Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter

Rong Chen, Michael R. Tilley, Hua Wei, Fuwen Zhou, Fuming Zhou, San Ching, Ning Quan, Robert L. Stephens, Erik R. Hill, Timothy Nottoli, Dawn D. Han, Howard H. Gu

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Abstract

There are three known high-affinity targets for cocaine: the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Decades of studies support the dopamine (DA) hypothesis that the blockade of DAT and the subsequent increase in extracellular DA primarily mediate cocaine reward and reinforcement. Contrary to expectations, DAT knock-out (DAT-KO) mice and SERT or NET knockout mice still self-administer cocaine and/or display conditioned place preference (CPP) to cocaine, which led to the reevaluation of the DA hypothesis and the proposal of redundant reward pathways. To study the role of DAT in cocaine reward, we have generated a knockin mouse line carrying a functional DAT that is insensitive to cocaine. In these mice, cocaine suppressed locomotor activity, did not elevate extracellular DA in the nucleus accumbens, and did not produce reward as measured by CPP. This result suggests that blockade of DAT is necessary for cocaine reward in mice with a functional DAT. 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.

Original languageEnglish (US)
Pages (from-to)9333-9338
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number24
DOIs
StatePublished - Jun 13 2006

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Dopamine Plasma Membrane Transport Proteins
Reward
Cocaine
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Dopamine
Knockout Mice
Nucleus Accumbens
Locomotion

All Science Journal Classification (ASJC) codes

  • General

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Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. / Chen, Rong; Tilley, Michael R.; Wei, Hua; Zhou, Fuwen; Zhou, Fuming; Ching, San; Quan, Ning; Stephens, Robert L.; Hill, Erik R.; Nottoli, Timothy; Han, Dawn D.; Gu, Howard H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 24, 13.06.2006, p. 9333-9338.

Research output: Contribution to journalArticle

Chen, R, Tilley, MR, Wei, H, Zhou, F, Zhou, F, Ching, S, Quan, N, Stephens, RL, Hill, ER, Nottoli, T, Han, DD & Gu, HH 2006, 'Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 24, pp. 9333-9338. https://doi.org/10.1073/pnas.0600905103
Chen, Rong ; Tilley, Michael R. ; Wei, Hua ; Zhou, Fuwen ; Zhou, Fuming ; Ching, San ; Quan, Ning ; Stephens, Robert L. ; Hill, Erik R. ; Nottoli, Timothy ; Han, Dawn D. ; Gu, Howard H. / Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 24. pp. 9333-9338.
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