Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse.
A single exposure to cocaine rapidly induces the brief activation of several immediate early genes, but the role of such short-term regulation in the enduring consequences of cocaine use is poorly understood. We found that 4 h of intravenous cocaine self-administration in rats induced a transient increase in brain-derived neurotrophic factor (BDNF) and activation of TrkB-mediated signaling in the nucleus accumbens (NAc). Augmenting this dynamic regulation with five daily NAc BDNF infusions caused enduring increases in cocaine self-administration, and facilitated relapse to cocaine seeking in withdrawal. In contrast, neutralizing endogenous BDNF regulation with intra-NAc infusions of antibody to BDNF subsequently reduced cocaine self-administration and attenuated relapse. Using localized inducible BDNF knockout in mice, we found that BDNF originating from NAc neurons was necessary for maintaining increased cocaine self-administration. These findings suggest that dynamic induction and release of BDNF from NAc neurons during cocaine use promotes the development and persistence of addictive behavior.
Graham
Danielle L
DL
Department of Psychiatry, The Seay Center for Basic and Applied Research in Psychiatric Illness, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Edwards
Scott
S
Bachtell
Ryan K
RK
DiLeone
Ralph J
RJ
Rios
Maribel
M
Self
David W
DW
D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods; D013997:Time Factors
D000779:Anesthetics, Local; D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D003042:Cocaine