Nuclear factor kappa B signaling within the rat nucleus accumbens core sex-dependently regulates cue-induced cocaine seeking and matrix metalloproteinase-9 expression.
Nuclear factor kappa B signaling within the rat nucleus accumbens core sex-dependently regulates cue-induced cocaine seeking and matrix metalloproteinase-9 expression.
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DOI：
10.1016/j.bbi.2022.03.002
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发表时间：
2022-05
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影响因子：
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慢性自我给药和戒断与不同的神经免疫适应相关，可能会增加人类的药物渴望和复发脆弱性。核因子κ-B（NF-κB）通路是许多免疫和成瘾相关基因（如细胞外基质酶基质金属蛋白酶-9（MMP-9））的关键调节因子，MMP-9是已知的学习、记忆和突触可塑性调节因子。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化行为，但迄今为止还没有研究检查过在强迫戒断一段时间后，核内的NF-κB信号传导是否改变下游神经免疫功能和线索动机的可卡因寻求，是否有任何影响是可卡因特异性的，或者是否存在性别差异。在此，我们研究了在一段时间的强迫戒断后，病毒介导的NAc核心内NF-κB p65亚基的敲低是否会改变MMP-9的表达以及线索诱导的雄性和雌性大鼠可卡因和蔗糖寻找行为。我们证明，NAc核心p65敲低导致线索诱导的可卡因寻求男性，但不是女性显着减少。这种效果是特定的可卡因，p65敲除没有显着影响线索诱导的蔗糖寻求在男性或女性。此外，我们表明，男性表达更高水平的MMP-9内的NAc核心和核壳（NAcSh）相比，女性，和p65敲低显着降低MMP-9的NAc核心的男性，但不是女性可卡因线索暴露的动物。总之，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作用。这些研究结果强调，需要考虑性别作为一个重要的生物变量时，检查可卡因寻求免疫调节机制。
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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DOI：
10.1016/j.bbi.2017.08.012
发表时间：
2018-01
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Brown KT;Levis SC;O'Neill CE;Northcutt AL;Fabisiak TJ;Watkins LR;Bachtell RK
通讯作者：
Bachtell RK
影响因子：
3.4
作者：
Corbett, Claire M;Dunn, Emily;Loweth, Jessica A
通讯作者：
Loweth, Jessica A
影响因子：
4.8
作者：
Bronson, Stefanie L.;Bale, Tracy L.
通讯作者：
Bale, Tracy L.
影响因子：
2.3
作者：
Brown, Travis E.;Forquer, Melissa R.;Sorg, Barbara A.
通讯作者：
Sorg, Barbara A.
影响因子：
3.7
作者：
Feltenstein, Matthew W.;Byrd, Elizabeth A.;See, Ronald E.
通讯作者：
See, Ronald E.