Adolescence is a period of increased exploration and novelty-seeking, which includes new social behaviors, as well as drug experimentation, often spurred on by peer pressure. This is unfortunate, as the immature state of the adolescent brain makes it particularly susceptible to the negative developmental impact of drug use. During adolescence, dopamine terminals, which have migrated from the ventral tegmental area, pause in the nucleus accumbens, before segregating by either forming local connections or growing towards the prefrontal cortex (PFC). This developmentally late and lengthy process renders adolescent dopamine axon pathfinding vulnerable to disruption by substance use. Indeed, exposure to stimulant drugs in adolescent male mice, but not females, triggers dopamine axons to mistarget the nucleus accumbens and to grow ectopically to the PFC. Some evidence suggests that at this novel site, the functional organization of the ectopic dopamine axons mirrors that of the intended target. The structural rewiring dysregulates local synaptic connectivity, leading to poor impulse control ability, deficits of which are a core symptom of substance-use disorders. In the present commentary, we argue that different substances of abuse induce dopamine mistargeting events with the off-target trajectory prescribed by the type of drug, leading to psychiatric outcomes later in life.

青春期是一个探索和寻求新奇事物增多的时期，其中包括新的社会行为以及药物实验，通常是在同伴压力的刺激下进行的。这是不幸的，因为青少年大脑的不成熟状态使其特别容易受到吸毒的负面发育影响。在青春期，从腹侧被盖区迁移的多巴胺末端在伏隔核中暂停，然后通过形成局部连接或向前额叶皮层 (PFC) 生长而分离。这种发育迟缓且漫长的过程使得青少年多巴胺轴突寻路容易受到药物滥用的干扰。事实上，青春期雄性小鼠（而非雌性小鼠）接触兴奋剂药物会触发多巴胺轴突错误定位伏核并异位生长到前额皮质。一些证据表明，在这个新位点，异位多巴胺轴突的功能组织反映了预期目标的功能组织。结构性重新布线使局部突触连接失调，导致冲动控制能力差，而这种能力的缺陷是物质使用障碍的核心症状。在本评论中，我们认为不同的滥用物质会导致多巴胺误定位事件，并按照药物类型规定的脱靶轨迹，导致晚年的精神后果。