Abstract
Cocaine addiction is a worldwide public health problem for which there are no established treatments. The dopamine transporter (DAT) is suspected as the primary target mediating cocaine's abuse-related effects based on numerous pharmacological studies. However, in a previous study, DAT knockout mice were reported to self-administer cocaine, generating much debate regarding the importance of the DAT in cocaine's abuse-related effects. Here, we show that mice expressing a “knockin” of a cocaine-insensitive but functional DAT did not self-administer cocaine intravenously despite normal food-maintained responding and normal intravenous self-administration of amphetamine and a direct dopamine agonist. Our results have three implications. First, they imply a crucial role for high-affinity DAT binding of cocaine in mediating its reinforcing effects, reconciling mouse genetic engineering approaches with data from classic pharmacological studies. Second, they demonstrate the usefulness of knockin strategies that modify specific amino acid sequences within a protein. Third, they show that it is possible to alter the DAT protein sequence in such a way as to selectively target its interaction with cocaine, while sparing other behaviors dependent on DAT function. Thus, molecular engineering technology could advance the development of highly specialized compounds such as a dopamine-sparing “cocaine antagonist.”
- ANOVA, analysis of variance
- DAT, dopamine transporter
- DATki, dopamine transporter knock-in
- DAT−/−, dopamine transporter knockout
- FR, fixed ratio
- PR, progressive ratio
- SERT, serotonin transporter
- NET, norepinephrine transporter
- SKF 82958, (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Footnotes
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This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R29-DA12142, R01-DA14644, R01-DA17323, T32-DA07232, R01-DA014610, R01-DA20124].
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This work was presented in part at the “Dopamine 50 Years” symposium in Göteborg, Sweden, May 30 to June 2, 2007.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- Received May 15, 2009.
- Accepted July 10, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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