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

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-KB) 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-KB signaling may regulate drug-conditioned behavior, no studies to date have examined whether NF-KB 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-KB 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-KB 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.