Deng Xiaofei, Xu Wei, Liu Yutong, Jing Haiyang, Zhong Jiafeng, Sun Kaige, Zhou Ruiyi, Xu Liang, Wu Xiaocong, Zhang Baofang, Chen Wanqi, Jiang Shaolei, Chen Gaowei, Zhu Yingjie
Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Shenzhen, China.
Nat Neurosci. 2025 May 12. doi: 10.1038/s41593-025-01951-0.
Social status has a profound impact on mental health and propensity towards drug addiction. However, the neural mechanisms underlying the effects of social rank on drug-seeking behavior remain unclear. Here we found that dominant male rodents (based on the tube test) had denser mesocortical dopaminergic projections and were more resistant to methamphetamine (METH)-seeking, whereas subordinates had heightened dopaminergic function in the mesolimbic pathway and were more vulnerable to METH seeking. Optogenetic activation of the mesocortical dopaminergic pathway promoted winning and suppressed METH seeking in subordinates, whereas lesions of the mesocortical pathway increased METH seeking in dominants. Elevation of social rank with forced win training in subordinates led to remodeling of the dopaminergic system and prevented METH-seeking behavior. In females, however, both ranks were susceptible to METH seeking, with mesocorticolimbic pathways comparable to those in subordinate males. These results provide a framework for understanding the neural basis of the impact of social status on drug-seeking.
社会地位对心理健康和药物成瘾倾向有着深远影响。然而，社会等级对觅药行为产生影响的神经机制仍不清楚。在此我们发现，占主导地位的雄性啮齿动物（基于管子测试）具有更密集的中脑皮质多巴胺能投射，并且对寻求甲基苯丙胺（METH）的行为更具抵抗力，而从属动物在中脑边缘通路中具有增强的多巴胺能功能，并且更容易出现寻求METH的行为。中脑皮质多巴胺能通路的光遗传学激活促进了从属动物的获胜并抑制了其对METH的寻求，而中脑皮质通路的损伤则增加了占主导地位动物的METH寻求行为。通过对从属动物进行强制获胜训练来提高其社会等级，导致多巴胺能系统重塑，并防止了METH寻求行为。然而，在雌性动物中，两个等级都容易出现寻求METH的行为，其中脑皮质边缘通路与从属雄性动物的相当。这些结果为理解社会地位对觅药行为影响的神经基础提供了一个框架。
