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 c...

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Autores principales:	Juan L. Gomez, Jordi Bonaventura, Jacqueline Keighron, Kelsey M. Wright, Dondre L. Marable, Lionel A. Rodriguez, Sherry Lam, Meghan L. Carlton, Randall J. Ellis, Chloe J. Jordan, Guo-hua Bi, Oscar Solis, Marco Pignatelli, Michael J. Bannon, Zheng-Xiong Xi, Gianluigi Tanda, Michael Michaelides
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/7c2c5e8de1754235a1d3f93bf616dd57
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spelling	oai:doaj.org-article:7c2c5e8de1754235a1d3f93bf616dd572021-11-14T12:11:30ZSynaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior10.1038/s41398-021-01693-02158-3188https://doaj.org/article/7c2c5e8de1754235a1d3f93bf616dd572021-11-01T00:00:00Zhttps://doi.org/10.1038/s41398-021-01693-0https://doaj.org/toc/2158-3188Abstract 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.Juan L. GomezJordi BonaventuraJacqueline KeighronKelsey M. WrightDondre L. MarableLionel A. RodriguezSherry LamMeghan L. CarltonRandall J. EllisChloe J. JordanGuo-hua BiOscar SolisMarco PignatelliMichael J. BannonZheng-Xiong XiGianluigi TandaMichael MichaelidesNature Publishing GrouparticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENTranslational Psychiatry, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Juan L. Gomez Jordi Bonaventura Jacqueline Keighron Kelsey M. Wright Dondre L. Marable Lionel A. Rodriguez Sherry Lam Meghan L. Carlton Randall J. Ellis Chloe J. Jordan Guo-hua Bi Oscar Solis Marco Pignatelli Michael J. Bannon Zheng-Xiong Xi Gianluigi Tanda Michael Michaelides Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
description	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.
format	article
author	Juan L. Gomez Jordi Bonaventura Jacqueline Keighron Kelsey M. Wright Dondre L. Marable Lionel A. Rodriguez Sherry Lam Meghan L. Carlton Randall J. Ellis Chloe J. Jordan Guo-hua Bi Oscar Solis Marco Pignatelli Michael J. Bannon Zheng-Xiong Xi Gianluigi Tanda Michael Michaelides
author_facet	Juan L. Gomez Jordi Bonaventura Jacqueline Keighron Kelsey M. Wright Dondre L. Marable Lionel A. Rodriguez Sherry Lam Meghan L. Carlton Randall J. Ellis Chloe J. Jordan Guo-hua Bi Oscar Solis Marco Pignatelli Michael J. Bannon Zheng-Xiong Xi Gianluigi Tanda Michael Michaelides
author_sort	Juan L. Gomez
title	Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
title_short	Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
title_full	Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
title_fullStr	Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
title_full_unstemmed	Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
title_sort	synaptic zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/7c2c5e8de1754235a1d3f93bf616dd57
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Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior

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