Tropomyosin-Related Kinase B in the Mesolimbic Dopamine System: Region-Specific Effects on Cocaine Reward

Danielle L. Graham, Vaishnav Krishnan, Erin B. Larson, Ami Graham, Scott Edwards, Ryan K. Bachtell, Diana Simmons, Lana M. Gent, Olivier Berton, Carlos A. Bolanos, Ralph J. DiLeone, Luis F. Parada, Eric J. Nestler, David W. Self

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Background: Previous studies found that brain-derived neurotrophic factor (BDNF) derived from nucleus accumbens (NAc) neurons can mediate persistent behavioral changes that contribute to cocaine addiction. Methods: To further investigate BDNF signaling in the mesolimbic dopamine system, we analyzed tropomyosin-related kinase B (TrkB) messenger RNA (mRNA) and protein changes in the NAc and ventral tegmental area (VTA) in rats following 3 weeks of cocaine self-administration. To study the role of BDNF-TrkB activity in the VTA and NAc in cocaine reward, we used localized viral-mediated Cre recombinase expression in floxed BDNF and floxed TrkB mice to knockdown BDNF or TrkB in the VTA and NAc in cocaine place conditioning tests and TrkB in the NAc in cocaine self-administration tests. Results: We found that 3 weeks of active cocaine self-administration significantly increased TrkB protein levels in the NAc shell, while yoked (passive) cocaine exposure produced a similar increase in the VTA. Localized BDNF knockdown in either region reduced cocaine reward in place conditioning, whereas only TrkB knockdown in the NAc reduced cocaine reward. In mice self-administering cocaine, TrkB knockdown in the NAc produced a downward shift in the cocaine self-administration dose-response curve but had no effect on the acquisition of cocaine or sucrose self-administration. Conclusions: Together, these data suggest that BDNF synthesized in either VTA or NAc neurons is important for maintaining sensitivity to cocaine reward but only BDNF activation of TrkB receptors in the NAc mediates this effect. In addition, up-regulation of NAc TrkB with chronic cocaine use could promote the transition to more addicted biological states.

Original languageEnglish (US)
Pages (from-to)696-701
Number of pages6
JournalBiological Psychiatry
Volume65
Issue number8
DOIs
StatePublished - Apr 15 2009

Fingerprint

Reward
Cocaine
Nucleus Accumbens
Dopamine
Brain-Derived Neurotrophic Factor
Ventral Tegmental Area
Self Administration
Tegmentum Mesencephali
tropomyosin kinase
Neurons
Cocaine-Related Disorders
Sucrose
Up-Regulation

Keywords

  • Addiction
  • BDNF
  • nucleus accumbens
  • place preference
  • self-administration
  • TrkB

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Tropomyosin-Related Kinase B in the Mesolimbic Dopamine System : Region-Specific Effects on Cocaine Reward. / Graham, Danielle L.; Krishnan, Vaishnav; Larson, Erin B.; Graham, Ami; Edwards, Scott; Bachtell, Ryan K.; Simmons, Diana; Gent, Lana M.; Berton, Olivier; Bolanos, Carlos A.; DiLeone, Ralph J.; Parada, Luis F.; Nestler, Eric J.; Self, David W.

In: Biological Psychiatry, Vol. 65, No. 8, 15.04.2009, p. 696-701.

Research output: Contribution to journalArticle

Graham, DL, Krishnan, V, Larson, EB, Graham, A, Edwards, S, Bachtell, RK, Simmons, D, Gent, LM, Berton, O, Bolanos, CA, DiLeone, RJ, Parada, LF, Nestler, EJ & Self, DW 2009, 'Tropomyosin-Related Kinase B in the Mesolimbic Dopamine System: Region-Specific Effects on Cocaine Reward', Biological Psychiatry, vol. 65, no. 8, pp. 696-701. https://doi.org/10.1016/j.biopsych.2008.09.032
Graham, Danielle L. ; Krishnan, Vaishnav ; Larson, Erin B. ; Graham, Ami ; Edwards, Scott ; Bachtell, Ryan K. ; Simmons, Diana ; Gent, Lana M. ; Berton, Olivier ; Bolanos, Carlos A. ; DiLeone, Ralph J. ; Parada, Luis F. ; Nestler, Eric J. ; Self, David W. / Tropomyosin-Related Kinase B in the Mesolimbic Dopamine System : Region-Specific Effects on Cocaine Reward. In: Biological Psychiatry. 2009 ; Vol. 65, No. 8. pp. 696-701.
@article{b2b707c258f54d46985e9ff411d6504b,
title = "Tropomyosin-Related Kinase B in the Mesolimbic Dopamine System: Region-Specific Effects on Cocaine Reward",
abstract = "Background: Previous studies found that brain-derived neurotrophic factor (BDNF) derived from nucleus accumbens (NAc) neurons can mediate persistent behavioral changes that contribute to cocaine addiction. Methods: To further investigate BDNF signaling in the mesolimbic dopamine system, we analyzed tropomyosin-related kinase B (TrkB) messenger RNA (mRNA) and protein changes in the NAc and ventral tegmental area (VTA) in rats following 3 weeks of cocaine self-administration. To study the role of BDNF-TrkB activity in the VTA and NAc in cocaine reward, we used localized viral-mediated Cre recombinase expression in floxed BDNF and floxed TrkB mice to knockdown BDNF or TrkB in the VTA and NAc in cocaine place conditioning tests and TrkB in the NAc in cocaine self-administration tests. Results: We found that 3 weeks of active cocaine self-administration significantly increased TrkB protein levels in the NAc shell, while yoked (passive) cocaine exposure produced a similar increase in the VTA. Localized BDNF knockdown in either region reduced cocaine reward in place conditioning, whereas only TrkB knockdown in the NAc reduced cocaine reward. In mice self-administering cocaine, TrkB knockdown in the NAc produced a downward shift in the cocaine self-administration dose-response curve but had no effect on the acquisition of cocaine or sucrose self-administration. Conclusions: Together, these data suggest that BDNF synthesized in either VTA or NAc neurons is important for maintaining sensitivity to cocaine reward but only BDNF activation of TrkB receptors in the NAc mediates this effect. In addition, up-regulation of NAc TrkB with chronic cocaine use could promote the transition to more addicted biological states.",
keywords = "Addiction, BDNF, nucleus accumbens, place preference, self-administration, TrkB",
author = "Graham, {Danielle L.} and Vaishnav Krishnan and Larson, {Erin B.} and Ami Graham and Scott Edwards and Bachtell, {Ryan K.} and Diana Simmons and Gent, {Lana M.} and Olivier Berton and Bolanos, {Carlos A.} and DiLeone, {Ralph J.} and Parada, {Luis F.} and Nestler, {Eric J.} and Self, {David W.}",
year = "2009",
month = "4",
day = "15",
doi = "10.1016/j.biopsych.2008.09.032",
language = "English (US)",
volume = "65",
pages = "696--701",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "8",

