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Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward.

ABSTRACT: 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 (NFkappaB), is rapidly activated by diverse stimuli and regulates expression of many genes known to maintain cell structure. Therefore, we evaluated the role of NFkappaB 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 NFkappaB-dependent transcription in the NAc of NFkappaB-Lac transgenic mice. This induction of NFkappaB activity is accompanied by increased expression of several NFkappaB 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 NFkappaB signaling, in the NAc. We found that activation of NFkappaB by IKKca increases the number of dendritic spines on NAc neurons, whereas inhibition of NFkappaB by IKKdn decreases basal dendritic spine number and blocks the increase in dendritic spines after chronic cocaine. Moreover, inhibition of NFkappaB 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 NFkappaB pathways in the NAc to regulate structural and behavioral plasticity to cocaine.

SUBMITTER: Russo SJ

PROVIDER: S-EPMC2677656 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward.

Russo Scott J SJ Wilkinson Matthew B MB Mazei-Robison Michelle S MS Dietz David M DM Maze Ian I Krishnan Vaishnav V Renthal William W Graham Ami A Birnbaum Shari G SG Green Thomas A TA Robison Bruce B Lesselyong Alan A Perrotti Linda I LI Bolaños Carlos A CA Kumar Arvind A Clark Michael S MS Neumaier John F JF Neve Rachael L RL Bhakar Asha L AL Barker Philip A PA Nestler Eric J EJ

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090301 11

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 (NFkappaB), is rapidly activated by diverse stimuli and regulates expression of many genes known to maintain cell structure. Therefore, we evaluated the role of NFkappaB in regulati ...[more]

PMID: 19295158

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Project description:Cocaine exhibits high liability for inducing addictive behaviors, but the mechanisms of neuroplasticity underlying the behavioral effects remain unclear. As a crucial mediator of neuroplasticity in diverse functional models, brain-derived neurotrophic factor (BDNF) could contribute to the mechanisms of addiction-related neuroplasticity. Here, we addressed the hypothesis that cocaine increases synaptic dopamine, which induces BDNF protein expression to initiate addiction-related behavior in the rat. An enzyme-linked immunosorbent assay was used to measure BDNF protein expression in rat striatal tissues. For behavioral readout, we used a noninvasive measurement system to measure the emission of 50-kHz ultrasonic vocalization (USV), a response that correlates with electrical brain stimulation and conditioned place preference behavior in rodents. A single injection of cocaine significantly increased BDNF protein expression, but this effect was not further augmented by repeated cocaine administration. A single administration of cocaine elicited significant and dose-related USV responses, and the magnitude of the behavior increased with repeated drug administration. R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), but not raclopride, significantly attenuated cocaine-induced BDNF protein expression, whereas either the D(1)-like or D(2)-like receptor antagonist blocked cocaine-induced USV behavior. Furthermore, significant USV behavior was elicited by the nonselective dopamine agonist, apomorphine, but not by agonists that are selective for D(1)-like or D(2)-like receptors. Intracerebroventricular injection of the neurotrophin TrkB receptor inhibitor, K252a, blocked cocaine-induced USV behavior but not locomotor activity. These results suggest that neurotrophin signaling downstream of dopamine receptor function probably constitutes a crucial link in cocaine induction of USV behavior and may contribute to the mechanisms underlying the development of addiction-related behaviors.

Dataset Information

Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward.

Publications

Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward.

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