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Nuclear factor kappa B signaling within the rat nucleus accumbens core sex-dependently regulates cue-induced cocaine seeking and matrix metalloproteinase-9 expression
Journal article   Open access   Peer reviewed

Nuclear factor kappa B signaling within the rat nucleus accumbens core sex-dependently regulates cue-induced cocaine seeking and matrix metalloproteinase-9 expression

Mark D. Namba, Megan N. Phillips, Janet L. Neisewander and M. Foster Olive
Brain, behavior, and immunity, v 102, pp 252-265
01 May 2022
DOI: https://doi.org/10.1016/j.bbi.2022.03.002
PMID: 35259426
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1016/j.bbi.2022.03.002View
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Abstract

Abstinence Addiction Cocaine seeking Cue reactivity Extracellular matrix Neuroimmune signaling NF-κB Relapse Sex differences
•Viral-mediated inhibition of nucleus accumbens core (NAc core) NF-κB signaling suppresses cue-motivated cocaine seeking in male, but not female, rats.•Inhibition of NAc core NF-κB signaling does not significantly alter cue-motivated sucrose seeking.•Suppression of NAc core NF-κB signaling decreases NAc core, but not NAcSh, MMP-9 expression in males but not females.•Male rats exhibit greater NAc core and NAcSh MMP-9 expression compared to females. Chronic drug self-administration and withdrawal are associated with distinct neuroimmune adaptations that may increase drug craving and relapse vulnerability in humans. The nuclear factor kappa-B (NF-κB) pathway is a critical regulator of many immune- and addiction-related genes such as the extracellular matrix enzyme matrix metalloproteinase-9 (MMP-9), which is a known modulator of learning, memory, and synaptic plasticity. While some studies suggest striatal NF-κB signaling may regulate drug-conditioned behavior, no studies to date have examined whether NF-κB signaling within the nucleus accumbens core (NAc core) alters downstream neuroimmune function and cue-motivated cocaine seeking following a period of forced abstinence, whether any effects are specific to cocaine over other reinforcers, or whether sex differences exist. Here, we examined whether viral-mediated knockdown of the p65 subunit of NF-κB within the NAc core would alter MMP-9 expression and cue-induced cocaine- and sucrose-seeking behavior following a period of forced abstinence in male and female rats. We demonstrate that NAc core p65 knockdown results in a significant decrease in cue-induced cocaine seeking in males but not females. This effect was specific to cocaine, as p65 knockdown did not significantly affect cue-induced sucrose seeking in either males or females. Moreover, we demonstrate that males express higher levels of MMP-9 within the NAc core and nucleus accumbens shell (NAcSh) compared to females, and that p65 knockdown significantly decreases MMP-9 in the NAc core of males but not females among cocaine cue-exposed animals. Altogether, these results suggest that NAc core NF-κB signaling exerts modulatory control over cue-motivated drug-seeking behavior and downstream neuroimmune function in a sex-specific manner. These findings highlight the need to consider sex as an important biological variable when examining immunomodulatory mechanisms of cocaine seeking.

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12 citations in Web of Science
10 citations in Scopus

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Web of Science research areas
Immunology
Neurosciences
Psychiatry
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