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The Journal of Neuroscience, March 18, 2009, 29(11):3529-3537; doi:10.1523/JNEUROSCI.6173-08.2009

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Behavioral/Systems/Cognitive
Nuclear Factor {kappa}B Signaling Regulates Neuronal Morphology and Cocaine Reward

Scott J. Russo,1 Matthew B. Wilkinson,1 * Michelle S. Mazei-Robison,1 * David M. Dietz,1 Ian Maze,1 Vaishnav Krishnan,2 William Renthal,2 Ami Graham,2 Shari G. Birnbaum,2 Thomas A. Green,2 Bruce Robison,2 Alan Lesselyong,2 Linda I. Perrotti,2 Carlos A. Bolaños,2 Arvind Kumar,2 Michael S. Clark,3 John F. Neumaier,3 Rachael L. Neve,4 Asha L. Bhakar,5 Philip A. Barker,5 and Eric J. Nestler1

1Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, 2Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, 3Harborview Medical Center, University of Washington, Seattle, Washington 98104, 4Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and 5Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4

Correspondence should be addressed to Dr. Eric J. Nestler, Fishberg Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029-6574. Email: eric.nestler{at}mssm.edu

Although chronic cocaine-induced changes in dendritic spines on nucleus accumbens (NAc) neurons have been correlated with behavioral sensitization, the molecular pathways governing these structural changes, and their resulting behavioral effects, are poorly understood. The transcription factor, nuclear factor {kappa} B (NF{kappa}B), is rapidly activated by diverse stimuli and regulates expression of many genes known to maintain cell structure. Therefore, we evaluated the role of NF{kappa}B in regulating cocaine-induced dendritic spine changes on medium spiny neurons of the NAc and the rewarding effects of cocaine. We show that chronic cocaine induces NF{kappa}B-dependent transcription in the NAc of NF{kappa}B-Lac transgenic mice. This induction of NF{kappa}B activity is accompanied by increased expression of several NF{kappa}B genes, the promoters of which show chromatin modifications after chronic cocaine exposure consistent with their transcriptional activation. To study the functional significance of this induction, we used viral-mediated gene transfer to express either a constitutively active or dominant-negative mutant of Inhibitor of {kappa} B kinase (IKKca or IKKdn), which normally activates NF{kappa}B signaling, in the NAc. We found that activation of NF{kappa}B by IKKca increases the number of dendritic spines on NAc neurons, whereas inhibition of NF{kappa}B by IKKdn decreases basal dendritic spine number and blocks the increase in dendritic spines after chronic cocaine. Moreover, inhibition of NF{kappa}B blocks the rewarding effects of cocaine and the ability of previous cocaine exposure to increase an animal's preference for cocaine. Together, these studies establish a direct role for NF{kappa}B pathways in the NAc to regulate structural and behavioral plasticity to cocaine.

Received Dec. 29, 2008; revised Feb. 5, 2009; accepted Feb. 5, 2009.

Correspondence should be addressed to Dr. Eric J. Nestler, Fishberg Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029-6574. Email: eric.nestler{at}mssm.edu






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