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

Maged M. Harraz, Prasun Guha, In Guk Kang, Evan R. Semenza, Adarsha P. Malla, Young Jun Song, Luke Reilly, Isaac Treisman, Pedro Cortés, Mark A. Coggiano, Vijayabhaskar Veeravalli, Rana Rais, Gianluigi Tanda, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)370-382
Number of pages13
JournalMolecular psychiatry
Volume26
Issue number2
DOIs
StatePublished - Feb 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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