Abstract
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.
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Acknowledgements
This work was supported by United States Public Health Service Grants DA 10460, DA 08227, DA 18743, DA 016857 (D.L.G.), and the Wesley Gilliland Professorship in Biomedical Research.
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D.L.G. conducted the majority of the experiments and all of the data analysis, with assistance in tissue generation from R.K.B. and S.E. R.J.D. provided the AAV viral vectors and M.R. provided the floxed BDNF mice. D.W.S. supervised the project and co-wrote the manuscript with D.L.G.
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Graham, D., Edwards, S., Bachtell, R. et al. Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci 10, 1029–1037 (2007). https://doi.org/10.1038/nn1929
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DOI: https://doi.org/10.1038/nn1929
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