Abstract：
The dopamine transporter (DAT) is a key site of action for cocaine and amphetamines. Dysfunctional DAT is associated with aberrant synaptic dopamine transmission and enhanced drug-seeking and taking behavior. Studies in cultured cells and ex vivo suggest that DAT function is sensitive to membrane cholesterol content. Although it is largely unknown whether psychostimulants alter cholesterol metabolism in the brain, emerging evidence indicates that peripheral cholesterol metabolism is altered in patients with psychostimulant use disorder and circulating cholesterol levels are associated with vulnerability to relapse. Cholesterol interacts with sphingolipids forming lipid raft microdomains on the membrane. These cholesterol-rich lipid raft microdomains serve to recruit and assemble other lipids and proteins to initiate signal transduction. There are two spatially and functionally distinct populations of the DAT segregated by cholesterol-rich lipid raft microdomains and cholesterol-scarce non-raft microdomains on the plasma membrane. These two DAT populations are differentially regulated by DAT blockers (e.g. cocaine), substrates (e.g. amphetamine), and protein kinase C providing distinct cholesterol-dependent modulation of dopamine uptake and efflux. In this chapter, we summarize the impact of depletion and addition of membrane cholesterol on DAT conformational changes between the outward-facing and the inward-facing states, lipid raft-associated DAT localization, basal and induced DAT internalization, and DAT function. In particular, we focus on how the interactions of the DAT with cocaine and amphetamine are influenced by membrane cholesterol. Lastly, we discuss the therapeutic potential of cholesterol-modifying drugs as a new avenue to normalize DAT function and dopamine transmission in patients with psychostimulant use disorder.
摘要：
多巴胺转运蛋白（DAT）是可卡因和苯丙胺的关键作用位点。功能失调的DAT与异常的突触多巴胺传递和增强的药物寻找和服用行为有关。在培养细胞和离体的研究表明DAT功能对膜胆固醇含量敏感。虽然目前尚不清楚精神兴奋剂是否会改变大脑中的胆固醇代谢，新出现的证据表明,精神兴奋剂使用障碍患者的外周胆固醇代谢改变,循环胆固醇水平与易复发相关.胆固醇与鞘脂相互作用,在膜上形成脂筏微域。这些富含胆固醇的脂筏微域用于募集和组装其他脂质和蛋白质以启动信号转导。DAT有两个在空间和功能上不同的种群，它们由质膜上富含胆固醇的脂筏微域和胆固醇稀缺的非筏微域隔离。这两个DAT群体受到DAT阻断剂（例如可卡因）的差异调节，底物（例如苯丙胺），和蛋白激酶C提供独特的胆固醇依赖性调节多巴胺摄取和流出。在这一章中,我们总结了消耗和添加膜胆固醇对DAT构象变化的影响，在面向外和面向内的状态之间，脂筏相关的DAT定位，基础和诱导DAT内化，和DAT函数。特别是,我们关注DAT与可卡因和苯丙胺的相互作用如何受膜胆固醇的影响。最后,我们讨论了胆固醇调节药物作为使精神兴奋剂使用障碍患者的DAT功能和多巴胺传递正常化的新途径的治疗潜力.
