Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
Brain Behav. 2024 Mar;14(3):e3457. doi: 10.1002/brb3.3457.
Repeated exposure to cocaine induces microglial activation. Cocaine exposure also induces a release of high mobility group box-1 (HMGB1) from neurons into the extracellular space in the nucleus accumbens (NAc). HMGB1 is an important late inflammatory mediator of microglial activation. However, whether the secretion of HMGB1 acts on microglia or contributes to cocaine addiction is largely unknown.
Rats were trained by intraperitoneal cocaine administration and cocaine-induced conditioned place preference (CPP). Expression of HMGB1 was regulated by viral vectors. Activation of microglia was inhibited by minocycline. Interaction of HMGB1 and the receptor for advanced glycation end products (RAGE) was disrupted by peptide.
Cocaine injection facilitated HMGB1 signaling, together with the delayed activation of microglia concurrently in the NAc. Furthermore, the inhibition of HMGB1 or microglia activation attenuated cocaine-induced CPP. Box A, a specific antagonist to interrupt the interaction of HMGB1 and RAGE, abolished the expression of cocaine reward memory. Meanwhile, the inhibition of HMGB1-RAGE interaction suppressed cocaine-induced microglial activation, as well as the consolidation of cocaine-induced memory.
All above results suggest that the neural HMGB1 induces activation of microglia through RAGE, which contributes to the consolidation of cocaine reward memory. These findings offer HMGB1-RAGE axis as a new target for the treatment of drug addiction.
反复接触可卡因会诱导小胶质细胞活化。可卡因暴露也会导致高迁移率族蛋白 B1（HMGB1）从神经元释放到伏隔核（NAc）的细胞外空间。HMGB1 是小胶质细胞活化的重要晚期炎症介质。然而，HMGB1 的分泌是否作用于小胶质细胞或导致可卡因成瘾在很大程度上尚不清楚。
通过腹腔内可卡因给药和可卡因诱导的条件位置偏好（CPP）训练大鼠。HMGB1 的表达受病毒载体调节。小胶质细胞的激活被米诺环素抑制。肽破坏 HMGB1 与晚期糖基化终产物受体（RAGE）的相互作用。
可卡因注射促进了 HMGB1 信号通路，同时在 NAc 中延迟激活小胶质细胞。此外，抑制 HMGB1 或小胶质细胞激活可减弱可卡因诱导的 CPP。Box A 是一种特异性拮抗剂，可以阻断 HMGB1 和 RAGE 的相互作用，从而消除可卡因奖赏记忆的表达。同时，抑制 HMGB1-RAGE 相互作用可抑制可卡因诱导的小胶质细胞激活和可卡因诱导的记忆巩固。
上述结果表明，神经 HMGB1 通过 RAGE 诱导小胶质细胞活化，有助于可卡因奖赏记忆的巩固。这些发现为 HMGB1-RAGE 轴作为治疗药物成瘾的新靶点提供了依据。
