Cheng Yan, Dempsey Rachael Elizabeth, Roodsari Soheil Kazemi, Shuboni-Mulligan Dorela D, George Olivier, Sanford Larry D, Guo Ming-Lei
Drug Addiction Laboratory, Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
Sleep Laboratory, Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
Biomedicines. 2023 Jun 23;11(7):1800. doi: 10.3390/biomedicines11071800.
Cocaine, one of the most abused drugs worldwide, is capable of activating microglia in vitro and in vivo. Several neuroimmune pathways have been suggested to play roles in cocaine-mediated microglial activation. Previous work showed that cocaine activates microglia in a region-specific manner in the brains of self-administered mice. To further characterize the effects of cocaine on microglia and neuroimmune signaling in vivo, we utilized the brains from both sexes of outbred rats with cocaine self-administration to explore the activation status of microglia, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activity, corticotropin-releasing factor (CRF) signaling, and NF-κB levels in the striatum and hippocampus (HP). Age-matched rats of the same sex (drug naïve) served as controls. Our results showed that cocaine increased neuroinflammation in the striatum and HP of both sexes with a relatively higher increases in male brains. In the striatum, cocaine upregulated NLRP3 inflammasome activity and CRF levels in males but not in females. In contrast, cocaine increased NLRP3 inflammasome activity in the HP of females but not in males, and no effects on CRF signaling were observed in this region of either sex. Interestingly, cocaine increased NF-κB levels in the striatum and HP with no sex difference. Taken together, our results provide evidence that cocaine can exert region- and sex-specific differences in neuroimmune signaling in the brain. Targeting neuroimmune signaling has been suggested as possible treatment for cocaine use disorders (CUDs). Our current results indicate that sex should be taken into consideration when determining the efficacy of these new therapeutic approaches.
可卡因是全球滥用最为严重的毒品之一，能够在体外和体内激活小胶质细胞。已有多种神经免疫途径被认为在可卡因介导的小胶质细胞激活过程中发挥作用。先前的研究表明，可卡因在自行给药小鼠的大脑中以区域特异性方式激活小胶质细胞。为了进一步表征可卡因对体内小胶质细胞和神经免疫信号传导的影响，我们利用自行给药可卡因的远交系大鼠两性的大脑，来探究纹状体和海马体（HP）中小胶质细胞的激活状态、含核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体活性、促肾上腺皮质激素释放因子（CRF）信号传导以及核因子κB（NF-κB）水平。年龄匹配的同性（未接触过毒品）大鼠作为对照。我们的结果表明，可卡因增加了两性纹状体和海马体中的神经炎症，雄性大脑中的增加相对更高。在纹状体中，可卡因上调了雄性而非雌性的NLRP3炎性小体活性和CRF水平。相反，可卡因增加了雌性而非雄性海马体中的NLRP3炎性小体活性，并且在两性的该区域均未观察到对CRF信号传导的影响。有趣的是，可卡因增加了纹状体和海马体中的NF-κB水平，且无性别差异。综上所述，我们的结果提供了证据表明可卡因可在大脑神经免疫信号传导中产生区域和性别特异性差异。针对神经免疫信号传导被认为是治疗可卡因使用障碍（CUDs）的可能方法。我们目前的结果表明，在确定这些新治疗方法的疗效时应考虑性别因素。
