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bioRxiv · 10.1101/2020.08.29.273482

Zinc potentiates dopamine neurotransmission and cocaine seeking

Gomez, J. L.·Bonaventura, J.·Keighron, J.·Wright, K. M.·Marable, D. L.·Rodriguez, L. A.·Lam, S.·Carlton, M. L.·Ellis, R. J.·Jordan, C.·Bi, G.-H.·Pignatelli, M.·Bannon, M. J.·Xi, Z.-X.·Tanda, G.·Michaelides, M.
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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 cocaines 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.

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Gomez, J. L., Bonaventura, J., Keighron, J., Wright, K. M., Marable, D. L., Rodriguez, L. A., Lam, S., Carlton, M. L., Ellis, R. J., Jordan, C., Bi, G.-H., Pignatelli, M., Bannon, M. J., Xi, Z.-X., Tanda, G., Michaelides, M.. 2020-08-31. Zinc potentiates dopamine neurotransmission and cocaine seeking. https://doi.org/10.1101/2020.08.29.273482

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