Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior

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.

Zinc in Cognitive Impairment and Aging

“…Further research found that after ZnT-3 gene knockout, mice became insensitive to increased Zn 2+ in the striatum. The electrically induced release of dopamine (DA) was significantly reduced, the clearance rate of DA was higher [ 124 ], and ARCD was induced, suggesting that there may be ZnT-3-dependent communication between plasma and neuronal zinc through the cerebrovascular wall [ 125 ].…”

“…Zinc affects learning and memory and is an important factor in ARCD because it regulates various cellular and molecular processes [ 100 , 248 ]. For example, during brain depolarization [ 101 , 124 ], zinc is released into synapses together with glutamate to regulate synaptic communication and neural plasticity [ 249 ].…”

“…Plasma and neurons depend on it to exchange through the blood vessel wall [117][118][119][120][123][124][125] ZnT-4…”

The Role of Zinc in Modulating Acid-Sensing Ion Channel Function

“…Cocaine triggers drug-seeking behavior by binding to the dopamine transporter at the synapse [122,123]. A 2021 study revealed that increased zinc concentrations in mice enhance cocaine binding to the dopamine transporter (DAT) protein.…”

Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release

“…Due to the calcium dependency of cocaine-induced stimulation of DA release, under the same FSCV experimental conditions, changes in free calcium fluctuations were assessed for typical and atypical DAT blockers using fiber photometry procedures. DAT function may be influenced by its interactions with other neuronal membrane proteins, small molecules, and cations [ 22 – 25 ]. Previous reports have attributed cocaine-induced enhancement of evoked DA release to an increased availability of DA-containing large dense-core vesicles (LDCVs) associated with the synapsin-mediated reserve pool of vesicles under resting conditions [ 26 , 27 ].…”