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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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.
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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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