Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada.
Douglas Mental Health University Institute, Montréal, QC, Canada.
Nat Commun. 2023 Jul 7;14(1):4035. doi: 10.1038/s41467-023-39665-1.
Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual's sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.
在青春期开始使用药物会增加以后患上成瘾或其他精神病理学的风险，其长期后果因性别和使用的确切时间而异。解释这种对有害药物作用的不同敏感性的细胞和分子基础仍未得到解释。Netrin-1/DCC 导向线索系统在青春期将皮质和边缘多巴胺途径分开。在这里，我们发现安非他命通过扰乱 Netrin-1/DCC 信号传导，触发中脑边缘多巴胺轴突的异位生长到前额叶皮层，仅在早期青春期雄性小鼠中发生，这是雄性对持久认知缺陷的易感性的基础。在青春期雌性中，Netrin-1 的代偿性变化可防止安非他命对多巴胺连接和认知结果的有害影响。Netrin-1/DCC 信号传导作为一种分子开关，可根据个体的性别和青春期年龄以及相同的药物体验进行差异调节，并导致与脆弱或弹性表型相关的不同的长期后果。
