Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward.
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.
Graham
Danielle L
DL
CNS Pharmacology, Merck Research Labs, Boston Massachusetts, USA.
Krishnan
Vaishnav
V
Larson
Erin B
EB
Graham
Ami
A
Edwards
Scott
S
Bachtell
Ryan K
RK
Simmons
Diana
D
Gent
Lana M
LM
Berton
Olivier
O
Bolanos
Carlos A
CA
DiLeone
Ralph J
RJ
Parada
Luis F
LF
Nestler
Eric J
EJ
Self
David W
DW
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019426:Integrases / Q000494:pharmacology; D008297:Male; D051379:Mice; D009434:Neural Pathways / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012201:Reward; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D020813:Receptor, trkB; C045073:Cre recombinase; D019426:Integrases; D003042:Cocaine; D004298:Dopamine