Cocaine binds to the dopamine transporter (DAT) in the striatum to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that cocaine abuse in humans correlated with low postmortem striatal Zn2+ content. In mice, cocaine decreased striatal vesicular Zn2+ and increased striatal synaptic Zn2+ concentrations and Zn2+ uptake. Striatal synaptic Zn2+ increased cocaine’s in vivo potency at the DAT and was required for cocaine-induced DAT upregulation. Finally, genetic or dietary Zn2+ manipulations modulated cocaine locomotor sensitization, conditioned place preference, self-administration, and reinstatement. These findings reveal new insights into cocaine’s pharmacological mechanism of action and indicate that Zn2+ can serve as a critical environmentally derived regulator of human cocaine addiction.
bioRxiv Subject Collection: Neuroscience