Abstract
Cocaine binds to the dopamine (DA) transporter (DAT) 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 Zn2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+ were dependent on the Zn2+ transporter 3 (ZnT3), a neuronal Zn2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+ deficiency in mice resulted in decreased striatal Zn2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+ release and turnover/metabolism in the striatum, and that synaptically released Zn2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that Zn2+ may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.
Highlights
Zinc (Zn2+) is an essential trace element necessary for normal brain function [1,2,3,4,5,6]
Here we show that human subjects who died of cocaine overdose had significantly lower Zn2+ content in the striatum compared to matched controls
We found that repeated cocaine (RC) injections increased striatal Zn2+ content in normal mice but not in mice lacking Zn2+ transporter 3 (ZnT3), indicating that cocaine exposure increases synaptic Zn2+ levels in the striatum via the actions of ZnT3
Summary
Zinc (Zn2+) is an essential trace element necessary for normal brain function [1,2,3,4,5,6]. Within the brain it exists in two forms; a “fixed”, protein-bound form, which serves as a catalytic co-factor or as a structural component to Zn2+ binding proteins, and comprises ~90% of total brain concentration, or a “free”, or labile/ chelatable form, comprising ~10% of total brain concentration. ZnT3 knockout (KO) mice lack the ability to package Zn2+ into these vesicles and lack synaptic Zn2+ release [9, 10]. ZnT3 KO mice are viable, fertile, and do not show major behavioral abnormalities across spatial learning, memory, or sensorimotor tasks, though they do exhibit small deficits in skilled reaching tasks [11, 12], fear learning [13], and sensory deficits [14, 15]
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