Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference

Ichiro Sora, F. Scott Hall, Anne M. Andrews, Masanari Itokawa, Xiao Fei Li, Hong Bing Wei, Christine Wichems, Klaus Peter Lesch, Dennis L. Murphy, George R. Uhl

Research output: Contribution to journalArticle

Abstract

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development.

Original languageEnglish (US)
Pages (from-to)5300-5305
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number9
DOIs
StatePublished - Apr 24 2001

Fingerprint

Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Reward
Cocaine
Serotonin
Knockout Mice
Genes
Cocaine-Related Disorders
Membrane Transport Proteins
Weight Gain
Uncertainty
Dopamine
Norepinephrine
Cell Membrane

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Molecular mechanisms of cocaine reward : Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. / Sora, Ichiro; Hall, F. Scott; Andrews, Anne M.; Itokawa, Masanari; Li, Xiao Fei; Wei, Hong Bing; Wichems, Christine; Lesch, Klaus Peter; Murphy, Dennis L.; Uhl, George R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 9, 24.04.2001, p. 5300-5305.

Research output: Contribution to journalArticle

Sora, Ichiro ; Hall, F. Scott ; Andrews, Anne M. ; Itokawa, Masanari ; Li, Xiao Fei ; Wei, Hong Bing ; Wichems, Christine ; Lesch, Klaus Peter ; Murphy, Dennis L. ; Uhl, George R. / Molecular mechanisms of cocaine reward : Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 9. pp. 5300-5305.
@article{1ba59c2a11bd4ec0af57e3efcecb865c,
title = "Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference",
abstract = "Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development.",
author = "Ichiro Sora and Hall, {F. Scott} and Andrews, {Anne M.} and Masanari Itokawa and Li, {Xiao Fei} and Wei, {Hong Bing} and Christine Wichems and Lesch, {Klaus Peter} and Murphy, {Dennis L.} and Uhl, {George R.}",
year = "2001",
month = "4",
day = "24",
doi = "10.1073/pnas.091039298",
language = "English (US)",
volume = "98",
pages = "5300--5305",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "9",

}

TY - JOUR

T1 - Molecular mechanisms of cocaine reward

T2 - Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference

AU - Sora, Ichiro

AU - Hall, F. Scott

AU - Andrews, Anne M.

AU - Itokawa, Masanari

AU - Li, Xiao Fei

AU - Wei, Hong Bing

AU - Wichems, Christine

AU - Lesch, Klaus Peter

AU - Murphy, Dennis L.

AU - Uhl, George R.

PY - 2001/4/24

Y1 - 2001/4/24

N2 - Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development.

AB - Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development.

UR - http://www.scopus.com/inward/record.url?scp=0035942241&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035942241&partnerID=8YFLogxK

U2 - 10.1073/pnas.091039298

DO - 10.1073/pnas.091039298

M3 - Article

C2 - 11320258

AN - SCOPUS:0035942241

VL - 98

SP - 5300

EP - 5305

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 9

ER -