Program, NIH/DHHS (Z1A DA000611).

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Author notes

  1. These authors contributed equally: Maged M. Harraz, Prasun Guha, Evan R. Semenza, Adarsha P. Malla

Authors and Affiliations

  1. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Maged M. Harraz, Prasun Guha, In Guk Kang, Evan R. Semenza, Adarsha P. Malla, Young Jun Song, Luke Reilly, Isaac Treisman, Pedro Cortés & Solomon H. Snyder

  2. Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA

    Mark A. Coggiano & Gianluigi Tanda

  3. Department of Neurology and Johns Hopkins Drug Discovery (JHDD) Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Vijayabhaskar Veeravalli & Rana Rais

  4. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Solomon H. Snyder

  5. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Solomon H. Snyder

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Contributions

MMH, PG, PC, IGK, ERS, YJS, LR, IT, APM, MAC, and VV performed experiments. MMH, PG, GT, RR, and SHS designed experiments, analyzed data, and wrote the manuscript.

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Correspondence to Solomon H. Snyder.

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Harraz, M.M., Guha, P., Kang, I.G. et al. Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter. Mol Psychiatry 26, 370–382 (2021). https://doi.org/10.1038/s41380-020-00978-y

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