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

Juan Gomez, Ph.D.

Featured Paper of the Month – January 2022

Published in Translational Psychiatry by Juan Gomez and Michael Michaelides of the NIDA IRP Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit.

Summary

Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc also binds to the DAT, but the in vivo relevance of this interaction is unknown. We examined this interaction by altering zinc availability and measuring behavior and physiology associated with cocaine exposure. To alter zinc levels, we manipulated dietary zinc or used a mouse model that lacked the zinc transporter ZnT3. The body has no storage system for zinc and one must consistently replenish this essential element via zinc-rich food sources. Of the 24 transporters dedicated to moving zinc around the body, ZnT3 is necessary to shuttle zinc around the brain. By putting mice on a zinc deficient diet or by genetically deleting ZnT3, we show that mice are less sensitive to cocaine and find it less rewarding. We also show that low brain zinc decreases cocaine’s effects on DA neurotransmission and that repeated cocaine use in humans lowers zinc levels in the brain. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that zinc may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.

Publication Information

Gomez, Juan L; Bonaventura, Jordi; Keighron, Jacqueline; Wright, Kelsey M; Marable, Dondre L; Rodriguez, Lionel A; Lam, Sherry; Carlton, Meghan L; Ellis, Randall J; Jordan, Chloe J; Bi, Guo-Hua; Solis, Oscar; Pignatelli, Marco; Bannon, Michael J; Xi, Zheng-Xiong; Tanda, Gianluigi; Michaelides, Michael

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

In: Transl Psychiatry, vol. 11, no. 1, pp. 570, 2021, ISSN: 2158-3188.

Abstract | Links

@article{pmid34750356,

title = {Synaptic Zn^{2+} potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior},

author = {Juan L Gomez and Jordi Bonaventura and Jacqueline Keighron and Kelsey M Wright and Dondre L Marable and Lionel A Rodriguez and Sherry Lam and Meghan L Carlton and Randall J Ellis and Chloe J Jordan and Guo-Hua Bi and Oscar Solis and Marco Pignatelli and Michael J Bannon and Zheng-Xiong Xi and Gianluigi Tanda and Michael Michaelides},

url = {https://pubmed.ncbi.nlm.nih.gov/34750356/},

doi = {10.1038/s41398-021-01693-0},

issn = {2158-3188},

year  = {2021},

date = {2021-11-01},

urldate = {2021-11-01},

journal = {Transl Psychiatry},

volume = {11},

number = {1},

pages = {570},

abstract = {Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn 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 Zn 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 Zn concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn were dependent on the Zn transporter 3 (ZnT3), a neuronal Zn transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn. 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 Zn deficiency in mice resulted in decreased striatal Zn content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn release and turnover/metabolism in the striatum, and that synaptically released Zn 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 Zn may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}