Guo Ming-Lei, Chivero Ernest T, Callen Shannon E, Buch Shilpa
Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
J Pers Med. 2021 Sep 27;11(10):963. doi: 10.3390/jpm11100963.
Microglia, the primary immunocompetent cells of the brain, are suggested to play a role in the development of drug addiction. Previous studies have identified the microglia-derived pro-inflammatory factor IL1β can promote the progression of cocaine addiction. Additionally, the activation status of microglia and "two-hit hypothesis" have been proposed in the field of drug addiction to explain how early life stress (ELS) could significantly increase the incidence of drug addiction in later life. However, the mechanisms underlying microglia prime and full activation and their roles in drug addiction remain greatly unexplored. Here, we employed CX3CR1-GFP mice (CX3CR1 functional deficiency, CX3CR1-/-) to explore whether primed microglia could potentiate cocaine-mediated behavioral changes and the possible underlying mechanisms. CX3CR1-/- mice revealed higher hyperlocomotion activity and conditional place preference than wild-type (WT) mice did under cocaine administration. In parallel, CX3CR1-/- mice showed higher activity of NLR family pyrin domain-containing 3 (NLRP3) inflammasome than WT mice. Interestingly, CX3CR1 deficiency itself could prime NLRP3 signaling by increasing the expression of NLPR3 and affect lysosome biogenesis under basal conditions. Taken together, our findings demonstrated that the functional status of microglia could have an impact on cocaine-mediated reward effects, and NLRP3 inflammasome activity was associated with this phenomenon. This study was consistent with the two-hit hypothesis and provided solid evidence to support the involvement of microglia in drug addiction. Targeting the NLRP3 inflammasome may represent a novel therapeutic approach for ameliorating or blocking the development of drug addiction.
小胶质细胞是大脑主要的免疫活性细胞，被认为在药物成瘾的发展过程中发挥作用。先前的研究已经确定，小胶质细胞衍生的促炎因子白细胞介素1β（IL1β）可促进可卡因成瘾的进展。此外，在药物成瘾领域已经提出了小胶质细胞的激活状态和“双打击假说”，以解释早期生活压力（ELS）如何在很大程度上增加后期药物成瘾的发生率。然而，小胶质细胞预激活和完全激活的潜在机制及其在药物成瘾中的作用仍未得到充分探索。在这里，我们使用CX3CR1绿色荧光蛋白小鼠（CX3CR1功能缺陷，CX3CR1-/-）来探究预激活的小胶质细胞是否会增强可卡因介导的行为变化以及可能的潜在机制。在给予可卡因的情况下，CX3CR1-/-小鼠比野生型（WT）小鼠表现出更高的运动亢进活性和条件性位置偏爱。同时，CX3CR1-/-小鼠比WT小鼠表现出更高的含NLR家族pyrin结构域3（NLRP3）炎性小体活性。有趣的是，CX3CR1缺陷本身可通过增加NLPR3的表达在基础条件下预激活NLRP3信号并影响溶酶体生物发生。综上所述，我们的研究结果表明，小胶质细胞的功能状态可能会影响可卡因介导的奖赏效应，并且NLRP3炎性小体活性与这一现象相关。本研究与双打击假说一致，并为支持小胶质细胞参与药物成瘾提供了确凿证据。靶向NLRP3炎性小体可能代表一种改善或阻断药物成瘾发展的新型治疗方法。
