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.

慢性自我给药和戒断与独特的神经免疫适应有关，这可能会增加人类对药物的渴望和复发的可能性。核因子 kappa-B (NF-κB) 通路是许多免疫和成瘾相关基因的关键调节因子，例如细胞外基质酶基质金属蛋白酶-9 (MMP-9)，它是一种已知的学习、记忆调节因子和突触可塑性。虽然一些研究表明纹状体 NF-κB 信号传导可能调节药物条件行为，但迄今为止还没有研究检验伏隔核核心 (NAc 核心) 内的 NF-κB 信号传导是否会改变下游神经免疫功能和线索激发的可卡因寻求一段时间后的结果。强迫戒酒，可卡因是否比其他强化剂有特定的效果，或者是否存在性别差异。在这里，我们检查了病毒介导的 NAc 核心内 NF-κB p65 亚基的敲低是否会改变雄性和雌性大鼠在强制戒酒一段时间后 MMP-9 的表达以及线索诱导的可卡因和蔗糖寻找行为。我们证明，NAc 核心 p65 敲低会导致男性而非女性中提示诱导的可卡因寻求显着减少。这种效应是可卡因特有的，因为 p65 敲低并没有显着影响男性或女性中线索诱导的蔗糖寻找。此外，我们证明，与女性相比，男性在 NAc 核心和伏核壳 (NAcSh) 内表达更高水平的 MMP-9，并且在可卡因线索中，p65 敲除显着降低了男性 NAc 核心中的 MMP-9，但对女性没有影响。暴露的动物。 总而言之，这些结果表明 NAc 核心 NF-κB 信号传导以性别特异性方式对线索驱动的药物寻求行为和下游神经免疫功能发挥调节控制。这些发现强调，在检查可卡因寻求的免疫调节机制时，需要将性别视为一个重要的生物学变量。