RT Journal Article
SR Electronic
T1 Nuclear Factor κB Signaling Regulates Neuronal Morphology and Cocaine Reward
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3529
OP 3537
DO 10.1523/JNEUROSCI.6173-08.2009
VO 29
IS 11
A1 Scott J. Russo
A1 Matthew B. Wilkinson
A1 Michelle S. Mazei-Robison
A1 David M. Dietz
A1 Ian Maze
A1 Vaishnav Krishnan
A1 William Renthal
A1 Ami Graham
A1 Shari G. Birnbaum
A1 Thomas A. Green
A1 Bruce Robison
A1 Alan Lesselyong
A1 Linda I. Perrotti
A1 Carlos A. Bolaños
A1 Arvind Kumar
A1 Michael S. Clark
A1 John F. Neumaier
A1 Rachael L. Neve
A1 Asha L. Bhakar
A1 Philip A. Barker
A1 Eric J. Nestler
YR 2009
UL http://www.jneurosci.org/content/29/11/3529.abstract
AB 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 κ B (NFκB), is rapidly activated by diverse stimuli and regulates expression of many genes known to maintain cell structure. Therefore, we evaluated the role of NFκB 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 NFκB-dependent transcription in the NAc of NFκB-Lac transgenic mice. This induction of NFκB activity is accompanied by increased expression of several NFκB 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 κ B kinase (IKKca or IKKdn), which normally activates NFκB signaling, in the NAc. We found that activation of NFκB by IKKca increases the number of dendritic spines on NAc neurons, whereas inhibition of NFκB by IKKdn decreases basal dendritic spine number and blocks the increase in dendritic spines after chronic cocaine. Moreover, inhibition of NFκB 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 NFκB pathways in the NAc to regulate structural and behavioral plasticity to cocaine.