Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Burjassot, Spain.
Front Immunol. 2021 Sep 20;12:689453. doi: 10.3389/fimmu.2021.689453. eCollection 2021.
Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1β also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1β, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1β, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.
近年来，关于酒精引起的神经炎症在酒精摄入和复发中的作用的证据有所增加。事实证明，μ-阿片受体（MORs）介导酒精的强化作用，有趣的是，先前的研究表明神经炎症和 MORs 可能有关联。我们的目标是研究在戒断和复发阶段，中边缘系统（MCLS）中的神经炎症状态和小胶质细胞激活以及 MOR 表达的适应性。为此，我们使用了一种依赖于性别差异的完全弗氏佐剂（CFA）诱导的酒精剥夺效应（ADE）大鼠模型。首先，我们的结果证实，只有接受 CFA 治疗的雌性大鼠，即唯一表现出类似复发行为的实验组，在 PFC 和 VTA 中观察到磷酸化 NFκB、iNOS 和 COX2 的表达发生了特定改变。更有趣的是，IBA1 表达的分析表明，在戒断期间 PFC 中的小胶质细胞激活减少，在复发阶段表达增加，并且在这两个阶段 NAc 中的这种激活增加，而这种增加仅发生在雌性 CFA 处理的大鼠中。此外，白细胞介素 1β（IL1β）的表达也通过这两个阶段的相似表达模式证明了这些动态变化。此外，细胞因子白细胞介素 10（IL10）的表达呈现出与 IL1β 不同的模式，表明仅在 CFA-雌性大鼠 PFC 的戒断期间发生抗炎过程，但在 PFC 的重新引入阶段或 NAc 中均未发生。这些数据表明，在 CFA 处理的雌性大鼠 PFC 的戒断期间，小胶质细胞激活和促炎过程下调，而在 NAc 中观察到上调，并且仅在 CFA 处理的雌性大鼠的重新引入阶段维持。其次，我们的数据揭示了 CFA 处理的雌性大鼠 PFC 和 NAc 中观察到的 IL1β、IBA1 水平和 MOR 水平变化之间的相关性。尽管为时过早，但我们的数据表明，神经炎症过程以及涉及 MOR 的神经适应性可能在雌性大鼠的酒精复发性中发挥重要作用，因此需要进一步研究。
