Cocaine-induced Locomotor Stimulation is Mediated by Autophagic Degradation of the Dopamine Transporter

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. Here we show that sub‐nanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Pharmacologic inhibition of autophagy significantly reduces the locomotor stimulant effect of cocaine in mice. Autophagy depletes transporters for dopamine but not serotonin in the nucleus accumbens following cocaine injection. The dopamine transporter is enriched in the ventral midbrain lysosomal fraction following intraperitoneal injection of cocaine, which is reversed by inhibition of autophagy. Furthermore, autophagy inhibitors significantly reduce dopamine levels in the nucleus accumbens following cocaine injection. Taken together, these findings suggest that the behavioral stimulant effect of cocaine is mediated at least in part by autophagic degradation of DAT.Support or Funding InformationFunding: this work was supported by U.S. Public Health Service Grants DA00266 and DA044123 to SHS and a NARSAD Young Investigator Grant (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).