Cocaine self-administration in dopamine-transporter knockout mice

@article{Rocha1998CocaineSI,
  title={Cocaine self-administration in dopamine-transporter knockout mice},
  author={Beatriz A. Rocha and Fabio Fumagalli and Raul R. Gainetdinov and Sara R. Jones and Robert Ator and Bruno Giros and Gary W. Miller and Marc G. Caron},
  journal={Nature Neuroscience},
  year={1998},
  volume={1},
  pages={132-137}
}
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… 
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Modulation of the serotonergic system in the ventral tegmental area, where the mesolimbic dopamine system originates, is a target of cocaine action, and the ultimate effect of this serotonin mechanism in animal models with sustained elevations of dopamine may be a feed-forward enhancement of dopamine levels in the nucleus accumbens.
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It is suggested that blockade of DAT is necessary for cocaine reward in mice with a functional DAT, and this mouse model is unique in that it is specifically designed to differentiate the role of Dat from the roles of NET and SERT in cocaine-induced biochemical and behavioral effects.
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It is reported that both cocaine and desipramine, a potent NET inhibitor, failed to change DA clearance or evoked release in the NAc of mutant mice, and the present findings suggest that in the DAT-KO mice, cocaine acts primarily outside theNAc to produce its effects.
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Findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine.
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A reduction in DAT expression and elevation of dopaminergic tone do not lead to adaptive changes that abolish the rewarding and stimulating effects of cocaine, and this study supports the conclusion that the blockade of DAT is required for cocaine reward and locomotor stimulation.
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New insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities.
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