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PNAS 103 (24): 9333-9338

Copyright © 2006 by the National Academy of Sciences.


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

Rong Chen*, Michael R. Tilley*, Hua Wei*, Fuwen Zhou{dagger}, Fu-Ming Zhou{dagger}, San Ching{ddagger}, Ning Quan{ddagger}, Robert L. Stephens§, Erik R. Hill*, Timothy Nottoli, Dawn D. Han*, and Howard H. Gu*,||,**

Departments of *Pharmacology, ||Psychiatry, {ddagger}Oral Biology, and §Physiology, Ohio State University, 5184b Graves Hall, 333 West 10th Avenue, Columbus, OH 43210; {dagger}Department of Pharmacology, University of Tennessee College of Medicine, Memphis, TN 38163; and Section of Comparative Medicine, Yale University, 375 Congress Avenue, New Haven, CT 06520

Edited by Susan G. Amara, University of Pittsburgh School of Medicine, Pittsburgh, PA, and approved May 2, 2006

Received for publication February 2, 2006.

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 knockout (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.

Key Words: addiction • amphetamine • conditioned place preference • knockin

Author contributions: H.H.G., R.C., and M.R.T. designed research; H.H.G., R.C., M.R.T., H.W., F.Z., F.-M.Z., S.C., N.Q., E.R.H., T.N., and D.D.H. performed research; F.-M.Z. and R.L.S. contributed new reagents/analytic tools; H.H.G., R.C., and M.R.T. analyzed data; and H.H.G., R.C., and M.R.T. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

**To whom correspondence should be addressed. E-mail: gu.37{at}

© 2006 by The National Academy of Sciences of the USA

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