Abstract
The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self-administer cocaine. Mapping of the sites of cocaine binding and neuronal activation suggests an involvement of serotonergic brain regions in this response. These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice.
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Acknowledgements
We would like to thank Julie K. Staley for comments regarding autoradiography and Anthony LaMantia for advice. Fabio Fumagalli is a visiting fellow from Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Raul R. Gainetdinov is a visiting fellow from Institute of Pharmacology RAMS, Baltiyskaya, 8, 125315, Moscow, Russia. This work was supported in part by the National Institutes of Health, U.S. Public Health Service grants MH-40159 (MCG), DA-10457A (BAR), ES-09248 (GWM), DA 05749 (SRJ), and unrestricted gifts from Bristol Myers Squibb and Zeneca Pharmaceuticals (MGC).
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Rocha, B., Fumagalli, F., Gainetdinov, R. et al. Cocaine self-administration in dopamine-transporter knockout mice. Nat Neurosci 1, 132–137 (1998). https://doi.org/10.1038/381
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DOI: https://doi.org/10.1038/381