Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1β (IL-1β), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor β (TGF-β). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.

青少年可能会故意滥用甲苯来体验精神活性。甲苯具有复杂的作用机理和广泛的行为影响，其中一致报道了记忆障碍。我们以前曾报道过，重复吸入甲苯（8000 ppm）可以增加青春期大鼠内侧前额叶皮层（mPFC）中第5层前肢锥体细胞的兴奋性。甲苯还会产生活性氧（ROS），从而激活神经胶质细胞。在这里，我们测试了以下假设：抗炎药美满霉素会降低甲苯的作用，因为它抑制了NF-κB（活化的B细胞的κ轻链的核因子增强剂）并减少了促炎性细胞因子和ROS的产生。我们的结果表明，米诺环素（50 mg / kg，ip，持续10天）可防止mPFC神经元在重复8000 ppm甲苯暴露（30分钟/天，2x /天，持续10天）后观察到的过度兴奋性。Minocycline通过一种机制来防止甲苯诱导的过度兴奋，该机制可避免缓慢的钙依赖性钾电流损失，并使mPFC神经元的放电频率正常化。这些作用伴随着mPFC中星形胶质细胞和小胶质细胞表达的显着降低，促炎性细胞因子白介素1β（IL-1β）的NLRP3炎症小体激活和mRNA表达水平降低以及抗炎性mRNA表达增加细胞因子转化生长因子β（TGF-β）。米诺环素还可以在被动回避任务和以mPFC发挥重要作用的时间顺序记忆测试中防止甲苯诱导的青春期大鼠记忆障碍。这些结果表明，神经炎症会产生高浓度重复施用甲苯的多种作用，而米诺环素可以明显地预防它们。