}

TY - JOUR

T1 - Tropomyosin-Related Kinase B in the Mesolimbic Dopamine System

T2 - Region-Specific Effects on Cocaine Reward

AU - Graham, Danielle L.

AU - Krishnan, Vaishnav

AU - Larson, Erin B.

AU - Graham, Ami

AU - Edwards, Scott

AU - Bachtell, Ryan K.

AU - Simmons, Diana

AU - Gent, Lana M.

AU - Berton, Olivier

AU - Bolanos, Carlos A.

AU - DiLeone, Ralph J.

AU - Parada, Luis F.

AU - Nestler, Eric J.

AU - Self, David W.

PY - 2009/4/15

Y1 - 2009/4/15

N2 - Background: Previous studies found that brain-derived neurotrophic factor (BDNF) derived from nucleus accumbens (NAc) neurons can mediate persistent behavioral changes that contribute to cocaine addiction. Methods: To further investigate BDNF signaling in the mesolimbic dopamine system, we analyzed tropomyosin-related kinase B (TrkB) messenger RNA (mRNA) and protein changes in the NAc and ventral tegmental area (VTA) in rats following 3 weeks of cocaine self-administration. To study the role of BDNF-TrkB activity in the VTA and NAc in cocaine reward, we used localized viral-mediated Cre recombinase expression in floxed BDNF and floxed TrkB mice to knockdown BDNF or TrkB in the VTA and NAc in cocaine place conditioning tests and TrkB in the NAc in cocaine self-administration tests. Results: We found that 3 weeks of active cocaine self-administration significantly increased TrkB protein levels in the NAc shell, while yoked (passive) cocaine exposure produced a similar increase in the VTA. Localized BDNF knockdown in either region reduced cocaine reward in place conditioning, whereas only TrkB knockdown in the NAc reduced cocaine reward. In mice self-administering cocaine, TrkB knockdown in the NAc produced a downward shift in the cocaine self-administration dose-response curve but had no effect on the acquisition of cocaine or sucrose self-administration. Conclusions: Together, these data suggest that BDNF synthesized in either VTA or NAc neurons is important for maintaining sensitivity to cocaine reward but only BDNF activation of TrkB receptors in the NAc mediates this effect. In addition, up-regulation of NAc TrkB with chronic cocaine use could promote the transition to more addicted biological states.

AB - Background: Previous studies found that brain-derived neurotrophic factor (BDNF) derived from nucleus accumbens (NAc) neurons can mediate persistent behavioral changes that contribute to cocaine addiction. Methods: To further investigate BDNF signaling in the mesolimbic dopamine system, we analyzed tropomyosin-related kinase B (TrkB) messenger RNA (mRNA) and protein changes in the NAc and ventral tegmental area (VTA) in rats following 3 weeks of cocaine self-administration. To study the role of BDNF-TrkB activity in the VTA and NAc in cocaine reward, we used localized viral-mediated Cre recombinase expression in floxed BDNF and floxed TrkB mice to knockdown BDNF or TrkB in the VTA and NAc in cocaine place conditioning tests and TrkB in the NAc in cocaine self-administration tests. Results: We found that 3 weeks of active cocaine self-administration significantly increased TrkB protein levels in the NAc shell, while yoked (passive) cocaine exposure produced a similar increase in the VTA. Localized BDNF knockdown in either region reduced cocaine reward in place conditioning, whereas only TrkB knockdown in the NAc reduced cocaine reward. In mice self-administering cocaine, TrkB knockdown in the NAc produced a downward shift in the cocaine self-administration dose-response curve but had no effect on the acquisition of cocaine or sucrose self-administration. Conclusions: Together, these data suggest that BDNF synthesized in either VTA or NAc neurons is important for maintaining sensitivity to cocaine reward but only BDNF activation of TrkB receptors in the NAc mediates this effect. In addition, up-regulation of NAc TrkB with chronic cocaine use could promote the transition to more addicted biological states.

KW - Addiction

KW - BDNF

KW - nucleus accumbens

KW - place preference

KW - self-administration

KW - TrkB

UR - http://www.scopus.com/inward/record.url?scp=62749141240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=62749141240&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2008.09.032

DO - 10.1016/j.biopsych.2008.09.032

M3 - Article

C2 - 18990365

AN - SCOPUS:62749141240

VL - 65

SP - 696

EP - 701

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 8

ER -